Michele G. Sullivan

Studies that use Alzheimer’s disease biomarkers to predict the clinical benefit of investigational treatments in families with autosomal-dominant mutations that cause early-onset disease could prove to be the saving grace for researchers who have seen one treatment after another fail in trials of symptomatic patients.

Two research projects – the Alzheimer’s Prevention Initiative (API) and the Dominantly Inherited Alzheimer Network (DIAN) – hope to provide biomarker evidence that companies can use to test promising presymptomatic treatments without having to conduct costly long-term trials in individuals who might not develop symptoms for many years.

"In order to approve a treatment based on biomarker, the regulatory agencies said: ‘Show us with demonstrably effective, clinically proven treatments that the treatments’ effects on the biomarker predict a clinical benefit.’ Well that sounds like a Catch-22. If we had clinically proven prevention therapies, what do we need a biomarker for?" said Dr. Eric Reiman, who is leading the API with Dr. Pierre Tariot at the Banner Alzheimer’s Institute in Phoenix.

"So, in the last few years, we’ve modified our approach to not only help provide the scientific means to evaluate the range of promising presymptomatic treatments as rapidly as possible, but to help provide the financial incentives – that is, the accelerated regulatory approval pathway needed to encourage everybody to go out and start studying their promising prevention therapies and everybody using biomarkers."

The API is raising funds from philanthropic organizations, industry, and federal grants to study presymptomatic anti-amyloid treatments in people who are at high imminent risk for developing symptoms of Alzheimer’s disease (AD), based on their genetic background and age.

Fortunately, the largest extended family of individuals in the world who carry an autosomal-dominant mutation in the presenilin 1 (PS1) gene – about 5,000 people – live in and around Medellín, Colombia; about one-third of them have the PS1 mutation. Because mutation carriers are destined to develop symptoms of AD, typically around 45 years of age, the risk-to-benefit ratio for treatment in this population is different from the ratio for other individuals at lower risk for AD, said Dr. Reiman, executive director of the Banner Alzheimer’s Institute and director of the Arizona Alzheimer’s Consortium.

In collaboration with Colombian neurologist Dr. Francisco Lopera, who brought the extended family to the attention of researchers, the API is enrolling about 2,000 members of this extended family who are within 10 years of their expected age of onset in a prevention trial. Investigators are currently obtaining baseline data with cognitive tests; volumetric MRI; ¹⁸fluorodeoxyglucose and amyloid PET imaging; and cerebrospinal fluid measurements of beta-amyloid 42 (Abeta 42), tau, and total tau, he said.

In the trial, about 150 PS1 carriers will receive an anti-amyloid treatment and about 150 noncarriers will get a placebo. The anti-amyloid treatment to be given in the trial has not yet been determined, according to Dr. Reiman.

"We’ll be pretty unique in having the adequate sample size to show not just the biomarker effects, but within 3 or 4 years, the clinical effect as they’re close to their age of onset," he said in an interview.

Dr. Reiman added that "if there’s no effect on the biomarkers after 2 years in the right direction, [we will] declare futility and give these people at highest imminent risk access to the next most promising treatment. If however, they do budge in the right direction, [we will] continue to follow them a little bit longer to see if it slows even subtle memory decline. And if it does, I have a feeling that may be enough evidence for regulatory agencies to consider using biomarkers under their accelerated approval mechanism in other [Alzheimer’s disease] populations."

A second study in the United States will create a national registry of 20,000-50,000 people to gather a large number of people with one or two copies of the apolipoprotein E (APOE) e4 gene, which substantially increases an individual’s risk for late-onset Alzheimer’s disease. About 400 homozygous (and possibly heterozygous) APOE e4 carriers, who begin to have symptoms at a mean age of 68 years, will be enrolled in a prevention trial with of an anti-amyloid treatment; this therapy might not be the same as the one used in the trial of PS1 carriers, Dr. Reiman said.

Investigators are hoping to start one or both studies in 2012.

Study results from DIAN will be complementary to those from the API in many ways. DIAN is a 6-year, cross-sectional, longitudinal study of families who carry an autosomal dominant mutation in one of the three genes that affect amyloid processing: amyloid precursor protein (APP), PS1, and presenilin 2 (PS2).

Preliminary findings from the first analysis of DIAN indicate that the pathologic changes of AD might begin as early as 20 years before the expected onset of disease in mutation carriers.

The use of PET and cerebrospinal fluid biomarkers of beta-amyloid and tau protein in these individuals might allow researchers to select enriched pools of subjects for the testing of potential drug treatments, and, someday, allow clinicians to target patients with incipient disease for preventive treatment, Dr. John Morris said at the International Conference on Alzheimer’s and Parkinson’s Diseases in Barcelona.

"I have not yet had sufficient sample size or follow-up to predict this completely," said Dr. Morris, DIAN’s principal investigator. "However, I think there are data both from Europe and the U.S. showing that low beta-amyloid 42 [Abeta 42] and high tau in the cerebrospinal fluid together will reach a hazard ratio of 5.2 for becoming demented within 3-4 years. We are just beginning to get these same data for amyloid imaging and the hazard ratio is about the same."

Dr. Morris, professor of neurology at Washington University in St. Louis, said the DIAN study hopes to recruit 400 subjects who are the children of a parent with one of the gene mutations. He expects that about half the group will carry one of the mutations, while the other half will be unaffected siblings, who will serve as controls. The study involves 10 research institutions in the United States, United Kingdom, and Australia.

Each participant will undergo genetic analysis and the same periodic assessments, including cognitive and clinical testing; brain imaging with Pittsburgh compound B, which binds to Abeta 42 plaques; ¹⁸fluorodeoxyglucose PET; MRI; and lumbar punctures to test cerebrospinal fluid levels of Abeta 42 and tau. If subjects die during the study, their brains will be autopsied.

"The goals are to try and determine when the pathologic process begins in asymptomatic mutation carriers," Dr. Morris said. "We know, based on the parent’s age of onset, approximately when these carriers will become symptomatic. We want to see the changes, the rates of these changes, and determine to what extent the changes resemble those seen in sporadic Alzheimer’s."

As of last fall, DIAN had collected 106 volunteers, Dr. Morris said. About 70% of those are asymptomatic carriers, with an average age of 37 years, although that varies from 19 to 56 years. The average age of parental onset of dementia symptoms is 47 years, "so we have these folks an average of 10 years before their expected age of onset."

The PS1 mutation is the most common in the group, occurring in 75%; PS2 is present in 10%, and the APP mutation, in 15%.

About 90% of DIAN participants do not know whether they are a carrier of one of the mutations or not, and most do not want to know their status, Dr. Morris said in an interview. If DIAN researchers decide to conduct a clinical trial of an anti-amyloid treatment in the participants who carry a mutation, they will have to figure out a way to ensure that noncarriers receive a placebo without revealing mutation status to participants who do not want to know – and thereby not risk potential harm to the noncarriers from the treatment.

Comparing the carriers with the noncarriers, the study’s "very preliminary" data indicate that cognitive decline begins as early as 10 years before the expected onset of symptoms, while neuropathologic changes start up to 20 years before.

But scores on the Mini-Mental State Exam (MMSE) for noncarrier siblings of these volunteers "have remained very clearly at 30," which is a normal score, Dr. Morris said. The noncarriers also had normal scores on the Clinical Dementia Rating Scale sum of boxes (CDR-SOB), another test used to identify Alzheimer’s-related cognitive changes.

This was not the case "for carriers, in whom we begin to see declines in the MMSE and the CDR about 10 years before the expected age of onset," Dr. Morris said.

The cerebrospinal fluid biomarkers followed a similar pattern. A decrease in spinal fluid Abeta 42 suggests that the protein is aggregating somewhere else in the body – probably in the characteristic brain plaques. These changes could be seen in carriers 20 years before the expected age of onset. Tau protein levels in the cerebrospinal fluid (CSF) of carriers begin to rise around 20 years before the onset of symptoms, "with a clear acceleration at the time they are changing from asymptomatic to symptomatic," he said.

However, noncarriers have stable levels of both proteins in the CSF at the same ages.

Imaging in the precuneus and caudate with Pittsburgh compound B shows no Abeta 42 accumulation in noncarriers, but in carriers, the protein begins to appear in those regions about the same time that the CSF biomarkers start to change – 20 years before the expected appearance of symptomatic disease.

If these findings can be confirmed, they prove the existence of a long prodromal stage in subjects who are genetically destined to develop AD. This has several important applications in both drug research and potential treatment, Dr. Morris noted.

First, the neuropsychological testing scores currently in use, which define normal cognitive function, might be incorrect, because they could be based on cohorts that included individuals who had already experienced cognitive decline, but still fell within the "normal" range.

To illustrate this problem, Dr. Morris referred to the cognitive testing of two subjects. One began with cognitive functioning at the mean of normal, while the other began at two standard deviations above the mean. Over a period of years, the first person remained stable at the mean, while the second declined to the mean – showing that this subject was experiencing significant cognitive decline on an individual basis, while still being considered cognitively normal. The patient quickly developed mild cognitive impairment and then AD.

"This interferes with the ability to detect very early stages of symptomatic Alzheimer’s based on neuropsychological testing, because the test norms are contaminated by the inclusion of subjects who may have preclinical disease," Dr. Morris said.

Comparative testing or the report of a close companion could detect change in a high-functioning individual, but the majority of people never undergo neuropsychological testing unless a problem is suspected.

Biomarkers, on the other hand, appear to predict decline very objectively. "People [with altered biomarkers] should be considered the real treatment target, so we are not focusing all of our efforts on curing people who already have the symptoms of Alzheimer’s dementia, but rather on trying to prevent those symptoms from appearing," Dr. Morris said.

DIAN is funded by a multiple-year research grant from the National Institute on Aging. Dr. Morris declared that he has served as a consultant, received speaking honoraria, and served as an investigator in industry-sponsored clinical trials from multiple drug companies. Dr. Reiman said he has no relevant personal financial disclosures.

Jeff Evans contributed to this report.

Studies that use Alzheimer’s disease biomarkers to predict the clinical benefit of investigational treatments in families with autosomal-dominant mutations that cause early-onset disease could prove to be the saving grace for researchers who have seen one treatment after another fail in trials of symptomatic patients.

Two research projects – the Alzheimer’s Prevention Initiative (API) and the Dominantly Inherited Alzheimer Network (DIAN) – hope to provide biomarker evidence that companies can use to test promising presymptomatic treatments without having to conduct costly long-term trials in individuals who might not develop symptoms for many years.

"In order to approve a treatment based on biomarker, the regulatory agencies said: ‘Show us with demonstrably effective, clinically proven treatments that the treatments’ effects on the biomarker predict a clinical benefit.’ Well that sounds like a Catch-22. If we had clinically proven prevention therapies, what do we need a biomarker for?" said Dr. Eric Reiman, who is leading the API with Dr. Pierre Tariot at the Banner Alzheimer’s Institute in Phoenix.

"So, in the last few years, we’ve modified our approach to not only help provide the scientific means to evaluate the range of promising presymptomatic treatments as rapidly as possible, but to help provide the financial incentives – that is, the accelerated regulatory approval pathway needed to encourage everybody to go out and start studying their promising prevention therapies and everybody using biomarkers."

The API is raising funds from philanthropic organizations, industry, and federal grants to study presymptomatic anti-amyloid treatments in people who are at high imminent risk for developing symptoms of Alzheimer’s disease (AD), based on their genetic background and age.

Fortunately, the largest extended family of individuals in the world who carry an autosomal-dominant mutation in the presenilin 1 (PS1) gene – about 5,000 people – live in and around Medellín, Colombia; about one-third of them have the PS1 mutation. Because mutation carriers are destined to develop symptoms of AD, typically around 45 years of age, the risk-to-benefit ratio for treatment in this population is different from the ratio for other individuals at lower risk for AD, said Dr. Reiman, executive director of the Banner Alzheimer’s Institute and director of the Arizona Alzheimer’s Consortium.

In collaboration with Colombian neurologist Dr. Francisco Lopera, who brought the extended family to the attention of researchers, the API is enrolling about 2,000 members of this extended family who are within 10 years of their expected age of onset in a prevention trial. Investigators are currently obtaining baseline data with cognitive tests; volumetric MRI; ¹⁸fluorodeoxyglucose and amyloid PET imaging; and cerebrospinal fluid measurements of beta-amyloid 42 (Abeta 42), tau, and total tau, he said.

In the trial, about 150 PS1 carriers will receive an anti-amyloid treatment and about 150 noncarriers will get a placebo. The anti-amyloid treatment to be given in the trial has not yet been determined, according to Dr. Reiman.

"We’ll be pretty unique in having the adequate sample size to show not just the biomarker effects, but within 3 or 4 years, the clinical effect as they’re close to their age of onset," he said in an interview.

Dr. Reiman added that "if there’s no effect on the biomarkers after 2 years in the right direction, [we will] declare futility and give these people at highest imminent risk access to the next most promising treatment. If however, they do budge in the right direction, [we will] continue to follow them a little bit longer to see if it slows even subtle memory decline. And if it does, I have a feeling that may be enough evidence for regulatory agencies to consider using biomarkers under their accelerated approval mechanism in other [Alzheimer’s disease] populations."

A second study in the United States will create a national registry of 20,000-50,000 people to gather a large number of people with one or two copies of the apolipoprotein E (APOE) e4 gene, which substantially increases an individual’s risk for late-onset Alzheimer’s disease. About 400 homozygous (and possibly heterozygous) APOE e4 carriers, who begin to have symptoms at a mean age of 68 years, will be enrolled in a prevention trial with of an anti-amyloid treatment; this therapy might not be the same as the one used in the trial of PS1 carriers, Dr. Reiman said.

Investigators are hoping to start one or both studies in 2012.

Study results from DIAN will be complementary to those from the API in many ways. DIAN is a 6-year, cross-sectional, longitudinal study of families who carry an autosomal dominant mutation in one of the three genes that affect amyloid processing: amyloid precursor protein (APP), PS1, and presenilin 2 (PS2).

Preliminary findings from the first analysis of DIAN indicate that the pathologic changes of AD might begin as early as 20 years before the expected onset of disease in mutation carriers.

The use of PET and cerebrospinal fluid biomarkers of beta-amyloid and tau protein in these individuals might allow researchers to select enriched pools of subjects for the testing of potential drug treatments, and, someday, allow clinicians to target patients with incipient disease for preventive treatment, Dr. John Morris said at the International Conference on Alzheimer’s and Parkinson’s Diseases in Barcelona.

"I have not yet had sufficient sample size or follow-up to predict this completely," said Dr. Morris, DIAN’s principal investigator. "However, I think there are data both from Europe and the U.S. showing that low beta-amyloid 42 [Abeta 42] and high tau in the cerebrospinal fluid together will reach a hazard ratio of 5.2 for becoming demented within 3-4 years. We are just beginning to get these same data for amyloid imaging and the hazard ratio is about the same."

Dr. Morris, professor of neurology at Washington University in St. Louis, said the DIAN study hopes to recruit 400 subjects who are the children of a parent with one of the gene mutations. He expects that about half the group will carry one of the mutations, while the other half will be unaffected siblings, who will serve as controls. The study involves 10 research institutions in the United States, United Kingdom, and Australia.

Each participant will undergo genetic analysis and the same periodic assessments, including cognitive and clinical testing; brain imaging with Pittsburgh compound B, which binds to Abeta 42 plaques; ¹⁸fluorodeoxyglucose PET; MRI; and lumbar punctures to test cerebrospinal fluid levels of Abeta 42 and tau. If subjects die during the study, their brains will be autopsied.

"The goals are to try and determine when the pathologic process begins in asymptomatic mutation carriers," Dr. Morris said. "We know, based on the parent’s age of onset, approximately when these carriers will become symptomatic. We want to see the changes, the rates of these changes, and determine to what extent the changes resemble those seen in sporadic Alzheimer’s."

As of last fall, DIAN had collected 106 volunteers, Dr. Morris said. About 70% of those are asymptomatic carriers, with an average age of 37 years, although that varies from 19 to 56 years. The average age of parental onset of dementia symptoms is 47 years, "so we have these folks an average of 10 years before their expected age of onset."

The PS1 mutation is the most common in the group, occurring in 75%; PS2 is present in 10%, and the APP mutation, in 15%.

About 90% of DIAN participants do not know whether they are a carrier of one of the mutations or not, and most do not want to know their status, Dr. Morris said in an interview. If DIAN researchers decide to conduct a clinical trial of an anti-amyloid treatment in the participants who carry a mutation, they will have to figure out a way to ensure that noncarriers receive a placebo without revealing mutation status to participants who do not want to know – and thereby not risk potential harm to the noncarriers from the treatment.

Comparing the carriers with the noncarriers, the study’s "very preliminary" data indicate that cognitive decline begins as early as 10 years before the expected onset of symptoms, while neuropathologic changes start up to 20 years before.

But scores on the Mini-Mental State Exam (MMSE) for noncarrier siblings of these volunteers "have remained very clearly at 30," which is a normal score, Dr. Morris said. The noncarriers also had normal scores on the Clinical Dementia Rating Scale sum of boxes (CDR-SOB), another test used to identify Alzheimer’s-related cognitive changes.

This was not the case "for carriers, in whom we begin to see declines in the MMSE and the CDR about 10 years before the expected age of onset," Dr. Morris said.

The cerebrospinal fluid biomarkers followed a similar pattern. A decrease in spinal fluid Abeta 42 suggests that the protein is aggregating somewhere else in the body – probably in the characteristic brain plaques. These changes could be seen in carriers 20 years before the expected age of onset. Tau protein levels in the cerebrospinal fluid (CSF) of carriers begin to rise around 20 years before the onset of symptoms, "with a clear acceleration at the time they are changing from asymptomatic to symptomatic," he said.

However, noncarriers have stable levels of both proteins in the CSF at the same ages.

Imaging in the precuneus and caudate with Pittsburgh compound B shows no Abeta 42 accumulation in noncarriers, but in carriers, the protein begins to appear in those regions about the same time that the CSF biomarkers start to change – 20 years before the expected appearance of symptomatic disease.

If these findings can be confirmed, they prove the existence of a long prodromal stage in subjects who are genetically destined to develop AD. This has several important applications in both drug research and potential treatment, Dr. Morris noted.

First, the neuropsychological testing scores currently in use, which define normal cognitive function, might be incorrect, because they could be based on cohorts that included individuals who had already experienced cognitive decline, but still fell within the "normal" range.

To illustrate this problem, Dr. Morris referred to the cognitive testing of two subjects. One began with cognitive functioning at the mean of normal, while the other began at two standard deviations above the mean. Over a period of years, the first person remained stable at the mean, while the second declined to the mean – showing that this subject was experiencing significant cognitive decline on an individual basis, while still being considered cognitively normal. The patient quickly developed mild cognitive impairment and then AD.

"This interferes with the ability to detect very early stages of symptomatic Alzheimer’s based on neuropsychological testing, because the test norms are contaminated by the inclusion of subjects who may have preclinical disease," Dr. Morris said.

Comparative testing or the report of a close companion could detect change in a high-functioning individual, but the majority of people never undergo neuropsychological testing unless a problem is suspected.

Biomarkers, on the other hand, appear to predict decline very objectively. "People [with altered biomarkers] should be considered the real treatment target, so we are not focusing all of our efforts on curing people who already have the symptoms of Alzheimer’s dementia, but rather on trying to prevent those symptoms from appearing," Dr. Morris said.

DIAN is funded by a multiple-year research grant from the National Institute on Aging. Dr. Morris declared that he has served as a consultant, received speaking honoraria, and served as an investigator in industry-sponsored clinical trials from multiple drug companies. Dr. Reiman said he has no relevant personal financial disclosures.

Jeff Evans contributed to this report.

Studies that use Alzheimer’s disease biomarkers to predict the clinical benefit of investigational treatments in families with autosomal-dominant mutations that cause early-onset disease could prove to be the saving grace for researchers who have seen one treatment after another fail in trials of symptomatic patients.

Two research projects – the Alzheimer’s Prevention Initiative (API) and the Dominantly Inherited Alzheimer Network (DIAN) – hope to provide biomarker evidence that companies can use to test promising presymptomatic treatments without having to conduct costly long-term trials in individuals who might not develop symptoms for many years.

"In order to approve a treatment based on biomarker, the regulatory agencies said: ‘Show us with demonstrably effective, clinically proven treatments that the treatments’ effects on the biomarker predict a clinical benefit.’ Well that sounds like a Catch-22. If we had clinically proven prevention therapies, what do we need a biomarker for?" said Dr. Eric Reiman, who is leading the API with Dr. Pierre Tariot at the Banner Alzheimer’s Institute in Phoenix.

"So, in the last few years, we’ve modified our approach to not only help provide the scientific means to evaluate the range of promising presymptomatic treatments as rapidly as possible, but to help provide the financial incentives – that is, the accelerated regulatory approval pathway needed to encourage everybody to go out and start studying their promising prevention therapies and everybody using biomarkers."

The API is raising funds from philanthropic organizations, industry, and federal grants to study presymptomatic anti-amyloid treatments in people who are at high imminent risk for developing symptoms of Alzheimer’s disease (AD), based on their genetic background and age.

Fortunately, the largest extended family of individuals in the world who carry an autosomal-dominant mutation in the presenilin 1 (PS1) gene – about 5,000 people – live in and around Medellín, Colombia; about one-third of them have the PS1 mutation. Because mutation carriers are destined to develop symptoms of AD, typically around 45 years of age, the risk-to-benefit ratio for treatment in this population is different from the ratio for other individuals at lower risk for AD, said Dr. Reiman, executive director of the Banner Alzheimer’s Institute and director of the Arizona Alzheimer’s Consortium.

In collaboration with Colombian neurologist Dr. Francisco Lopera, who brought the extended family to the attention of researchers, the API is enrolling about 2,000 members of this extended family who are within 10 years of their expected age of onset in a prevention trial. Investigators are currently obtaining baseline data with cognitive tests; volumetric MRI; ¹⁸fluorodeoxyglucose and amyloid PET imaging; and cerebrospinal fluid measurements of beta-amyloid 42 (Abeta 42), tau, and total tau, he said.

In the trial, about 150 PS1 carriers will receive an anti-amyloid treatment and about 150 noncarriers will get a placebo. The anti-amyloid treatment to be given in the trial has not yet been determined, according to Dr. Reiman.

"We’ll be pretty unique in having the adequate sample size to show not just the biomarker effects, but within 3 or 4 years, the clinical effect as they’re close to their age of onset," he said in an interview.

Dr. Reiman added that "if there’s no effect on the biomarkers after 2 years in the right direction, [we will] declare futility and give these people at highest imminent risk access to the next most promising treatment. If however, they do budge in the right direction, [we will] continue to follow them a little bit longer to see if it slows even subtle memory decline. And if it does, I have a feeling that may be enough evidence for regulatory agencies to consider using biomarkers under their accelerated approval mechanism in other [Alzheimer’s disease] populations."

A second study in the United States will create a national registry of 20,000-50,000 people to gather a large number of people with one or two copies of the apolipoprotein E (APOE) e4 gene, which substantially increases an individual’s risk for late-onset Alzheimer’s disease. About 400 homozygous (and possibly heterozygous) APOE e4 carriers, who begin to have symptoms at a mean age of 68 years, will be enrolled in a prevention trial with of an anti-amyloid treatment; this therapy might not be the same as the one used in the trial of PS1 carriers, Dr. Reiman said.

Investigators are hoping to start one or both studies in 2012.

Study results from DIAN will be complementary to those from the API in many ways. DIAN is a 6-year, cross-sectional, longitudinal study of families who carry an autosomal dominant mutation in one of the three genes that affect amyloid processing: amyloid precursor protein (APP), PS1, and presenilin 2 (PS2).

Preliminary findings from the first analysis of DIAN indicate that the pathologic changes of AD might begin as early as 20 years before the expected onset of disease in mutation carriers.

The use of PET and cerebrospinal fluid biomarkers of beta-amyloid and tau protein in these individuals might allow researchers to select enriched pools of subjects for the testing of potential drug treatments, and, someday, allow clinicians to target patients with incipient disease for preventive treatment, Dr. John Morris said at the International Conference on Alzheimer’s and Parkinson’s Diseases in Barcelona.

"I have not yet had sufficient sample size or follow-up to predict this completely," said Dr. Morris, DIAN’s principal investigator. "However, I think there are data both from Europe and the U.S. showing that low beta-amyloid 42 [Abeta 42] and high tau in the cerebrospinal fluid together will reach a hazard ratio of 5.2 for becoming demented within 3-4 years. We are just beginning to get these same data for amyloid imaging and the hazard ratio is about the same."

Dr. Morris, professor of neurology at Washington University in St. Louis, said the DIAN study hopes to recruit 400 subjects who are the children of a parent with one of the gene mutations. He expects that about half the group will carry one of the mutations, while the other half will be unaffected siblings, who will serve as controls. The study involves 10 research institutions in the United States, United Kingdom, and Australia.

Each participant will undergo genetic analysis and the same periodic assessments, including cognitive and clinical testing; brain imaging with Pittsburgh compound B, which binds to Abeta 42 plaques; ¹⁸fluorodeoxyglucose PET; MRI; and lumbar punctures to test cerebrospinal fluid levels of Abeta 42 and tau. If subjects die during the study, their brains will be autopsied.

"The goals are to try and determine when the pathologic process begins in asymptomatic mutation carriers," Dr. Morris said. "We know, based on the parent’s age of onset, approximately when these carriers will become symptomatic. We want to see the changes, the rates of these changes, and determine to what extent the changes resemble those seen in sporadic Alzheimer’s."

As of last fall, DIAN had collected 106 volunteers, Dr. Morris said. About 70% of those are asymptomatic carriers, with an average age of 37 years, although that varies from 19 to 56 years. The average age of parental onset of dementia symptoms is 47 years, "so we have these folks an average of 10 years before their expected age of onset."

The PS1 mutation is the most common in the group, occurring in 75%; PS2 is present in 10%, and the APP mutation, in 15%.

About 90% of DIAN participants do not know whether they are a carrier of one of the mutations or not, and most do not want to know their status, Dr. Morris said in an interview. If DIAN researchers decide to conduct a clinical trial of an anti-amyloid treatment in the participants who carry a mutation, they will have to figure out a way to ensure that noncarriers receive a placebo without revealing mutation status to participants who do not want to know – and thereby not risk potential harm to the noncarriers from the treatment.

Comparing the carriers with the noncarriers, the study’s "very preliminary" data indicate that cognitive decline begins as early as 10 years before the expected onset of symptoms, while neuropathologic changes start up to 20 years before.

But scores on the Mini-Mental State Exam (MMSE) for noncarrier siblings of these volunteers "have remained very clearly at 30," which is a normal score, Dr. Morris said. The noncarriers also had normal scores on the Clinical Dementia Rating Scale sum of boxes (CDR-SOB), another test used to identify Alzheimer’s-related cognitive changes.

This was not the case "for carriers, in whom we begin to see declines in the MMSE and the CDR about 10 years before the expected age of onset," Dr. Morris said.

The cerebrospinal fluid biomarkers followed a similar pattern. A decrease in spinal fluid Abeta 42 suggests that the protein is aggregating somewhere else in the body – probably in the characteristic brain plaques. These changes could be seen in carriers 20 years before the expected age of onset. Tau protein levels in the cerebrospinal fluid (CSF) of carriers begin to rise around 20 years before the onset of symptoms, "with a clear acceleration at the time they are changing from asymptomatic to symptomatic," he said.

However, noncarriers have stable levels of both proteins in the CSF at the same ages.

Imaging in the precuneus and caudate with Pittsburgh compound B shows no Abeta 42 accumulation in noncarriers, but in carriers, the protein begins to appear in those regions about the same time that the CSF biomarkers start to change – 20 years before the expected appearance of symptomatic disease.

If these findings can be confirmed, they prove the existence of a long prodromal stage in subjects who are genetically destined to develop AD. This has several important applications in both drug research and potential treatment, Dr. Morris noted.

First, the neuropsychological testing scores currently in use, which define normal cognitive function, might be incorrect, because they could be based on cohorts that included individuals who had already experienced cognitive decline, but still fell within the "normal" range.

To illustrate this problem, Dr. Morris referred to the cognitive testing of two subjects. One began with cognitive functioning at the mean of normal, while the other began at two standard deviations above the mean. Over a period of years, the first person remained stable at the mean, while the second declined to the mean – showing that this subject was experiencing significant cognitive decline on an individual basis, while still being considered cognitively normal. The patient quickly developed mild cognitive impairment and then AD.

"This interferes with the ability to detect very early stages of symptomatic Alzheimer’s based on neuropsychological testing, because the test norms are contaminated by the inclusion of subjects who may have preclinical disease," Dr. Morris said.

Comparative testing or the report of a close companion could detect change in a high-functioning individual, but the majority of people never undergo neuropsychological testing unless a problem is suspected.

Biomarkers, on the other hand, appear to predict decline very objectively. "People [with altered biomarkers] should be considered the real treatment target, so we are not focusing all of our efforts on curing people who already have the symptoms of Alzheimer’s dementia, but rather on trying to prevent those symptoms from appearing," Dr. Morris said.

DIAN is funded by a multiple-year research grant from the National Institute on Aging. Dr. Morris declared that he has served as a consultant, received speaking honoraria, and served as an investigator in industry-sponsored clinical trials from multiple drug companies. Dr. Reiman said he has no relevant personal financial disclosures.

Jeff Evans contributed to this report.

Studies that use Alzheimer’s disease biomarkers to predict the clinical benefit of investigational treatments in families with autosomal-dominant mutations that cause early-onset disease could prove to be the saving grace for researchers who have seen one treatment after another fail in trials of symptomatic patients.

Two research projects – the Alzheimer’s Prevention Initiative (API) and the Dominantly Inherited Alzheimer Network (DIAN) – hope to provide biomarker evidence that companies can use to test promising presymptomatic treatments without having to conduct costly long-term trials in individuals who might not develop symptoms for many years.

"In order to approve a treatment based on biomarker, the regulatory agencies said: ‘Show us with demonstrably effective, clinically proven treatments that the treatments’ effects on the biomarker predict a clinical benefit.’ Well that sounds like a Catch-22. If we had clinically proven prevention therapies, what do we need a biomarker for?" said Dr. Eric Reiman, who is leading the API with Dr. Pierre Tariot at the Banner Alzheimer’s Institute in Phoenix.

"So, in the last few years, we’ve modified our approach to not only help provide the scientific means to evaluate the range of promising presymptomatic treatments as rapidly as possible, but to help provide the financial incentives – that is, the accelerated regulatory approval pathway needed to encourage everybody to go out and start studying their promising prevention therapies and everybody using biomarkers."

The API is raising funds from philanthropic organizations, industry, and federal grants to study presymptomatic anti-amyloid treatments in people who are at high imminent risk for developing symptoms of Alzheimer’s disease (AD), based on their genetic background and age.

Fortunately, the largest extended family of individuals in the world who carry an autosomal-dominant mutation in the presenilin 1 (PS1) gene – about 5,000 people – live in and around Medellín, Colombia; about one-third of them have the PS1 mutation. Because mutation carriers are destined to develop symptoms of AD, typically around 45 years of age, the risk-to-benefit ratio for treatment in this population is different from the ratio for other individuals at lower risk for AD, said Dr. Reiman, executive director of the Banner Alzheimer’s Institute and director of the Arizona Alzheimer’s Consortium.

In collaboration with Colombian neurologist Dr. Francisco Lopera, who brought the extended family to the attention of researchers, the API is enrolling about 2,000 members of this extended family who are within 10 years of their expected age of onset in a prevention trial. Investigators are currently obtaining baseline data with cognitive tests; volumetric MRI; ¹⁸fluorodeoxyglucose and amyloid PET imaging; and cerebrospinal fluid measurements of beta-amyloid 42 (Abeta 42), tau, and total tau, he said.

In the trial, about 150 PS1 carriers will receive an anti-amyloid treatment and about 150 noncarriers will get a placebo. The anti-amyloid treatment to be given in the trial has not yet been determined, according to Dr. Reiman.

"We’ll be pretty unique in having the adequate sample size to show not just the biomarker effects, but within 3 or 4 years, the clinical effect as they’re close to their age of onset," he said in an interview.

Dr. Reiman added that "if there’s no effect on the biomarkers after 2 years in the right direction, [we will] declare futility and give these people at highest imminent risk access to the next most promising treatment. If however, they do budge in the right direction, [we will] continue to follow them a little bit longer to see if it slows even subtle memory decline. And if it does, I have a feeling that may be enough evidence for regulatory agencies to consider using biomarkers under their accelerated approval mechanism in other [Alzheimer’s disease] populations."

A second study in the United States will create a national registry of 20,000-50,000 people to gather a large number of people with one or two copies of the apolipoprotein E (APOE) e4 gene, which substantially increases an individual’s risk for late-onset Alzheimer’s disease. About 400 homozygous (and possibly heterozygous) APOE e4 carriers, who begin to have symptoms at a mean age of 68 years, will be enrolled in a prevention trial with of an anti-amyloid treatment; this therapy might not be the same as the one used in the trial of PS1 carriers, Dr. Reiman said.

Investigators are hoping to start one or both studies in 2012.

Study results from DIAN will be complementary to those from the API in many ways. DIAN is a 6-year, cross-sectional, longitudinal study of families who carry an autosomal dominant mutation in one of the three genes that affect amyloid processing: amyloid precursor protein (APP), PS1, and presenilin 2 (PS2).

Preliminary findings from the first analysis of DIAN indicate that the pathologic changes of AD might begin as early as 20 years before the expected onset of disease in mutation carriers.

The use of PET and cerebrospinal fluid biomarkers of beta-amyloid and tau protein in these individuals might allow researchers to select enriched pools of subjects for the testing of potential drug treatments, and, someday, allow clinicians to target patients with incipient disease for preventive treatment, Dr. John Morris said at the International Conference on Alzheimer’s and Parkinson’s Diseases in Barcelona.

"I have not yet had sufficient sample size or follow-up to predict this completely," said Dr. Morris, DIAN’s principal investigator. "However, I think there are data both from Europe and the U.S. showing that low beta-amyloid 42 [Abeta 42] and high tau in the cerebrospinal fluid together will reach a hazard ratio of 5.2 for becoming demented within 3-4 years. We are just beginning to get these same data for amyloid imaging and the hazard ratio is about the same."

Dr. Morris, professor of neurology at Washington University in St. Louis, said the DIAN study hopes to recruit 400 subjects who are the children of a parent with one of the gene mutations. He expects that about half the group will carry one of the mutations, while the other half will be unaffected siblings, who will serve as controls. The study involves 10 research institutions in the United States, United Kingdom, and Australia.

Each participant will undergo genetic analysis and the same periodic assessments, including cognitive and clinical testing; brain imaging with Pittsburgh compound B, which binds to Abeta 42 plaques; ¹⁸fluorodeoxyglucose PET; MRI; and lumbar punctures to test cerebrospinal fluid levels of Abeta 42 and tau. If subjects die during the study, their brains will be autopsied.

"The goals are to try and determine when the pathologic process begins in asymptomatic mutation carriers," Dr. Morris said. "We know, based on the parent’s age of onset, approximately when these carriers will become symptomatic. We want to see the changes, the rates of these changes, and determine to what extent the changes resemble those seen in sporadic Alzheimer’s."

As of last fall, DIAN had collected 106 volunteers, Dr. Morris said. About 70% of those are asymptomatic carriers, with an average age of 37 years, although that varies from 19 to 56 years. The average age of parental onset of dementia symptoms is 47 years, "so we have these folks an average of 10 years before their expected age of onset."

The PS1 mutation is the most common in the group, occurring in 75%; PS2 is present in 10%, and the APP mutation, in 15%.

About 90% of DIAN participants do not know whether they are a carrier of one of the mutations or not, and most do not want to know their status, Dr. Morris said in an interview. If DIAN researchers decide to conduct a clinical trial of an anti-amyloid treatment in the participants who carry a mutation, they will have to figure out a way to ensure that noncarriers receive a placebo without revealing mutation status to participants who do not want to know – and thereby not risk potential harm to the noncarriers from the treatment.

Comparing the carriers with the noncarriers, the study’s "very preliminary" data indicate that cognitive decline begins as early as 10 years before the expected onset of symptoms, while neuropathologic changes start up to 20 years before.

But scores on the Mini-Mental State Exam (MMSE) for noncarrier siblings of these volunteers "have remained very clearly at 30," which is a normal score, Dr. Morris said. The noncarriers also had normal scores on the Clinical Dementia Rating Scale sum of boxes (CDR-SOB), another test used to identify Alzheimer’s-related cognitive changes.

This was not the case "for carriers, in whom we begin to see declines in the MMSE and the CDR about 10 years before the expected age of onset," Dr. Morris said.

The cerebrospinal fluid biomarkers followed a similar pattern. A decrease in spinal fluid Abeta 42 suggests that the protein is aggregating somewhere else in the body – probably in the characteristic brain plaques. These changes could be seen in carriers 20 years before the expected age of onset. Tau protein levels in the cerebrospinal fluid (CSF) of carriers begin to rise around 20 years before the onset of symptoms, "with a clear acceleration at the time they are changing from asymptomatic to symptomatic," he said.

However, noncarriers have stable levels of both proteins in the CSF at the same ages.

Imaging in the precuneus and caudate with Pittsburgh compound B shows no Abeta 42 accumulation in noncarriers, but in carriers, the protein begins to appear in those regions about the same time that the CSF biomarkers start to change – 20 years before the expected appearance of symptomatic disease.

If these findings can be confirmed, they prove the existence of a long prodromal stage in subjects who are genetically destined to develop AD. This has several important applications in both drug research and potential treatment, Dr. Morris noted.

First, the neuropsychological testing scores currently in use, which define normal cognitive function, might be incorrect, because they could be based on cohorts that included individuals who had already experienced cognitive decline, but still fell within the "normal" range.

To illustrate this problem, Dr. Morris referred to the cognitive testing of two subjects. One began with cognitive functioning at the mean of normal, while the other began at two standard deviations above the mean. Over a period of years, the first person remained stable at the mean, while the second declined to the mean – showing that this subject was experiencing significant cognitive decline on an individual basis, while still being considered cognitively normal. The patient quickly developed mild cognitive impairment and then AD.

"This interferes with the ability to detect very early stages of symptomatic Alzheimer’s based on neuropsychological testing, because the test norms are contaminated by the inclusion of subjects who may have preclinical disease," Dr. Morris said.

Comparative testing or the report of a close companion could detect change in a high-functioning individual, but the majority of people never undergo neuropsychological testing unless a problem is suspected.

Biomarkers, on the other hand, appear to predict decline very objectively. "People [with altered biomarkers] should be considered the real treatment target, so we are not focusing all of our efforts on curing people who already have the symptoms of Alzheimer’s dementia, but rather on trying to prevent those symptoms from appearing," Dr. Morris said.

DIAN is funded by a multiple-year research grant from the National Institute on Aging. Dr. Morris declared that he has served as a consultant, received speaking honoraria, and served as an investigator in industry-sponsored clinical trials from multiple drug companies. Dr. Reiman said he has no relevant personal financial disclosures.

Jeff Evans contributed to this report.

Studies that use Alzheimer’s disease biomarkers to predict the clinical benefit of investigational treatments in families with autosomal-dominant mutations that cause early-onset disease could prove to be the saving grace for researchers who have seen one treatment after another fail in trials of symptomatic patients.

Two research projects – the Alzheimer’s Prevention Initiative (API) and the Dominantly Inherited Alzheimer Network (DIAN) – hope to provide biomarker evidence that companies can use to test promising presymptomatic treatments without having to conduct costly long-term trials in individuals who might not develop symptoms for many years.

"In order to approve a treatment based on biomarker, the regulatory agencies said: ‘Show us with demonstrably effective, clinically proven treatments that the treatments’ effects on the biomarker predict a clinical benefit.’ Well that sounds like a Catch-22. If we had clinically proven prevention therapies, what do we need a biomarker for?" said Dr. Eric Reiman, who is leading the API with Dr. Pierre Tariot at the Banner Alzheimer’s Institute in Phoenix.

"So, in the last few years, we’ve modified our approach to not only help provide the scientific means to evaluate the range of promising presymptomatic treatments as rapidly as possible, but to help provide the financial incentives – that is, the accelerated regulatory approval pathway needed to encourage everybody to go out and start studying their promising prevention therapies and everybody using biomarkers."

The API is raising funds from philanthropic organizations, industry, and federal grants to study presymptomatic anti-amyloid treatments in people who are at high imminent risk for developing symptoms of Alzheimer’s disease (AD), based on their genetic background and age.

Fortunately, the largest extended family of individuals in the world who carry an autosomal-dominant mutation in the presenilin 1 (PS1) gene – about 5,000 people – live in and around Medellín, Colombia; about one-third of them have the PS1 mutation. Because mutation carriers are destined to develop symptoms of AD, typically around 45 years of age, the risk-to-benefit ratio for treatment in this population is different from the ratio for other individuals at lower risk for AD, said Dr. Reiman, executive director of the Banner Alzheimer’s Institute and director of the Arizona Alzheimer’s Consortium.

In collaboration with Colombian neurologist Dr. Francisco Lopera, who brought the extended family to the attention of researchers, the API is enrolling about 2,000 members of this extended family who are within 10 years of their expected age of onset in a prevention trial. Investigators are currently obtaining baseline data with cognitive tests; volumetric MRI; ¹⁸fluorodeoxyglucose and amyloid PET imaging; and cerebrospinal fluid measurements of beta-amyloid 42 (Abeta 42), tau, and total tau, he said.

In the trial, about 150 PS1 carriers will receive an anti-amyloid treatment and about 150 noncarriers will get a placebo. The anti-amyloid treatment to be given in the trial has not yet been determined, according to Dr. Reiman.

"We’ll be pretty unique in having the adequate sample size to show not just the biomarker effects, but within 3 or 4 years, the clinical effect as they’re close to their age of onset," he said in an interview.

Dr. Reiman added that "if there’s no effect on the biomarkers after 2 years in the right direction, [we will] declare futility and give these people at highest imminent risk access to the next most promising treatment. If however, they do budge in the right direction, [we will] continue to follow them a little bit longer to see if it slows even subtle memory decline. And if it does, I have a feeling that may be enough evidence for regulatory agencies to consider using biomarkers under their accelerated approval mechanism in other [Alzheimer’s disease] populations."

A second study in the United States will create a national registry of 20,000-50,000 people to gather a large number of people with one or two copies of the apolipoprotein E (APOE) e4 gene, which substantially increases an individual’s risk for late-onset Alzheimer’s disease. About 400 homozygous (and possibly heterozygous) APOE e4 carriers, who begin to have symptoms at a mean age of 68 years, will be enrolled in a prevention trial with of an anti-amyloid treatment; this therapy might not be the same as the one used in the trial of PS1 carriers, Dr. Reiman said.

Investigators are hoping to start one or both studies in 2012.

Study results from DIAN will be complementary to those from the API in many ways. DIAN is a 6-year, cross-sectional, longitudinal study of families who carry an autosomal dominant mutation in one of the three genes that affect amyloid processing: amyloid precursor protein (APP), PS1, and presenilin 2 (PS2).

Preliminary findings from the first analysis of DIAN indicate that the pathologic changes of AD might begin as early as 20 years before the expected onset of disease in mutation carriers.

The use of PET and cerebrospinal fluid biomarkers of beta-amyloid and tau protein in these individuals might allow researchers to select enriched pools of subjects for the testing of potential drug treatments, and, someday, allow clinicians to target patients with incipient disease for preventive treatment, Dr. John Morris said at the International Conference on Alzheimer’s and Parkinson’s Diseases in Barcelona.

"I have not yet had sufficient sample size or follow-up to predict this completely," said Dr. Morris, DIAN’s principal investigator. "However, I think there are data both from Europe and the U.S. showing that low beta-amyloid 42 [Abeta 42] and high tau in the cerebrospinal fluid together will reach a hazard ratio of 5.2 for becoming demented within 3-4 years. We are just beginning to get these same data for amyloid imaging and the hazard ratio is about the same."

Dr. Morris, professor of neurology at Washington University in St. Louis, said the DIAN study hopes to recruit 400 subjects who are the children of a parent with one of the gene mutations. He expects that about half the group will carry one of the mutations, while the other half will be unaffected siblings, who will serve as controls. The study involves 10 research institutions in the United States, United Kingdom, and Australia.

Each participant will undergo genetic analysis and the same periodic assessments, including cognitive and clinical testing; brain imaging with Pittsburgh compound B, which binds to Abeta 42 plaques; ¹⁸fluorodeoxyglucose PET; MRI; and lumbar punctures to test cerebrospinal fluid levels of Abeta 42 and tau. If subjects die during the study, their brains will be autopsied.

"The goals are to try and determine when the pathologic process begins in asymptomatic mutation carriers," Dr. Morris said. "We know, based on the parent’s age of onset, approximately when these carriers will become symptomatic. We want to see the changes, the rates of these changes, and determine to what extent the changes resemble those seen in sporadic Alzheimer’s."

As of last fall, DIAN had collected 106 volunteers, Dr. Morris said. About 70% of those are asymptomatic carriers, with an average age of 37 years, although that varies from 19 to 56 years. The average age of parental onset of dementia symptoms is 47 years, "so we have these folks an average of 10 years before their expected age of onset."

The PS1 mutation is the most common in the group, occurring in 75%; PS2 is present in 10%, and the APP mutation, in 15%.

About 90% of DIAN participants do not know whether they are a carrier of one of the mutations or not, and most do not want to know their status, Dr. Morris said in an interview. If DIAN researchers decide to conduct a clinical trial of an anti-amyloid treatment in the participants who carry a mutation, they will have to figure out a way to ensure that noncarriers receive a placebo without revealing mutation status to participants who do not want to know – and thereby not risk potential harm to the noncarriers from the treatment.

Comparing the carriers with the noncarriers, the study’s "very preliminary" data indicate that cognitive decline begins as early as 10 years before the expected onset of symptoms, while neuropathologic changes start up to 20 years before.

But scores on the Mini-Mental State Exam (MMSE) for noncarrier siblings of these volunteers "have remained very clearly at 30," which is a normal score, Dr. Morris said. The noncarriers also had normal scores on the Clinical Dementia Rating Scale sum of boxes (CDR-SOB), another test used to identify Alzheimer’s-related cognitive changes.

This was not the case "for carriers, in whom we begin to see declines in the MMSE and the CDR about 10 years before the expected age of onset," Dr. Morris said.

The cerebrospinal fluid biomarkers followed a similar pattern. A decrease in spinal fluid Abeta 42 suggests that the protein is aggregating somewhere else in the body – probably in the characteristic brain plaques. These changes could be seen in carriers 20 years before the expected age of onset. Tau protein levels in the cerebrospinal fluid (CSF) of carriers begin to rise around 20 years before the onset of symptoms, "with a clear acceleration at the time they are changing from asymptomatic to symptomatic," he said.

However, noncarriers have stable levels of both proteins in the CSF at the same ages.

Imaging in the precuneus and caudate with Pittsburgh compound B shows no Abeta 42 accumulation in noncarriers, but in carriers, the protein begins to appear in those regions about the same time that the CSF biomarkers start to change – 20 years before the expected appearance of symptomatic disease.

If these findings can be confirmed, they prove the existence of a long prodromal stage in subjects who are genetically destined to develop AD. This has several important applications in both drug research and potential treatment, Dr. Morris noted.

First, the neuropsychological testing scores currently in use, which define normal cognitive function, might be incorrect, because they could be based on cohorts that included individuals who had already experienced cognitive decline, but still fell within the "normal" range.

To illustrate this problem, Dr. Morris referred to the cognitive testing of two subjects. One began with cognitive functioning at the mean of normal, while the other began at two standard deviations above the mean. Over a period of years, the first person remained stable at the mean, while the second declined to the mean – showing that this subject was experiencing significant cognitive decline on an individual basis, while still being considered cognitively normal. The patient quickly developed mild cognitive impairment and then AD.

"This interferes with the ability to detect very early stages of symptomatic Alzheimer’s based on neuropsychological testing, because the test norms are contaminated by the inclusion of subjects who may have preclinical disease," Dr. Morris said.

Comparative testing or the report of a close companion could detect change in a high-functioning individual, but the majority of people never undergo neuropsychological testing unless a problem is suspected.

Biomarkers, on the other hand, appear to predict decline very objectively. "People [with altered biomarkers] should be considered the real treatment target, so we are not focusing all of our efforts on curing people who already have the symptoms of Alzheimer’s dementia, but rather on trying to prevent those symptoms from appearing," Dr. Morris said.

DIAN is funded by a multiple-year research grant from the National Institute on Aging. Dr. Morris declared that he has served as a consultant, received speaking honoraria, and served as an investigator in industry-sponsored clinical trials from multiple drug companies. Dr. Reiman said he has no relevant personal financial disclosures.

Jeff Evans contributed to this report.

Studies that use Alzheimer’s disease biomarkers to predict the clinical benefit of investigational treatments in families with autosomal-dominant mutations that cause early-onset disease could prove to be the saving grace for researchers who have seen one treatment after another fail in trials of symptomatic patients.

Two research projects – the Alzheimer’s Prevention Initiative (API) and the Dominantly Inherited Alzheimer Network (DIAN) – hope to provide biomarker evidence that companies can use to test promising presymptomatic treatments without having to conduct costly long-term trials in individuals who might not develop symptoms for many years.

"In order to approve a treatment based on biomarker, the regulatory agencies said: ‘Show us with demonstrably effective, clinically proven treatments that the treatments’ effects on the biomarker predict a clinical benefit.’ Well that sounds like a Catch-22. If we had clinically proven prevention therapies, what do we need a biomarker for?" said Dr. Eric Reiman, who is leading the API with Dr. Pierre Tariot at the Banner Alzheimer’s Institute in Phoenix.

"So, in the last few years, we’ve modified our approach to not only help provide the scientific means to evaluate the range of promising presymptomatic treatments as rapidly as possible, but to help provide the financial incentives – that is, the accelerated regulatory approval pathway needed to encourage everybody to go out and start studying their promising prevention therapies and everybody using biomarkers."

The API is raising funds from philanthropic organizations, industry, and federal grants to study presymptomatic anti-amyloid treatments in people who are at high imminent risk for developing symptoms of Alzheimer’s disease (AD), based on their genetic background and age.

Fortunately, the largest extended family of individuals in the world who carry an autosomal-dominant mutation in the presenilin 1 (PS1) gene – about 5,000 people – live in and around Medellín, Colombia; about one-third of them have the PS1 mutation. Because mutation carriers are destined to develop symptoms of AD, typically around 45 years of age, the risk-to-benefit ratio for treatment in this population is different from the ratio for other individuals at lower risk for AD, said Dr. Reiman, executive director of the Banner Alzheimer’s Institute and director of the Arizona Alzheimer’s Consortium.

In collaboration with Colombian neurologist Dr. Francisco Lopera, who brought the extended family to the attention of researchers, the API is enrolling about 2,000 members of this extended family who are within 10 years of their expected age of onset in a prevention trial. Investigators are currently obtaining baseline data with cognitive tests; volumetric MRI; ¹⁸fluorodeoxyglucose and amyloid PET imaging; and cerebrospinal fluid measurements of beta-amyloid 42 (Abeta 42), tau, and total tau, he said.

In the trial, about 150 PS1 carriers will receive an anti-amyloid treatment and about 150 noncarriers will get a placebo. The anti-amyloid treatment to be given in the trial has not yet been determined, according to Dr. Reiman.

"We’ll be pretty unique in having the adequate sample size to show not just the biomarker effects, but within 3 or 4 years, the clinical effect as they’re close to their age of onset," he said in an interview.

Dr. Reiman added that "if there’s no effect on the biomarkers after 2 years in the right direction, [we will] declare futility and give these people at highest imminent risk access to the next most promising treatment. If however, they do budge in the right direction, [we will] continue to follow them a little bit longer to see if it slows even subtle memory decline. And if it does, I have a feeling that may be enough evidence for regulatory agencies to consider using biomarkers under their accelerated approval mechanism in other [Alzheimer’s disease] populations."

A second study in the United States will create a national registry of 20,000-50,000 people to gather a large number of people with one or two copies of the apolipoprotein E (APOE) e4 gene, which substantially increases an individual’s risk for late-onset Alzheimer’s disease. About 400 homozygous (and possibly heterozygous) APOE e4 carriers, who begin to have symptoms at a mean age of 68 years, will be enrolled in a prevention trial with of an anti-amyloid treatment; this therapy might not be the same as the one used in the trial of PS1 carriers, Dr. Reiman said.

Investigators are hoping to start one or both studies in 2012.

Study results from DIAN will be complementary to those from the API in many ways. DIAN is a 6-year, cross-sectional, longitudinal study of families who carry an autosomal dominant mutation in one of the three genes that affect amyloid processing: amyloid precursor protein (APP), PS1, and presenilin 2 (PS2).

Preliminary findings from the first analysis of DIAN indicate that the pathologic changes of AD might begin as early as 20 years before the expected onset of disease in mutation carriers.

The use of PET and cerebrospinal fluid biomarkers of beta-amyloid and tau protein in these individuals might allow researchers to select enriched pools of subjects for the testing of potential drug treatments, and, someday, allow clinicians to target patients with incipient disease for preventive treatment, Dr. John Morris said at the International Conference on Alzheimer’s and Parkinson’s Diseases in Barcelona.

"I have not yet had sufficient sample size or follow-up to predict this completely," said Dr. Morris, DIAN’s principal investigator. "However, I think there are data both from Europe and the U.S. showing that low beta-amyloid 42 [Abeta 42] and high tau in the cerebrospinal fluid together will reach a hazard ratio of 5.2 for becoming demented within 3-4 years. We are just beginning to get these same data for amyloid imaging and the hazard ratio is about the same."

Dr. Morris, professor of neurology at Washington University in St. Louis, said the DIAN study hopes to recruit 400 subjects who are the children of a parent with one of the gene mutations. He expects that about half the group will carry one of the mutations, while the other half will be unaffected siblings, who will serve as controls. The study involves 10 research institutions in the United States, United Kingdom, and Australia.

Each participant will undergo genetic analysis and the same periodic assessments, including cognitive and clinical testing; brain imaging with Pittsburgh compound B, which binds to Abeta 42 plaques; ¹⁸fluorodeoxyglucose PET; MRI; and lumbar punctures to test cerebrospinal fluid levels of Abeta 42 and tau. If subjects die during the study, their brains will be autopsied.

"The goals are to try and determine when the pathologic process begins in asymptomatic mutation carriers," Dr. Morris said. "We know, based on the parent’s age of onset, approximately when these carriers will become symptomatic. We want to see the changes, the rates of these changes, and determine to what extent the changes resemble those seen in sporadic Alzheimer’s."

As of last fall, DIAN had collected 106 volunteers, Dr. Morris said. About 70% of those are asymptomatic carriers, with an average age of 37 years, although that varies from 19 to 56 years. The average age of parental onset of dementia symptoms is 47 years, "so we have these folks an average of 10 years before their expected age of onset."

The PS1 mutation is the most common in the group, occurring in 75%; PS2 is present in 10%, and the APP mutation, in 15%.

About 90% of DIAN participants do not know whether they are a carrier of one of the mutations or not, and most do not want to know their status, Dr. Morris said in an interview. If DIAN researchers decide to conduct a clinical trial of an anti-amyloid treatment in the participants who carry a mutation, they will have to figure out a way to ensure that noncarriers receive a placebo without revealing mutation status to participants who do not want to know – and thereby not risk potential harm to the noncarriers from the treatment.

Comparing the carriers with the noncarriers, the study’s "very preliminary" data indicate that cognitive decline begins as early as 10 years before the expected onset of symptoms, while neuropathologic changes start up to 20 years before.

But scores on the Mini-Mental State Exam (MMSE) for noncarrier siblings of these volunteers "have remained very clearly at 30," which is a normal score, Dr. Morris said. The noncarriers also had normal scores on the Clinical Dementia Rating Scale sum of boxes (CDR-SOB), another test used to identify Alzheimer’s-related cognitive changes.

This was not the case "for carriers, in whom we begin to see declines in the MMSE and the CDR about 10 years before the expected age of onset," Dr. Morris said.

The cerebrospinal fluid biomarkers followed a similar pattern. A decrease in spinal fluid Abeta 42 suggests that the protein is aggregating somewhere else in the body – probably in the characteristic brain plaques. These changes could be seen in carriers 20 years before the expected age of onset. Tau protein levels in the cerebrospinal fluid (CSF) of carriers begin to rise around 20 years before the onset of symptoms, "with a clear acceleration at the time they are changing from asymptomatic to symptomatic," he said.

However, noncarriers have stable levels of both proteins in the CSF at the same ages.

Imaging in the precuneus and caudate with Pittsburgh compound B shows no Abeta 42 accumulation in noncarriers, but in carriers, the protein begins to appear in those regions about the same time that the CSF biomarkers start to change – 20 years before the expected appearance of symptomatic disease.

If these findings can be confirmed, they prove the existence of a long prodromal stage in subjects who are genetically destined to develop AD. This has several important applications in both drug research and potential treatment, Dr. Morris noted.

First, the neuropsychological testing scores currently in use, which define normal cognitive function, might be incorrect, because they could be based on cohorts that included individuals who had already experienced cognitive decline, but still fell within the "normal" range.

To illustrate this problem, Dr. Morris referred to the cognitive testing of two subjects. One began with cognitive functioning at the mean of normal, while the other began at two standard deviations above the mean. Over a period of years, the first person remained stable at the mean, while the second declined to the mean – showing that this subject was experiencing significant cognitive decline on an individual basis, while still being considered cognitively normal. The patient quickly developed mild cognitive impairment and then AD.

"This interferes with the ability to detect very early stages of symptomatic Alzheimer’s based on neuropsychological testing, because the test norms are contaminated by the inclusion of subjects who may have preclinical disease," Dr. Morris said.

Comparative testing or the report of a close companion could detect change in a high-functioning individual, but the majority of people never undergo neuropsychological testing unless a problem is suspected.

Biomarkers, on the other hand, appear to predict decline very objectively. "People [with altered biomarkers] should be considered the real treatment target, so we are not focusing all of our efforts on curing people who already have the symptoms of Alzheimer’s dementia, but rather on trying to prevent those symptoms from appearing," Dr. Morris said.

DIAN is funded by a multiple-year research grant from the National Institute on Aging. Dr. Morris declared that he has served as a consultant, received speaking honoraria, and served as an investigator in industry-sponsored clinical trials from multiple drug companies. Dr. Reiman said he has no relevant personal financial disclosures.

Jeff Evans contributed to this report.

Studies that use Alzheimer’s disease biomarkers to predict the clinical benefit of investigational treatments in families with autosomal-dominant mutations that cause early-onset disease could prove to be the saving grace for researchers who have seen one treatment after another fail in trials of symptomatic patients.

Two research projects – the Alzheimer’s Prevention Initiative (API) and the Dominantly Inherited Alzheimer Network (DIAN) – hope to provide biomarker evidence that companies can use to test promising presymptomatic treatments without having to conduct costly long-term trials in individuals who might not develop symptoms for many years.

"In order to approve a treatment based on biomarker, the regulatory agencies said: ‘Show us with demonstrably effective, clinically proven treatments that the treatments’ effects on the biomarker predict a clinical benefit.’ Well that sounds like a Catch-22. If we had clinically proven prevention therapies, what do we need a biomarker for?" said Dr. Eric Reiman, who is leading the API with Dr. Pierre Tariot at the Banner Alzheimer’s Institute in Phoenix.

"So, in the last few years, we’ve modified our approach to not only help provide the scientific means to evaluate the range of promising presymptomatic treatments as rapidly as possible, but to help provide the financial incentives – that is, the accelerated regulatory approval pathway needed to encourage everybody to go out and start studying their promising prevention therapies and everybody using biomarkers."

The API is raising funds from philanthropic organizations, industry, and federal grants to study presymptomatic anti-amyloid treatments in people who are at high imminent risk for developing symptoms of Alzheimer’s disease (AD), based on their genetic background and age.

Fortunately, the largest extended family of individuals in the world who carry an autosomal-dominant mutation in the presenilin 1 (PS1) gene – about 5,000 people – live in and around Medellín, Colombia; about one-third of them have the PS1 mutation. Because mutation carriers are destined to develop symptoms of AD, typically around 45 years of age, the risk-to-benefit ratio for treatment in this population is different from the ratio for other individuals at lower risk for AD, said Dr. Reiman, executive director of the Banner Alzheimer’s Institute and director of the Arizona Alzheimer’s Consortium.

In collaboration with Colombian neurologist Dr. Francisco Lopera, who brought the extended family to the attention of researchers, the API is enrolling about 2,000 members of this extended family who are within 10 years of their expected age of onset in a prevention trial. Investigators are currently obtaining baseline data with cognitive tests; volumetric MRI; ¹⁸fluorodeoxyglucose and amyloid PET imaging; and cerebrospinal fluid measurements of beta-amyloid 42 (Abeta 42), tau, and total tau, he said.

In the trial, about 150 PS1 carriers will receive an anti-amyloid treatment and about 150 noncarriers will get a placebo. The anti-amyloid treatment to be given in the trial has not yet been determined, according to Dr. Reiman.

"We’ll be pretty unique in having the adequate sample size to show not just the biomarker effects, but within 3 or 4 years, the clinical effect as they’re close to their age of onset," he said in an interview.

Dr. Reiman added that "if there’s no effect on the biomarkers after 2 years in the right direction, [we will] declare futility and give these people at highest imminent risk access to the next most promising treatment. If however, they do budge in the right direction, [we will] continue to follow them a little bit longer to see if it slows even subtle memory decline. And if it does, I have a feeling that may be enough evidence for regulatory agencies to consider using biomarkers under their accelerated approval mechanism in other [Alzheimer’s disease] populations."

A second study in the United States will create a national registry of 20,000-50,000 people to gather a large number of people with one or two copies of the apolipoprotein E (APOE) e4 gene, which substantially increases an individual’s risk for late-onset Alzheimer’s disease. About 400 homozygous (and possibly heterozygous) APOE e4 carriers, who begin to have symptoms at a mean age of 68 years, will be enrolled in a prevention trial with of an anti-amyloid treatment; this therapy might not be the same as the one used in the trial of PS1 carriers, Dr. Reiman said.

Investigators are hoping to start one or both studies in 2012.

Study results from DIAN will be complementary to those from the API in many ways. DIAN is a 6-year, cross-sectional, longitudinal study of families who carry an autosomal dominant mutation in one of the three genes that affect amyloid processing: amyloid precursor protein (APP), PS1, and presenilin 2 (PS2).

Preliminary findings from the first analysis of DIAN indicate that the pathologic changes of AD might begin as early as 20 years before the expected onset of disease in mutation carriers.

The use of PET and cerebrospinal fluid biomarkers of beta-amyloid and tau protein in these individuals might allow researchers to select enriched pools of subjects for the testing of potential drug treatments, and, someday, allow clinicians to target patients with incipient disease for preventive treatment, Dr. John Morris said at the International Conference on Alzheimer’s and Parkinson’s Diseases in Barcelona.

"I have not yet had sufficient sample size or follow-up to predict this completely," said Dr. Morris, DIAN’s principal investigator. "However, I think there are data both from Europe and the U.S. showing that low beta-amyloid 42 [Abeta 42] and high tau in the cerebrospinal fluid together will reach a hazard ratio of 5.2 for becoming demented within 3-4 years. We are just beginning to get these same data for amyloid imaging and the hazard ratio is about the same."

Dr. Morris, professor of neurology at Washington University in St. Louis, said the DIAN study hopes to recruit 400 subjects who are the children of a parent with one of the gene mutations. He expects that about half the group will carry one of the mutations, while the other half will be unaffected siblings, who will serve as controls. The study involves 10 research institutions in the United States, United Kingdom, and Australia.

Each participant will undergo genetic analysis and the same periodic assessments, including cognitive and clinical testing; brain imaging with Pittsburgh compound B, which binds to Abeta 42 plaques; ¹⁸fluorodeoxyglucose PET; MRI; and lumbar punctures to test cerebrospinal fluid levels of Abeta 42 and tau. If subjects die during the study, their brains will be autopsied.

"The goals are to try and determine when the pathologic process begins in asymptomatic mutation carriers," Dr. Morris said. "We know, based on the parent’s age of onset, approximately when these carriers will become symptomatic. We want to see the changes, the rates of these changes, and determine to what extent the changes resemble those seen in sporadic Alzheimer’s."

As of last fall, DIAN had collected 106 volunteers, Dr. Morris said. About 70% of those are asymptomatic carriers, with an average age of 37 years, although that varies from 19 to 56 years. The average age of parental onset of dementia symptoms is 47 years, "so we have these folks an average of 10 years before their expected age of onset."

The PS1 mutation is the most common in the group, occurring in 75%; PS2 is present in 10%, and the APP mutation, in 15%.

About 90% of DIAN participants do not know whether they are a carrier of one of the mutations or not, and most do not want to know their status, Dr. Morris said in an interview. If DIAN researchers decide to conduct a clinical trial of an anti-amyloid treatment in the participants who carry a mutation, they will have to figure out a way to ensure that noncarriers receive a placebo without revealing mutation status to participants who do not want to know – and thereby not risk potential harm to the noncarriers from the treatment.

Comparing the carriers with the noncarriers, the study’s "very preliminary" data indicate that cognitive decline begins as early as 10 years before the expected onset of symptoms, while neuropathologic changes start up to 20 years before.

But scores on the Mini-Mental State Exam (MMSE) for noncarrier siblings of these volunteers "have remained very clearly at 30," which is a normal score, Dr. Morris said. The noncarriers also had normal scores on the Clinical Dementia Rating Scale sum of boxes (CDR-SOB), another test used to identify Alzheimer’s-related cognitive changes.

This was not the case "for carriers, in whom we begin to see declines in the MMSE and the CDR about 10 years before the expected age of onset," Dr. Morris said.

The cerebrospinal fluid biomarkers followed a similar pattern. A decrease in spinal fluid Abeta 42 suggests that the protein is aggregating somewhere else in the body – probably in the characteristic brain plaques. These changes could be seen in carriers 20 years before the expected age of onset. Tau protein levels in the cerebrospinal fluid (CSF) of carriers begin to rise around 20 years before the onset of symptoms, "with a clear acceleration at the time they are changing from asymptomatic to symptomatic," he said.

However, noncarriers have stable levels of both proteins in the CSF at the same ages.

Imaging in the precuneus and caudate with Pittsburgh compound B shows no Abeta 42 accumulation in noncarriers, but in carriers, the protein begins to appear in those regions about the same time that the CSF biomarkers start to change – 20 years before the expected appearance of symptomatic disease.

If these findings can be confirmed, they prove the existence of a long prodromal stage in subjects who are genetically destined to develop AD. This has several important applications in both drug research and potential treatment, Dr. Morris noted.

First, the neuropsychological testing scores currently in use, which define normal cognitive function, might be incorrect, because they could be based on cohorts that included individuals who had already experienced cognitive decline, but still fell within the "normal" range.

To illustrate this problem, Dr. Morris referred to the cognitive testing of two subjects. One began with cognitive functioning at the mean of normal, while the other began at two standard deviations above the mean. Over a period of years, the first person remained stable at the mean, while the second declined to the mean – showing that this subject was experiencing significant cognitive decline on an individual basis, while still being considered cognitively normal. The patient quickly developed mild cognitive impairment and then AD.

"This interferes with the ability to detect very early stages of symptomatic Alzheimer’s based on neuropsychological testing, because the test norms are contaminated by the inclusion of subjects who may have preclinical disease," Dr. Morris said.

Comparative testing or the report of a close companion could detect change in a high-functioning individual, but the majority of people never undergo neuropsychological testing unless a problem is suspected.

Biomarkers, on the other hand, appear to predict decline very objectively. "People [with altered biomarkers] should be considered the real treatment target, so we are not focusing all of our efforts on curing people who already have the symptoms of Alzheimer’s dementia, but rather on trying to prevent those symptoms from appearing," Dr. Morris said.

DIAN is funded by a multiple-year research grant from the National Institute on Aging. Dr. Morris declared that he has served as a consultant, received speaking honoraria, and served as an investigator in industry-sponsored clinical trials from multiple drug companies. Dr. Reiman said he has no relevant personal financial disclosures.

Jeff Evans contributed to this report.

Studies that use Alzheimer’s disease biomarkers to predict the clinical benefit of investigational treatments in families with autosomal-dominant mutations that cause early-onset disease could prove to be the saving grace for researchers who have seen one treatment after another fail in trials of symptomatic patients.

Two research projects – the Alzheimer’s Prevention Initiative (API) and the Dominantly Inherited Alzheimer Network (DIAN) – hope to provide biomarker evidence that companies can use to test promising presymptomatic treatments without having to conduct costly long-term trials in individuals who might not develop symptoms for many years.

"In order to approve a treatment based on biomarker, the regulatory agencies said: ‘Show us with demonstrably effective, clinically proven treatments that the treatments’ effects on the biomarker predict a clinical benefit.’ Well that sounds like a Catch-22. If we had clinically proven prevention therapies, what do we need a biomarker for?" said Dr. Eric Reiman, who is leading the API with Dr. Pierre Tariot at the Banner Alzheimer’s Institute in Phoenix.

"So, in the last few years, we’ve modified our approach to not only help provide the scientific means to evaluate the range of promising presymptomatic treatments as rapidly as possible, but to help provide the financial incentives – that is, the accelerated regulatory approval pathway needed to encourage everybody to go out and start studying their promising prevention therapies and everybody using biomarkers."

The API is raising funds from philanthropic organizations, industry, and federal grants to study presymptomatic anti-amyloid treatments in people who are at high imminent risk for developing symptoms of Alzheimer’s disease (AD), based on their genetic background and age.

Fortunately, the largest extended family of individuals in the world who carry an autosomal-dominant mutation in the presenilin 1 (PS1) gene – about 5,000 people – live in and around Medellín, Colombia; about one-third of them have the PS1 mutation. Because mutation carriers are destined to develop symptoms of AD, typically around 45 years of age, the risk-to-benefit ratio for treatment in this population is different from the ratio for other individuals at lower risk for AD, said Dr. Reiman, executive director of the Banner Alzheimer’s Institute and director of the Arizona Alzheimer’s Consortium.

In collaboration with Colombian neurologist Dr. Francisco Lopera, who brought the extended family to the attention of researchers, the API is enrolling about 2,000 members of this extended family who are within 10 years of their expected age of onset in a prevention trial. Investigators are currently obtaining baseline data with cognitive tests; volumetric MRI; ¹⁸fluorodeoxyglucose and amyloid PET imaging; and cerebrospinal fluid measurements of beta-amyloid 42 (Abeta 42), tau, and total tau, he said.

In the trial, about 150 PS1 carriers will receive an anti-amyloid treatment and about 150 noncarriers will get a placebo. The anti-amyloid treatment to be given in the trial has not yet been determined, according to Dr. Reiman.

"We’ll be pretty unique in having the adequate sample size to show not just the biomarker effects, but within 3 or 4 years, the clinical effect as they’re close to their age of onset," he said in an interview.

Dr. Reiman added that "if there’s no effect on the biomarkers after 2 years in the right direction, [we will] declare futility and give these people at highest imminent risk access to the next most promising treatment. If however, they do budge in the right direction, [we will] continue to follow them a little bit longer to see if it slows even subtle memory decline. And if it does, I have a feeling that may be enough evidence for regulatory agencies to consider using biomarkers under their accelerated approval mechanism in other [Alzheimer’s disease] populations."

A second study in the United States will create a national registry of 20,000-50,000 people to gather a large number of people with one or two copies of the apolipoprotein E (APOE) e4 gene, which substantially increases an individual’s risk for late-onset Alzheimer’s disease. About 400 homozygous (and possibly heterozygous) APOE e4 carriers, who begin to have symptoms at a mean age of 68 years, will be enrolled in a prevention trial with of an anti-amyloid treatment; this therapy might not be the same as the one used in the trial of PS1 carriers, Dr. Reiman said.

Investigators are hoping to start one or both studies in 2012.

Study results from DIAN will be complementary to those from the API in many ways. DIAN is a 6-year, cross-sectional, longitudinal study of families who carry an autosomal dominant mutation in one of the three genes that affect amyloid processing: amyloid precursor protein (APP), PS1, and presenilin 2 (PS2).

Preliminary findings from the first analysis of DIAN indicate that the pathologic changes of AD might begin as early as 20 years before the expected onset of disease in mutation carriers.

The use of PET and cerebrospinal fluid biomarkers of beta-amyloid and tau protein in these individuals might allow researchers to select enriched pools of subjects for the testing of potential drug treatments, and, someday, allow clinicians to target patients with incipient disease for preventive treatment, Dr. John Morris said at the International Conference on Alzheimer’s and Parkinson’s Diseases in Barcelona.

"I have not yet had sufficient sample size or follow-up to predict this completely," said Dr. Morris, DIAN’s principal investigator. "However, I think there are data both from Europe and the U.S. showing that low beta-amyloid 42 [Abeta 42] and high tau in the cerebrospinal fluid together will reach a hazard ratio of 5.2 for becoming demented within 3-4 years. We are just beginning to get these same data for amyloid imaging and the hazard ratio is about the same."

Dr. Morris, professor of neurology at Washington University in St. Louis, said the DIAN study hopes to recruit 400 subjects who are the children of a parent with one of the gene mutations. He expects that about half the group will carry one of the mutations, while the other half will be unaffected siblings, who will serve as controls. The study involves 10 research institutions in the United States, United Kingdom, and Australia.

Each participant will undergo genetic analysis and the same periodic assessments, including cognitive and clinical testing; brain imaging with Pittsburgh compound B, which binds to Abeta 42 plaques; ¹⁸fluorodeoxyglucose PET; MRI; and lumbar punctures to test cerebrospinal fluid levels of Abeta 42 and tau. If subjects die during the study, their brains will be autopsied.

"The goals are to try and determine when the pathologic process begins in asymptomatic mutation carriers," Dr. Morris said. "We know, based on the parent’s age of onset, approximately when these carriers will become symptomatic. We want to see the changes, the rates of these changes, and determine to what extent the changes resemble those seen in sporadic Alzheimer’s."

As of last fall, DIAN had collected 106 volunteers, Dr. Morris said. About 70% of those are asymptomatic carriers, with an average age of 37 years, although that varies from 19 to 56 years. The average age of parental onset of dementia symptoms is 47 years, "so we have these folks an average of 10 years before their expected age of onset."

The PS1 mutation is the most common in the group, occurring in 75%; PS2 is present in 10%, and the APP mutation, in 15%.

About 90% of DIAN participants do not know whether they are a carrier of one of the mutations or not, and most do not want to know their status, Dr. Morris said in an interview. If DIAN researchers decide to conduct a clinical trial of an anti-amyloid treatment in the participants who carry a mutation, they will have to figure out a way to ensure that noncarriers receive a placebo without revealing mutation status to participants who do not want to know – and thereby not risk potential harm to the noncarriers from the treatment.

Comparing the carriers with the noncarriers, the study’s "very preliminary" data indicate that cognitive decline begins as early as 10 years before the expected onset of symptoms, while neuropathologic changes start up to 20 years before.

But scores on the Mini-Mental State Exam (MMSE) for noncarrier siblings of these volunteers "have remained very clearly at 30," which is a normal score, Dr. Morris said. The noncarriers also had normal scores on the Clinical Dementia Rating Scale sum of boxes (CDR-SOB), another test used to identify Alzheimer’s-related cognitive changes.

This was not the case "for carriers, in whom we begin to see declines in the MMSE and the CDR about 10 years before the expected age of onset," Dr. Morris said.

The cerebrospinal fluid biomarkers followed a similar pattern. A decrease in spinal fluid Abeta 42 suggests that the protein is aggregating somewhere else in the body – probably in the characteristic brain plaques. These changes could be seen in carriers 20 years before the expected age of onset. Tau protein levels in the cerebrospinal fluid (CSF) of carriers begin to rise around 20 years before the onset of symptoms, "with a clear acceleration at the time they are changing from asymptomatic to symptomatic," he said.

However, noncarriers have stable levels of both proteins in the CSF at the same ages.

Imaging in the precuneus and caudate with Pittsburgh compound B shows no Abeta 42 accumulation in noncarriers, but in carriers, the protein begins to appear in those regions about the same time that the CSF biomarkers start to change – 20 years before the expected appearance of symptomatic disease.

If these findings can be confirmed, they prove the existence of a long prodromal stage in subjects who are genetically destined to develop AD. This has several important applications in both drug research and potential treatment, Dr. Morris noted.

First, the neuropsychological testing scores currently in use, which define normal cognitive function, might be incorrect, because they could be based on cohorts that included individuals who had already experienced cognitive decline, but still fell within the "normal" range.

To illustrate this problem, Dr. Morris referred to the cognitive testing of two subjects. One began with cognitive functioning at the mean of normal, while the other began at two standard deviations above the mean. Over a period of years, the first person remained stable at the mean, while the second declined to the mean – showing that this subject was experiencing significant cognitive decline on an individual basis, while still being considered cognitively normal. The patient quickly developed mild cognitive impairment and then AD.

"This interferes with the ability to detect very early stages of symptomatic Alzheimer’s based on neuropsychological testing, because the test norms are contaminated by the inclusion of subjects who may have preclinical disease," Dr. Morris said.

Comparative testing or the report of a close companion could detect change in a high-functioning individual, but the majority of people never undergo neuropsychological testing unless a problem is suspected.

Biomarkers, on the other hand, appear to predict decline very objectively. "People [with altered biomarkers] should be considered the real treatment target, so we are not focusing all of our efforts on curing people who already have the symptoms of Alzheimer’s dementia, but rather on trying to prevent those symptoms from appearing," Dr. Morris said.

DIAN is funded by a multiple-year research grant from the National Institute on Aging. Dr. Morris declared that he has served as a consultant, received speaking honoraria, and served as an investigator in industry-sponsored clinical trials from multiple drug companies. Dr. Reiman said he has no relevant personal financial disclosures.

Jeff Evans contributed to this report.

Studies that use Alzheimer’s disease biomarkers to predict the clinical benefit of investigational treatments in families with autosomal-dominant mutations that cause early-onset disease could prove to be the saving grace for researchers who have seen one treatment after another fail in trials of symptomatic patients.

Two research projects – the Alzheimer’s Prevention Initiative (API) and the Dominantly Inherited Alzheimer Network (DIAN) – hope to provide biomarker evidence that companies can use to test promising presymptomatic treatments without having to conduct costly long-term trials in individuals who might not develop symptoms for many years.

"In order to approve a treatment based on biomarker, the regulatory agencies said: ‘Show us with demonstrably effective, clinically proven treatments that the treatments’ effects on the biomarker predict a clinical benefit.’ Well that sounds like a Catch-22. If we had clinically proven prevention therapies, what do we need a biomarker for?" said Dr. Eric Reiman, who is leading the API with Dr. Pierre Tariot at the Banner Alzheimer’s Institute in Phoenix.

"So, in the last few years, we’ve modified our approach to not only help provide the scientific means to evaluate the range of promising presymptomatic treatments as rapidly as possible, but to help provide the financial incentives – that is, the accelerated regulatory approval pathway needed to encourage everybody to go out and start studying their promising prevention therapies and everybody using biomarkers."

The API is raising funds from philanthropic organizations, industry, and federal grants to study presymptomatic anti-amyloid treatments in people who are at high imminent risk for developing symptoms of Alzheimer’s disease (AD), based on their genetic background and age.

Fortunately, the largest extended family of individuals in the world who carry an autosomal-dominant mutation in the presenilin 1 (PS1) gene – about 5,000 people – live in and around Medellín, Colombia; about one-third of them have the PS1 mutation. Because mutation carriers are destined to develop symptoms of AD, typically around 45 years of age, the risk-to-benefit ratio for treatment in this population is different from the ratio for other individuals at lower risk for AD, said Dr. Reiman, executive director of the Banner Alzheimer’s Institute and director of the Arizona Alzheimer’s Consortium.

In collaboration with Colombian neurologist Dr. Francisco Lopera, who brought the extended family to the attention of researchers, the API is enrolling about 2,000 members of this extended family who are within 10 years of their expected age of onset in a prevention trial. Investigators are currently obtaining baseline data with cognitive tests; volumetric MRI; ¹⁸fluorodeoxyglucose and amyloid PET imaging; and cerebrospinal fluid measurements of beta-amyloid 42 (Abeta 42), tau, and total tau, he said.

In the trial, about 150 PS1 carriers will receive an anti-amyloid treatment and about 150 noncarriers will get a placebo. The anti-amyloid treatment to be given in the trial has not yet been determined, according to Dr. Reiman.

"We’ll be pretty unique in having the adequate sample size to show not just the biomarker effects, but within 3 or 4 years, the clinical effect as they’re close to their age of onset," he said in an interview.

Dr. Reiman added that "if there’s no effect on the biomarkers after 2 years in the right direction, [we will] declare futility and give these people at highest imminent risk access to the next most promising treatment. If however, they do budge in the right direction, [we will] continue to follow them a little bit longer to see if it slows even subtle memory decline. And if it does, I have a feeling that may be enough evidence for regulatory agencies to consider using biomarkers under their accelerated approval mechanism in other [Alzheimer’s disease] populations."

A second study in the United States will create a national registry of 20,000-50,000 people to gather a large number of people with one or two copies of the apolipoprotein E (APOE) e4 gene, which substantially increases an individual’s risk for late-onset Alzheimer’s disease. About 400 homozygous (and possibly heterozygous) APOE e4 carriers, who begin to have symptoms at a mean age of 68 years, will be enrolled in a prevention trial with of an anti-amyloid treatment; this therapy might not be the same as the one used in the trial of PS1 carriers, Dr. Reiman said.

Investigators are hoping to start one or both studies in 2012.

Study results from DIAN will be complementary to those from the API in many ways. DIAN is a 6-year, cross-sectional, longitudinal study of families who carry an autosomal dominant mutation in one of the three genes that affect amyloid processing: amyloid precursor protein (APP), PS1, and presenilin 2 (PS2).

Preliminary findings from the first analysis of DIAN indicate that the pathologic changes of AD might begin as early as 20 years before the expected onset of disease in mutation carriers.

The use of PET and cerebrospinal fluid biomarkers of beta-amyloid and tau protein in these individuals might allow researchers to select enriched pools of subjects for the testing of potential drug treatments, and, someday, allow clinicians to target patients with incipient disease for preventive treatment, Dr. John Morris said at the International Conference on Alzheimer’s and Parkinson’s Diseases in Barcelona.

"I have not yet had sufficient sample size or follow-up to predict this completely," said Dr. Morris, DIAN’s principal investigator. "However, I think there are data both from Europe and the U.S. showing that low beta-amyloid 42 [Abeta 42] and high tau in the cerebrospinal fluid together will reach a hazard ratio of 5.2 for becoming demented within 3-4 years. We are just beginning to get these same data for amyloid imaging and the hazard ratio is about the same."

Dr. Morris, professor of neurology at Washington University in St. Louis, said the DIAN study hopes to recruit 400 subjects who are the children of a parent with one of the gene mutations. He expects that about half the group will carry one of the mutations, while the other half will be unaffected siblings, who will serve as controls. The study involves 10 research institutions in the United States, United Kingdom, and Australia.

Each participant will undergo genetic analysis and the same periodic assessments, including cognitive and clinical testing; brain imaging with Pittsburgh compound B, which binds to Abeta 42 plaques; ¹⁸fluorodeoxyglucose PET; MRI; and lumbar punctures to test cerebrospinal fluid levels of Abeta 42 and tau. If subjects die during the study, their brains will be autopsied.

"The goals are to try and determine when the pathologic process begins in asymptomatic mutation carriers," Dr. Morris said. "We know, based on the parent’s age of onset, approximately when these carriers will become symptomatic. We want to see the changes, the rates of these changes, and determine to what extent the changes resemble those seen in sporadic Alzheimer’s."

As of last fall, DIAN had collected 106 volunteers, Dr. Morris said. About 70% of those are asymptomatic carriers, with an average age of 37 years, although that varies from 19 to 56 years. The average age of parental onset of dementia symptoms is 47 years, "so we have these folks an average of 10 years before their expected age of onset."

The PS1 mutation is the most common in the group, occurring in 75%; PS2 is present in 10%, and the APP mutation, in 15%.

About 90% of DIAN participants do not know whether they are a carrier of one of the mutations or not, and most do not want to know their status, Dr. Morris said in an interview. If DIAN researchers decide to conduct a clinical trial of an anti-amyloid treatment in the participants who carry a mutation, they will have to figure out a way to ensure that noncarriers receive a placebo without revealing mutation status to participants who do not want to know – and thereby not risk potential harm to the noncarriers from the treatment.

Comparing the carriers with the noncarriers, the study’s "very preliminary" data indicate that cognitive decline begins as early as 10 years before the expected onset of symptoms, while neuropathologic changes start up to 20 years before.

But scores on the Mini-Mental State Exam (MMSE) for noncarrier siblings of these volunteers "have remained very clearly at 30," which is a normal score, Dr. Morris said. The noncarriers also had normal scores on the Clinical Dementia Rating Scale sum of boxes (CDR-SOB), another test used to identify Alzheimer’s-related cognitive changes.

This was not the case "for carriers, in whom we begin to see declines in the MMSE and the CDR about 10 years before the expected age of onset," Dr. Morris said.

The cerebrospinal fluid biomarkers followed a similar pattern. A decrease in spinal fluid Abeta 42 suggests that the protein is aggregating somewhere else in the body – probably in the characteristic brain plaques. These changes could be seen in carriers 20 years before the expected age of onset. Tau protein levels in the cerebrospinal fluid (CSF) of carriers begin to rise around 20 years before the onset of symptoms, "with a clear acceleration at the time they are changing from asymptomatic to symptomatic," he said.

However, noncarriers have stable levels of both proteins in the CSF at the same ages.

Imaging in the precuneus and caudate with Pittsburgh compound B shows no Abeta 42 accumulation in noncarriers, but in carriers, the protein begins to appear in those regions about the same time that the CSF biomarkers start to change – 20 years before the expected appearance of symptomatic disease.

If these findings can be confirmed, they prove the existence of a long prodromal stage in subjects who are genetically destined to develop AD. This has several important applications in both drug research and potential treatment, Dr. Morris noted.

First, the neuropsychological testing scores currently in use, which define normal cognitive function, might be incorrect, because they could be based on cohorts that included individuals who had already experienced cognitive decline, but still fell within the "normal" range.

To illustrate this problem, Dr. Morris referred to the cognitive testing of two subjects. One began with cognitive functioning at the mean of normal, while the other began at two standard deviations above the mean. Over a period of years, the first person remained stable at the mean, while the second declined to the mean – showing that this subject was experiencing significant cognitive decline on an individual basis, while still being considered cognitively normal. The patient quickly developed mild cognitive impairment and then AD.

"This interferes with the ability to detect very early stages of symptomatic Alzheimer’s based on neuropsychological testing, because the test norms are contaminated by the inclusion of subjects who may have preclinical disease," Dr. Morris said.

Comparative testing or the report of a close companion could detect change in a high-functioning individual, but the majority of people never undergo neuropsychological testing unless a problem is suspected.

Biomarkers, on the other hand, appear to predict decline very objectively. "People [with altered biomarkers] should be considered the real treatment target, so we are not focusing all of our efforts on curing people who already have the symptoms of Alzheimer’s dementia, but rather on trying to prevent those symptoms from appearing," Dr. Morris said.

DIAN is funded by a multiple-year research grant from the National Institute on Aging. Dr. Morris declared that he has served as a consultant, received speaking honoraria, and served as an investigator in industry-sponsored clinical trials from multiple drug companies. Dr. Reiman said he has no relevant personal financial disclosures.

Jeff Evans contributed to this report.

MADRID – There are no easy choices for women who present with mood disorders during pregnancy – or for the physicians who treat them.

The decision to treat prenatal depression or anxiety is not to be taken lightly, but often must be considered, despite a relative dearth of data supporting or refuting drug safety during pregnancy, Dr. Shari I. Lusskin said at the World Conference on Women’s Mental Health.

"There are data, but not great data," said Dr. Lusskin, director of reproductive psychiatry at the NYU Langone Medical Center, New York. "We will never have 10,000 patients taking medication compared to 10,000 not taking it, compared to a control group that is not depressed or anxious, nor will we have years of follow-up data on their children."

The data that do exist are mostly comprised of case series, which are small and lack controls. "When you see a negative study [about the effect of treating mental disorders in a pregnant woman], keep in mind that there is often a lack of information about the mother’s diagnosis. Reports of smoking and substance abuse are notoriously unreliable," and can’t be accounted for in the results, she said. "We also know nothing about the mother’s body mass index, which is associated with many fetal complications that have nothing to do with drug exposure. And different studies use different comparison scales – you can’t compare apples and oranges."

The biggest exception is sodium valproate, an anticonvulsant also used to treat mood disorders, Dr. Lusskin said. The ongoing Neurodevelopmental Effects of Antiepileptic Drugs (NEAD) study has found in utero exposure to be associated with an increase in birth defects, and with cognitive problems in 3-year-olds whose mothers took it during pregnancy.

The uncertainty of treatment leaves pregnant women and their physicians to weigh the risks of psychotropic medications against the risks of untreated mood disorders. "There is no such thing as nonexposure," Dr. Lusskin said. If the mother is not treated, "the fetus is going to be exposed to the mother’s illness, which can create phenotypic changes with lifelong effects. If the mother is treated inadequately, the fetus will be exposed to both the effects of the illness and the medication. And if the mother is treated to remission, with the medication titrated to her response, medication exposure can be at least limited," while the new mother becomes healthy enough to give her baby the best possible care.

The biggest barrier to treating mental illness during pregnancy is fear of fetal harm: teratogenicity, neonatal complications from drug exposure, and long-term neurodevelopmental effects. But these risks must be considered in light of real world experience – not just based on numbers from a study, Dr. Lusskin said. "Any risk of impairment has to be compared to the background risk. The background risk of a birth defect is 2%-4%. If a drug increases this risk in a clinically meaningful way, it has to be over and above this background rate."

Even a substantial increase in a rare birth defect can be misleading, she said. For instance, Ebstein’s anomaly is a heart defect that occurs in 1 in 20,000 births. "Lithium is said to increase this rate to about 1 in 2,000 births. But this is still way below the expected background rate of birth defects. Risks are relevant in terms of their relativity – the absolute risk is just quoting a figure," Dr. Lusskin said.

But untreated mental illness poses its own risk. Babies exposed in utero to the chronic stress hormones associated with anxiety and depressive disorders might become phenotypically programmed, prone themselves to early childhood behavioral problems and, in later life, to mental illness. "The fetal programming hypothesis is the interaction between the baby’s genetics and the environmental exposure in utero, and it’s mediated by the sex of the fetus and the timing of exposure," Dr. Lusskin said. "This can actually alter the development of the fetus during particularly sensitive periods, with a permanent effect on its phenotype."

The risks do not stop with delivery, however. If mothers or physicians hesitate to treat during breastfeeding, mood disorders can persist and even escalate, interfering with mother-child bonding and even contributing to real risks for the baby’s physical well-being.

The best course for a physician is to pick a medication that works for the individual patient, and titrate the dose to maintain euthymia. "Make the diagnosis, pick the best medication, and treat to remission – which means you will be changing the dose during pregnancy. Untreated mental illness is not a benign condition for either mother or baby," she said.

Dr. Lusskin said she consults for the nonprofit drug safety database www.reprotox.org and has authored a chapter in uptodate.com, an Internet-based textbook on the use of medication in pregnancy and lactation.

MADRID – There are no easy choices for women who present with mood disorders during pregnancy – or for the physicians who treat them.

The decision to treat prenatal depression or anxiety is not to be taken lightly, but often must be considered, despite a relative dearth of data supporting or refuting drug safety during pregnancy, Dr. Shari I. Lusskin said at the World Conference on Women’s Mental Health.

"There are data, but not great data," said Dr. Lusskin, director of reproductive psychiatry at the NYU Langone Medical Center, New York. "We will never have 10,000 patients taking medication compared to 10,000 not taking it, compared to a control group that is not depressed or anxious, nor will we have years of follow-up data on their children."

The data that do exist are mostly comprised of case series, which are small and lack controls. "When you see a negative study [about the effect of treating mental disorders in a pregnant woman], keep in mind that there is often a lack of information about the mother’s diagnosis. Reports of smoking and substance abuse are notoriously unreliable," and can’t be accounted for in the results, she said. "We also know nothing about the mother’s body mass index, which is associated with many fetal complications that have nothing to do with drug exposure. And different studies use different comparison scales – you can’t compare apples and oranges."

The biggest exception is sodium valproate, an anticonvulsant also used to treat mood disorders, Dr. Lusskin said. The ongoing Neurodevelopmental Effects of Antiepileptic Drugs (NEAD) study has found in utero exposure to be associated with an increase in birth defects, and with cognitive problems in 3-year-olds whose mothers took it during pregnancy.

The uncertainty of treatment leaves pregnant women and their physicians to weigh the risks of psychotropic medications against the risks of untreated mood disorders. "There is no such thing as nonexposure," Dr. Lusskin said. If the mother is not treated, "the fetus is going to be exposed to the mother’s illness, which can create phenotypic changes with lifelong effects. If the mother is treated inadequately, the fetus will be exposed to both the effects of the illness and the medication. And if the mother is treated to remission, with the medication titrated to her response, medication exposure can be at least limited," while the new mother becomes healthy enough to give her baby the best possible care.

The biggest barrier to treating mental illness during pregnancy is fear of fetal harm: teratogenicity, neonatal complications from drug exposure, and long-term neurodevelopmental effects. But these risks must be considered in light of real world experience – not just based on numbers from a study, Dr. Lusskin said. "Any risk of impairment has to be compared to the background risk. The background risk of a birth defect is 2%-4%. If a drug increases this risk in a clinically meaningful way, it has to be over and above this background rate."

Even a substantial increase in a rare birth defect can be misleading, she said. For instance, Ebstein’s anomaly is a heart defect that occurs in 1 in 20,000 births. "Lithium is said to increase this rate to about 1 in 2,000 births. But this is still way below the expected background rate of birth defects. Risks are relevant in terms of their relativity – the absolute risk is just quoting a figure," Dr. Lusskin said.

But untreated mental illness poses its own risk. Babies exposed in utero to the chronic stress hormones associated with anxiety and depressive disorders might become phenotypically programmed, prone themselves to early childhood behavioral problems and, in later life, to mental illness. "The fetal programming hypothesis is the interaction between the baby’s genetics and the environmental exposure in utero, and it’s mediated by the sex of the fetus and the timing of exposure," Dr. Lusskin said. "This can actually alter the development of the fetus during particularly sensitive periods, with a permanent effect on its phenotype."

The risks do not stop with delivery, however. If mothers or physicians hesitate to treat during breastfeeding, mood disorders can persist and even escalate, interfering with mother-child bonding and even contributing to real risks for the baby’s physical well-being.

The best course for a physician is to pick a medication that works for the individual patient, and titrate the dose to maintain euthymia. "Make the diagnosis, pick the best medication, and treat to remission – which means you will be changing the dose during pregnancy. Untreated mental illness is not a benign condition for either mother or baby," she said.

Dr. Lusskin said she consults for the nonprofit drug safety database www.reprotox.org and has authored a chapter in uptodate.com, an Internet-based textbook on the use of medication in pregnancy and lactation.

MADRID – There are no easy choices for women who present with mood disorders during pregnancy – or for the physicians who treat them.

The decision to treat prenatal depression or anxiety is not to be taken lightly, but often must be considered, despite a relative dearth of data supporting or refuting drug safety during pregnancy, Dr. Shari I. Lusskin said at the World Conference on Women’s Mental Health.

"There are data, but not great data," said Dr. Lusskin, director of reproductive psychiatry at the NYU Langone Medical Center, New York. "We will never have 10,000 patients taking medication compared to 10,000 not taking it, compared to a control group that is not depressed or anxious, nor will we have years of follow-up data on their children."

The data that do exist are mostly comprised of case series, which are small and lack controls. "When you see a negative study [about the effect of treating mental disorders in a pregnant woman], keep in mind that there is often a lack of information about the mother’s diagnosis. Reports of smoking and substance abuse are notoriously unreliable," and can’t be accounted for in the results, she said. "We also know nothing about the mother’s body mass index, which is associated with many fetal complications that have nothing to do with drug exposure. And different studies use different comparison scales – you can’t compare apples and oranges."

The biggest exception is sodium valproate, an anticonvulsant also used to treat mood disorders, Dr. Lusskin said. The ongoing Neurodevelopmental Effects of Antiepileptic Drugs (NEAD) study has found in utero exposure to be associated with an increase in birth defects, and with cognitive problems in 3-year-olds whose mothers took it during pregnancy.

The uncertainty of treatment leaves pregnant women and their physicians to weigh the risks of psychotropic medications against the risks of untreated mood disorders. "There is no such thing as nonexposure," Dr. Lusskin said. If the mother is not treated, "the fetus is going to be exposed to the mother’s illness, which can create phenotypic changes with lifelong effects. If the mother is treated inadequately, the fetus will be exposed to both the effects of the illness and the medication. And if the mother is treated to remission, with the medication titrated to her response, medication exposure can be at least limited," while the new mother becomes healthy enough to give her baby the best possible care.

The biggest barrier to treating mental illness during pregnancy is fear of fetal harm: teratogenicity, neonatal complications from drug exposure, and long-term neurodevelopmental effects. But these risks must be considered in light of real world experience – not just based on numbers from a study, Dr. Lusskin said. "Any risk of impairment has to be compared to the background risk. The background risk of a birth defect is 2%-4%. If a drug increases this risk in a clinically meaningful way, it has to be over and above this background rate."

Even a substantial increase in a rare birth defect can be misleading, she said. For instance, Ebstein’s anomaly is a heart defect that occurs in 1 in 20,000 births. "Lithium is said to increase this rate to about 1 in 2,000 births. But this is still way below the expected background rate of birth defects. Risks are relevant in terms of their relativity – the absolute risk is just quoting a figure," Dr. Lusskin said.

But untreated mental illness poses its own risk. Babies exposed in utero to the chronic stress hormones associated with anxiety and depressive disorders might become phenotypically programmed, prone themselves to early childhood behavioral problems and, in later life, to mental illness. "The fetal programming hypothesis is the interaction between the baby’s genetics and the environmental exposure in utero, and it’s mediated by the sex of the fetus and the timing of exposure," Dr. Lusskin said. "This can actually alter the development of the fetus during particularly sensitive periods, with a permanent effect on its phenotype."

The risks do not stop with delivery, however. If mothers or physicians hesitate to treat during breastfeeding, mood disorders can persist and even escalate, interfering with mother-child bonding and even contributing to real risks for the baby’s physical well-being.

The best course for a physician is to pick a medication that works for the individual patient, and titrate the dose to maintain euthymia. "Make the diagnosis, pick the best medication, and treat to remission – which means you will be changing the dose during pregnancy. Untreated mental illness is not a benign condition for either mother or baby," she said.

Dr. Lusskin said she consults for the nonprofit drug safety database www.reprotox.org and has authored a chapter in uptodate.com, an Internet-based textbook on the use of medication in pregnancy and lactation.

MADRID – There are no easy choices for women who present with mood disorders during pregnancy – or for the physicians who treat them.

The decision to treat prenatal depression or anxiety is not to be taken lightly, but often must be considered, despite a relative dearth of data supporting or refuting drug safety during pregnancy, Dr. Shari I. Lusskin said at the World Conference on Women’s Mental Health.

"There are data, but not great data," said Dr. Lusskin, director of reproductive psychiatry at the NYU Langone Medical Center, New York. "We will never have 10,000 patients taking medication compared to 10,000 not taking it, compared to a control group that is not depressed or anxious, nor will we have years of follow-up data on their children."

The data that do exist are mostly comprised of case series, which are small and lack controls. "When you see a negative study [about the effect of treating mental disorders in a pregnant woman], keep in mind that there is often a lack of information about the mother’s diagnosis. Reports of smoking and substance abuse are notoriously unreliable," and can’t be accounted for in the results, she said. "We also know nothing about the mother’s body mass index, which is associated with many fetal complications that have nothing to do with drug exposure. And different studies use different comparison scales – you can’t compare apples and oranges."

The biggest exception is sodium valproate, an anticonvulsant also used to treat mood disorders, Dr. Lusskin said. The ongoing Neurodevelopmental Effects of Antiepileptic Drugs (NEAD) study has found in utero exposure to be associated with an increase in birth defects, and with cognitive problems in 3-year-olds whose mothers took it during pregnancy.

The uncertainty of treatment leaves pregnant women and their physicians to weigh the risks of psychotropic medications against the risks of untreated mood disorders. "There is no such thing as nonexposure," Dr. Lusskin said. If the mother is not treated, "the fetus is going to be exposed to the mother’s illness, which can create phenotypic changes with lifelong effects. If the mother is treated inadequately, the fetus will be exposed to both the effects of the illness and the medication. And if the mother is treated to remission, with the medication titrated to her response, medication exposure can be at least limited," while the new mother becomes healthy enough to give her baby the best possible care.

The biggest barrier to treating mental illness during pregnancy is fear of fetal harm: teratogenicity, neonatal complications from drug exposure, and long-term neurodevelopmental effects. But these risks must be considered in light of real world experience – not just based on numbers from a study, Dr. Lusskin said. "Any risk of impairment has to be compared to the background risk. The background risk of a birth defect is 2%-4%. If a drug increases this risk in a clinically meaningful way, it has to be over and above this background rate."

Even a substantial increase in a rare birth defect can be misleading, she said. For instance, Ebstein’s anomaly is a heart defect that occurs in 1 in 20,000 births. "Lithium is said to increase this rate to about 1 in 2,000 births. But this is still way below the expected background rate of birth defects. Risks are relevant in terms of their relativity – the absolute risk is just quoting a figure," Dr. Lusskin said.

But untreated mental illness poses its own risk. Babies exposed in utero to the chronic stress hormones associated with anxiety and depressive disorders might become phenotypically programmed, prone themselves to early childhood behavioral problems and, in later life, to mental illness. "The fetal programming hypothesis is the interaction between the baby’s genetics and the environmental exposure in utero, and it’s mediated by the sex of the fetus and the timing of exposure," Dr. Lusskin said. "This can actually alter the development of the fetus during particularly sensitive periods, with a permanent effect on its phenotype."

The risks do not stop with delivery, however. If mothers or physicians hesitate to treat during breastfeeding, mood disorders can persist and even escalate, interfering with mother-child bonding and even contributing to real risks for the baby’s physical well-being.

The best course for a physician is to pick a medication that works for the individual patient, and titrate the dose to maintain euthymia. "Make the diagnosis, pick the best medication, and treat to remission – which means you will be changing the dose during pregnancy. Untreated mental illness is not a benign condition for either mother or baby," she said.

Dr. Lusskin said she consults for the nonprofit drug safety database www.reprotox.org and has authored a chapter in uptodate.com, an Internet-based textbook on the use of medication in pregnancy and lactation.

MADRID – There are no easy choices for women who present with mood disorders during pregnancy – or for the physicians who treat them.

The decision to treat prenatal depression or anxiety is not to be taken lightly, but often must be considered, despite a relative dearth of data supporting or refuting drug safety during pregnancy, Dr. Shari I. Lusskin said at the World Conference on Women’s Mental Health.

"There are data, but not great data," said Dr. Lusskin, director of reproductive psychiatry at the NYU Langone Medical Center, New York. "We will never have 10,000 patients taking medication compared to 10,000 not taking it, compared to a control group that is not depressed or anxious, nor will we have years of follow-up data on their children."

The data that do exist are mostly comprised of case series, which are small and lack controls. "When you see a negative study [about the effect of treating mental disorders in a pregnant woman], keep in mind that there is often a lack of information about the mother’s diagnosis. Reports of smoking and substance abuse are notoriously unreliable," and can’t be accounted for in the results, she said. "We also know nothing about the mother’s body mass index, which is associated with many fetal complications that have nothing to do with drug exposure. And different studies use different comparison scales – you can’t compare apples and oranges."

The biggest exception is sodium valproate, an anticonvulsant also used to treat mood disorders, Dr. Lusskin said. The ongoing Neurodevelopmental Effects of Antiepileptic Drugs (NEAD) study has found in utero exposure to be associated with an increase in birth defects, and with cognitive problems in 3-year-olds whose mothers took it during pregnancy.

The uncertainty of treatment leaves pregnant women and their physicians to weigh the risks of psychotropic medications against the risks of untreated mood disorders. "There is no such thing as nonexposure," Dr. Lusskin said. If the mother is not treated, "the fetus is going to be exposed to the mother’s illness, which can create phenotypic changes with lifelong effects. If the mother is treated inadequately, the fetus will be exposed to both the effects of the illness and the medication. And if the mother is treated to remission, with the medication titrated to her response, medication exposure can be at least limited," while the new mother becomes healthy enough to give her baby the best possible care.

The biggest barrier to treating mental illness during pregnancy is fear of fetal harm: teratogenicity, neonatal complications from drug exposure, and long-term neurodevelopmental effects. But these risks must be considered in light of real world experience – not just based on numbers from a study, Dr. Lusskin said. "Any risk of impairment has to be compared to the background risk. The background risk of a birth defect is 2%-4%. If a drug increases this risk in a clinically meaningful way, it has to be over and above this background rate."

Even a substantial increase in a rare birth defect can be misleading, she said. For instance, Ebstein’s anomaly is a heart defect that occurs in 1 in 20,000 births. "Lithium is said to increase this rate to about 1 in 2,000 births. But this is still way below the expected background rate of birth defects. Risks are relevant in terms of their relativity – the absolute risk is just quoting a figure," Dr. Lusskin said.

But untreated mental illness poses its own risk. Babies exposed in utero to the chronic stress hormones associated with anxiety and depressive disorders might become phenotypically programmed, prone themselves to early childhood behavioral problems and, in later life, to mental illness. "The fetal programming hypothesis is the interaction between the baby’s genetics and the environmental exposure in utero, and it’s mediated by the sex of the fetus and the timing of exposure," Dr. Lusskin said. "This can actually alter the development of the fetus during particularly sensitive periods, with a permanent effect on its phenotype."

The risks do not stop with delivery, however. If mothers or physicians hesitate to treat during breastfeeding, mood disorders can persist and even escalate, interfering with mother-child bonding and even contributing to real risks for the baby’s physical well-being.

The best course for a physician is to pick a medication that works for the individual patient, and titrate the dose to maintain euthymia. "Make the diagnosis, pick the best medication, and treat to remission – which means you will be changing the dose during pregnancy. Untreated mental illness is not a benign condition for either mother or baby," she said.

Dr. Lusskin said she consults for the nonprofit drug safety database www.reprotox.org and has authored a chapter in uptodate.com, an Internet-based textbook on the use of medication in pregnancy and lactation.

MADRID – There are no easy choices for women who present with mood disorders during pregnancy – or for the physicians who treat them.

The decision to treat prenatal depression or anxiety is not to be taken lightly, but often must be considered, despite a relative dearth of data supporting or refuting drug safety during pregnancy, Dr. Shari I. Lusskin said at the World Conference on Women’s Mental Health.

"There are data, but not great data," said Dr. Lusskin, director of reproductive psychiatry at the NYU Langone Medical Center, New York. "We will never have 10,000 patients taking medication compared to 10,000 not taking it, compared to a control group that is not depressed or anxious, nor will we have years of follow-up data on their children."

The data that do exist are mostly comprised of case series, which are small and lack controls. "When you see a negative study [about the effect of treating mental disorders in a pregnant woman], keep in mind that there is often a lack of information about the mother’s diagnosis. Reports of smoking and substance abuse are notoriously unreliable," and can’t be accounted for in the results, she said. "We also know nothing about the mother’s body mass index, which is associated with many fetal complications that have nothing to do with drug exposure. And different studies use different comparison scales – you can’t compare apples and oranges."

The biggest exception is sodium valproate, an anticonvulsant also used to treat mood disorders, Dr. Lusskin said. The ongoing Neurodevelopmental Effects of Antiepileptic Drugs (NEAD) study has found in utero exposure to be associated with an increase in birth defects, and with cognitive problems in 3-year-olds whose mothers took it during pregnancy.

The uncertainty of treatment leaves pregnant women and their physicians to weigh the risks of psychotropic medications against the risks of untreated mood disorders. "There is no such thing as nonexposure," Dr. Lusskin said. If the mother is not treated, "the fetus is going to be exposed to the mother’s illness, which can create phenotypic changes with lifelong effects. If the mother is treated inadequately, the fetus will be exposed to both the effects of the illness and the medication. And if the mother is treated to remission, with the medication titrated to her response, medication exposure can be at least limited," while the new mother becomes healthy enough to give her baby the best possible care.

The biggest barrier to treating mental illness during pregnancy is fear of fetal harm: teratogenicity, neonatal complications from drug exposure, and long-term neurodevelopmental effects. But these risks must be considered in light of real world experience – not just based on numbers from a study, Dr. Lusskin said. "Any risk of impairment has to be compared to the background risk. The background risk of a birth defect is 2%-4%. If a drug increases this risk in a clinically meaningful way, it has to be over and above this background rate."

Even a substantial increase in a rare birth defect can be misleading, she said. For instance, Ebstein’s anomaly is a heart defect that occurs in 1 in 20,000 births. "Lithium is said to increase this rate to about 1 in 2,000 births. But this is still way below the expected background rate of birth defects. Risks are relevant in terms of their relativity – the absolute risk is just quoting a figure," Dr. Lusskin said.

But untreated mental illness poses its own risk. Babies exposed in utero to the chronic stress hormones associated with anxiety and depressive disorders might become phenotypically programmed, prone themselves to early childhood behavioral problems and, in later life, to mental illness. "The fetal programming hypothesis is the interaction between the baby’s genetics and the environmental exposure in utero, and it’s mediated by the sex of the fetus and the timing of exposure," Dr. Lusskin said. "This can actually alter the development of the fetus during particularly sensitive periods, with a permanent effect on its phenotype."

The risks do not stop with delivery, however. If mothers or physicians hesitate to treat during breastfeeding, mood disorders can persist and even escalate, interfering with mother-child bonding and even contributing to real risks for the baby’s physical well-being.

The best course for a physician is to pick a medication that works for the individual patient, and titrate the dose to maintain euthymia. "Make the diagnosis, pick the best medication, and treat to remission – which means you will be changing the dose during pregnancy. Untreated mental illness is not a benign condition for either mother or baby," she said.

Dr. Lusskin said she consults for the nonprofit drug safety database www.reprotox.org and has authored a chapter in uptodate.com, an Internet-based textbook on the use of medication in pregnancy and lactation.

MADRID – Beefing up a pregnant woman’s diet with tryptophan and tyrosine might one day help avoid the "baby blues" – or even a downward slide into postpartum depression.

The proteins – found naturally in eggs, poultry, milk products, and some nuts and seeds – are important precursors of the mood-regulating brain monoamines dopamine, serotonin, and norepinephrine. Boosting them before giving birth could provide just enough cushion to counteract the effects of increased monoamine oxidase A (MAO-A). MAO-A rises sharply in the week after childbirth, metabolizing these neurotransmitters at a highly increased rate, which probably plays a key role in the emotional dysregulation many women experience, Dr. Jeffrey Meyer said March 17 at the World Conference on Women’s Mental Health .

"What we are emphasizing now in our research is trying to compensate for this increased MAO-A metabolism of serotonin, norepinephrine, and dopamine," he said. "Giving these precursor proteins might be a potential strategy to lower the intensity of the postpartum ‘blues’ and possibly lead to a treatment for postpartum depression."

Recent work in humans shows that MAO-A in postpartum women is inversely related to estrogen. This relationship, in which estrogen declines as MAO-A rises, could underlie the feelings of sadness that affect up to 75% of women around postpartum days 3-6, said Dr. Meyer, an associate professor in the psychiatry department at the University of Toronto.

Since he and his colleagues published their initial work on the MAO-A/estrogen connection last May (Arch. Gen. Psychiatry 2010;67:468-74), Dr. Meyer has begun to investigate whether nutritional supplementation with the precursor proteins could boost a woman’s mood-regulating neurotransmitters enough to ward off the enzyme’s postpartum effects.

The first step of that research is to examine how tyrosine and tryptophan – the proteins under investigation – affect breast milk. "If we see that there is a negligible level in milk relative to plasma, our next step will be to investigate whether their administration could attenuate postpartum blues," he said.

The ultimate goal, however, would not be yet another prenatal supplement. "Ideally, instead of giving a powder as we’re doing now [during research], we could offer some specific dietary recommendations – maybe recommending that a pregnant woman should have a diet rich in tryptophan and tyrosine."

Such an intervention would probably be more acceptable than a medication, because it would circumvent concerns about drug excretion into breast milk, he added.

Dr. Meyer’s research is based on previous animal studies – including his own – that show a precipitous drop in plasma estrogen within 48 hours of birth. Almost simultaneously and nearly in concert, Dr. Meyer said, MAO-A levels begin to rise. Plasma estrogen reaches its nadir around day 3, while MAO-A peaks around day 4. "Coincidentally, this is the typical time of postpartum sadness– this period of low mood, irritability, and sleeplessness," Dr. Meyer said. He also said that his work represents the only MAO-A/estrogen investigation in humans.

That study looked at 15 immediately postpartum women and 15 age-matched controls, all of whom underwent positron emission tomography with the radiotracer carbon 11–labeled harmine. The compound is extremely reliable for identifying brain levels of MAO-A, and has a 20-minute half-life, making it a good choice for lactating women, he noted. To further allay safety concerns, breast feeding was delayed for 12 half-lives of the radiotracer, with a test sample confirming that the milk was clear. Geiger counters placed on the mothers’ chests also ensured that background radiation was normal.

The new mothers all were scanned on postpartum days 4-6 – the most common time for symptoms of postpartum sadness to appear. The scans revealed 43% more MAO-A bound to the radiotracer in the postpartum group than in the controls, with significant differences seen in all the brain regions measured (prefrontal cortex, anterior cingulate cortex, anterior temporal cortex, thalamus, dorsal putamen, hippocampus, and midbrain).

The findings mesh with a wealth of literature confirming the relationship between depression, low neurotransmitter levels, and MAO-A levels, Dr. Meyer noted, as well as with an entire class of antidepressants aimed at inhibiting the enzyme.

"I’m not saying this is the only mechanism" underlying postpartum mood changes, he noted. "But this is an important one, because there is a strong magnitude of effect, and MAO-A is a target that directly affects mood. This is something we should be looking at.

"We give women all kinds of recommendations during pregnancy," such as iron to prevent anemia and folate to prevent neural tube defects. "But no one has ever said to a woman, ‘Look, there is a biological underpinning for the sadness you might feel after delivery, and here is something we might be able to do about it.’ "

The initial study was funded by the Canadian Institutes of Health Research and other national Canadian health alliances. Dr. Meyer said he has no financial conflicts with regard to the work.

MADRID – Beefing up a pregnant woman’s diet with tryptophan and tyrosine might one day help avoid the "baby blues" – or even a downward slide into postpartum depression.

The proteins – found naturally in eggs, poultry, milk products, and some nuts and seeds – are important precursors of the mood-regulating brain monoamines dopamine, serotonin, and norepinephrine. Boosting them before giving birth could provide just enough cushion to counteract the effects of increased monoamine oxidase A (MAO-A). MAO-A rises sharply in the week after childbirth, metabolizing these neurotransmitters at a highly increased rate, which probably plays a key role in the emotional dysregulation many women experience, Dr. Jeffrey Meyer said March 17 at the World Conference on Women’s Mental Health .

"What we are emphasizing now in our research is trying to compensate for this increased MAO-A metabolism of serotonin, norepinephrine, and dopamine," he said. "Giving these precursor proteins might be a potential strategy to lower the intensity of the postpartum ‘blues’ and possibly lead to a treatment for postpartum depression."

Recent work in humans shows that MAO-A in postpartum women is inversely related to estrogen. This relationship, in which estrogen declines as MAO-A rises, could underlie the feelings of sadness that affect up to 75% of women around postpartum days 3-6, said Dr. Meyer, an associate professor in the psychiatry department at the University of Toronto.

Since he and his colleagues published their initial work on the MAO-A/estrogen connection last May (Arch. Gen. Psychiatry 2010;67:468-74), Dr. Meyer has begun to investigate whether nutritional supplementation with the precursor proteins could boost a woman’s mood-regulating neurotransmitters enough to ward off the enzyme’s postpartum effects.

The first step of that research is to examine how tyrosine and tryptophan – the proteins under investigation – affect breast milk. "If we see that there is a negligible level in milk relative to plasma, our next step will be to investigate whether their administration could attenuate postpartum blues," he said.

The ultimate goal, however, would not be yet another prenatal supplement. "Ideally, instead of giving a powder as we’re doing now [during research], we could offer some specific dietary recommendations – maybe recommending that a pregnant woman should have a diet rich in tryptophan and tyrosine."

Such an intervention would probably be more acceptable than a medication, because it would circumvent concerns about drug excretion into breast milk, he added.

Dr. Meyer’s research is based on previous animal studies – including his own – that show a precipitous drop in plasma estrogen within 48 hours of birth. Almost simultaneously and nearly in concert, Dr. Meyer said, MAO-A levels begin to rise. Plasma estrogen reaches its nadir around day 3, while MAO-A peaks around day 4. "Coincidentally, this is the typical time of postpartum sadness– this period of low mood, irritability, and sleeplessness," Dr. Meyer said. He also said that his work represents the only MAO-A/estrogen investigation in humans.

That study looked at 15 immediately postpartum women and 15 age-matched controls, all of whom underwent positron emission tomography with the radiotracer carbon 11–labeled harmine. The compound is extremely reliable for identifying brain levels of MAO-A, and has a 20-minute half-life, making it a good choice for lactating women, he noted. To further allay safety concerns, breast feeding was delayed for 12 half-lives of the radiotracer, with a test sample confirming that the milk was clear. Geiger counters placed on the mothers’ chests also ensured that background radiation was normal.

The new mothers all were scanned on postpartum days 4-6 – the most common time for symptoms of postpartum sadness to appear. The scans revealed 43% more MAO-A bound to the radiotracer in the postpartum group than in the controls, with significant differences seen in all the brain regions measured (prefrontal cortex, anterior cingulate cortex, anterior temporal cortex, thalamus, dorsal putamen, hippocampus, and midbrain).

The findings mesh with a wealth of literature confirming the relationship between depression, low neurotransmitter levels, and MAO-A levels, Dr. Meyer noted, as well as with an entire class of antidepressants aimed at inhibiting the enzyme.

"I’m not saying this is the only mechanism" underlying postpartum mood changes, he noted. "But this is an important one, because there is a strong magnitude of effect, and MAO-A is a target that directly affects mood. This is something we should be looking at.

"We give women all kinds of recommendations during pregnancy," such as iron to prevent anemia and folate to prevent neural tube defects. "But no one has ever said to a woman, ‘Look, there is a biological underpinning for the sadness you might feel after delivery, and here is something we might be able to do about it.’ "

The initial study was funded by the Canadian Institutes of Health Research and other national Canadian health alliances. Dr. Meyer said he has no financial conflicts with regard to the work.

MADRID – Beefing up a pregnant woman’s diet with tryptophan and tyrosine might one day help avoid the "baby blues" – or even a downward slide into postpartum depression.

The proteins – found naturally in eggs, poultry, milk products, and some nuts and seeds – are important precursors of the mood-regulating brain monoamines dopamine, serotonin, and norepinephrine. Boosting them before giving birth could provide just enough cushion to counteract the effects of increased monoamine oxidase A (MAO-A). MAO-A rises sharply in the week after childbirth, metabolizing these neurotransmitters at a highly increased rate, which probably plays a key role in the emotional dysregulation many women experience, Dr. Jeffrey Meyer said March 17 at the World Conference on Women’s Mental Health .

"What we are emphasizing now in our research is trying to compensate for this increased MAO-A metabolism of serotonin, norepinephrine, and dopamine," he said. "Giving these precursor proteins might be a potential strategy to lower the intensity of the postpartum ‘blues’ and possibly lead to a treatment for postpartum depression."

Recent work in humans shows that MAO-A in postpartum women is inversely related to estrogen. This relationship, in which estrogen declines as MAO-A rises, could underlie the feelings of sadness that affect up to 75% of women around postpartum days 3-6, said Dr. Meyer, an associate professor in the psychiatry department at the University of Toronto.

Since he and his colleagues published their initial work on the MAO-A/estrogen connection last May (Arch. Gen. Psychiatry 2010;67:468-74), Dr. Meyer has begun to investigate whether nutritional supplementation with the precursor proteins could boost a woman’s mood-regulating neurotransmitters enough to ward off the enzyme’s postpartum effects.

The first step of that research is to examine how tyrosine and tryptophan – the proteins under investigation – affect breast milk. "If we see that there is a negligible level in milk relative to plasma, our next step will be to investigate whether their administration could attenuate postpartum blues," he said.

The ultimate goal, however, would not be yet another prenatal supplement. "Ideally, instead of giving a powder as we’re doing now [during research], we could offer some specific dietary recommendations – maybe recommending that a pregnant woman should have a diet rich in tryptophan and tyrosine."

Such an intervention would probably be more acceptable than a medication, because it would circumvent concerns about drug excretion into breast milk, he added.

Dr. Meyer’s research is based on previous animal studies – including his own – that show a precipitous drop in plasma estrogen within 48 hours of birth. Almost simultaneously and nearly in concert, Dr. Meyer said, MAO-A levels begin to rise. Plasma estrogen reaches its nadir around day 3, while MAO-A peaks around day 4. "Coincidentally, this is the typical time of postpartum sadness– this period of low mood, irritability, and sleeplessness," Dr. Meyer said. He also said that his work represents the only MAO-A/estrogen investigation in humans.

That study looked at 15 immediately postpartum women and 15 age-matched controls, all of whom underwent positron emission tomography with the radiotracer carbon 11–labeled harmine. The compound is extremely reliable for identifying brain levels of MAO-A, and has a 20-minute half-life, making it a good choice for lactating women, he noted. To further allay safety concerns, breast feeding was delayed for 12 half-lives of the radiotracer, with a test sample confirming that the milk was clear. Geiger counters placed on the mothers’ chests also ensured that background radiation was normal.

The new mothers all were scanned on postpartum days 4-6 – the most common time for symptoms of postpartum sadness to appear. The scans revealed 43% more MAO-A bound to the radiotracer in the postpartum group than in the controls, with significant differences seen in all the brain regions measured (prefrontal cortex, anterior cingulate cortex, anterior temporal cortex, thalamus, dorsal putamen, hippocampus, and midbrain).

The findings mesh with a wealth of literature confirming the relationship between depression, low neurotransmitter levels, and MAO-A levels, Dr. Meyer noted, as well as with an entire class of antidepressants aimed at inhibiting the enzyme.

"I’m not saying this is the only mechanism" underlying postpartum mood changes, he noted. "But this is an important one, because there is a strong magnitude of effect, and MAO-A is a target that directly affects mood. This is something we should be looking at.

"We give women all kinds of recommendations during pregnancy," such as iron to prevent anemia and folate to prevent neural tube defects. "But no one has ever said to a woman, ‘Look, there is a biological underpinning for the sadness you might feel after delivery, and here is something we might be able to do about it.’ "

The initial study was funded by the Canadian Institutes of Health Research and other national Canadian health alliances. Dr. Meyer said he has no financial conflicts with regard to the work.

MADRID – Beefing up a pregnant woman’s diet with tryptophan and tyrosine might one day help avoid the "baby blues" – or even a downward slide into postpartum depression.

The proteins – found naturally in eggs, poultry, milk products, and some nuts and seeds – are important precursors of the mood-regulating brain monoamines dopamine, serotonin, and norepinephrine. Boosting them before giving birth could provide just enough cushion to counteract the effects of increased monoamine oxidase A (MAO-A). MAO-A rises sharply in the week after childbirth, metabolizing these neurotransmitters at a highly increased rate, which probably plays a key role in the emotional dysregulation many women experience, Dr. Jeffrey Meyer said March 17 at the World Conference on Women’s Mental Health .

"What we are emphasizing now in our research is trying to compensate for this increased MAO-A metabolism of serotonin, norepinephrine, and dopamine," he said. "Giving these precursor proteins might be a potential strategy to lower the intensity of the postpartum ‘blues’ and possibly lead to a treatment for postpartum depression."

Recent work in humans shows that MAO-A in postpartum women is inversely related to estrogen. This relationship, in which estrogen declines as MAO-A rises, could underlie the feelings of sadness that affect up to 75% of women around postpartum days 3-6, said Dr. Meyer, an associate professor in the psychiatry department at the University of Toronto.

Since he and his colleagues published their initial work on the MAO-A/estrogen connection last May (Arch. Gen. Psychiatry 2010;67:468-74), Dr. Meyer has begun to investigate whether nutritional supplementation with the precursor proteins could boost a woman’s mood-regulating neurotransmitters enough to ward off the enzyme’s postpartum effects.

The first step of that research is to examine how tyrosine and tryptophan – the proteins under investigation – affect breast milk. "If we see that there is a negligible level in milk relative to plasma, our next step will be to investigate whether their administration could attenuate postpartum blues," he said.

The ultimate goal, however, would not be yet another prenatal supplement. "Ideally, instead of giving a powder as we’re doing now [during research], we could offer some specific dietary recommendations – maybe recommending that a pregnant woman should have a diet rich in tryptophan and tyrosine."

Such an intervention would probably be more acceptable than a medication, because it would circumvent concerns about drug excretion into breast milk, he added.

Dr. Meyer’s research is based on previous animal studies – including his own – that show a precipitous drop in plasma estrogen within 48 hours of birth. Almost simultaneously and nearly in concert, Dr. Meyer said, MAO-A levels begin to rise. Plasma estrogen reaches its nadir around day 3, while MAO-A peaks around day 4. "Coincidentally, this is the typical time of postpartum sadness– this period of low mood, irritability, and sleeplessness," Dr. Meyer said. He also said that his work represents the only MAO-A/estrogen investigation in humans.

That study looked at 15 immediately postpartum women and 15 age-matched controls, all of whom underwent positron emission tomography with the radiotracer carbon 11–labeled harmine. The compound is extremely reliable for identifying brain levels of MAO-A, and has a 20-minute half-life, making it a good choice for lactating women, he noted. To further allay safety concerns, breast feeding was delayed for 12 half-lives of the radiotracer, with a test sample confirming that the milk was clear. Geiger counters placed on the mothers’ chests also ensured that background radiation was normal.

The new mothers all were scanned on postpartum days 4-6 – the most common time for symptoms of postpartum sadness to appear. The scans revealed 43% more MAO-A bound to the radiotracer in the postpartum group than in the controls, with significant differences seen in all the brain regions measured (prefrontal cortex, anterior cingulate cortex, anterior temporal cortex, thalamus, dorsal putamen, hippocampus, and midbrain).

The findings mesh with a wealth of literature confirming the relationship between depression, low neurotransmitter levels, and MAO-A levels, Dr. Meyer noted, as well as with an entire class of antidepressants aimed at inhibiting the enzyme.

"I’m not saying this is the only mechanism" underlying postpartum mood changes, he noted. "But this is an important one, because there is a strong magnitude of effect, and MAO-A is a target that directly affects mood. This is something we should be looking at.

"We give women all kinds of recommendations during pregnancy," such as iron to prevent anemia and folate to prevent neural tube defects. "But no one has ever said to a woman, ‘Look, there is a biological underpinning for the sadness you might feel after delivery, and here is something we might be able to do about it.’ "

The initial study was funded by the Canadian Institutes of Health Research and other national Canadian health alliances. Dr. Meyer said he has no financial conflicts with regard to the work.

MADRID – Beefing up a pregnant woman’s diet with tryptophan and tyrosine might one day help avoid the "baby blues" – or even a downward slide into postpartum depression.

The proteins – found naturally in eggs, poultry, milk products, and some nuts and seeds – are important precursors of the mood-regulating brain monoamines dopamine, serotonin, and norepinephrine. Boosting them before giving birth could provide just enough cushion to counteract the effects of increased monoamine oxidase A (MAO-A). MAO-A rises sharply in the week after childbirth, metabolizing these neurotransmitters at a highly increased rate, which probably plays a key role in the emotional dysregulation many women experience, Dr. Jeffrey Meyer said March 17 at the World Conference on Women’s Mental Health .

"What we are emphasizing now in our research is trying to compensate for this increased MAO-A metabolism of serotonin, norepinephrine, and dopamine," he said. "Giving these precursor proteins might be a potential strategy to lower the intensity of the postpartum ‘blues’ and possibly lead to a treatment for postpartum depression."

Recent work in humans shows that MAO-A in postpartum women is inversely related to estrogen. This relationship, in which estrogen declines as MAO-A rises, could underlie the feelings of sadness that affect up to 75% of women around postpartum days 3-6, said Dr. Meyer, an associate professor in the psychiatry department at the University of Toronto.

Since he and his colleagues published their initial work on the MAO-A/estrogen connection last May (Arch. Gen. Psychiatry 2010;67:468-74), Dr. Meyer has begun to investigate whether nutritional supplementation with the precursor proteins could boost a woman’s mood-regulating neurotransmitters enough to ward off the enzyme’s postpartum effects.

The first step of that research is to examine how tyrosine and tryptophan – the proteins under investigation – affect breast milk. "If we see that there is a negligible level in milk relative to plasma, our next step will be to investigate whether their administration could attenuate postpartum blues," he said.

The ultimate goal, however, would not be yet another prenatal supplement. "Ideally, instead of giving a powder as we’re doing now [during research], we could offer some specific dietary recommendations – maybe recommending that a pregnant woman should have a diet rich in tryptophan and tyrosine."

Such an intervention would probably be more acceptable than a medication, because it would circumvent concerns about drug excretion into breast milk, he added.

Dr. Meyer’s research is based on previous animal studies – including his own – that show a precipitous drop in plasma estrogen within 48 hours of birth. Almost simultaneously and nearly in concert, Dr. Meyer said, MAO-A levels begin to rise. Plasma estrogen reaches its nadir around day 3, while MAO-A peaks around day 4. "Coincidentally, this is the typical time of postpartum sadness– this period of low mood, irritability, and sleeplessness," Dr. Meyer said. He also said that his work represents the only MAO-A/estrogen investigation in humans.

That study looked at 15 immediately postpartum women and 15 age-matched controls, all of whom underwent positron emission tomography with the radiotracer carbon 11–labeled harmine. The compound is extremely reliable for identifying brain levels of MAO-A, and has a 20-minute half-life, making it a good choice for lactating women, he noted. To further allay safety concerns, breast feeding was delayed for 12 half-lives of the radiotracer, with a test sample confirming that the milk was clear. Geiger counters placed on the mothers’ chests also ensured that background radiation was normal.

The new mothers all were scanned on postpartum days 4-6 – the most common time for symptoms of postpartum sadness to appear. The scans revealed 43% more MAO-A bound to the radiotracer in the postpartum group than in the controls, with significant differences seen in all the brain regions measured (prefrontal cortex, anterior cingulate cortex, anterior temporal cortex, thalamus, dorsal putamen, hippocampus, and midbrain).

The findings mesh with a wealth of literature confirming the relationship between depression, low neurotransmitter levels, and MAO-A levels, Dr. Meyer noted, as well as with an entire class of antidepressants aimed at inhibiting the enzyme.

"I’m not saying this is the only mechanism" underlying postpartum mood changes, he noted. "But this is an important one, because there is a strong magnitude of effect, and MAO-A is a target that directly affects mood. This is something we should be looking at.

"We give women all kinds of recommendations during pregnancy," such as iron to prevent anemia and folate to prevent neural tube defects. "But no one has ever said to a woman, ‘Look, there is a biological underpinning for the sadness you might feel after delivery, and here is something we might be able to do about it.’ "

The initial study was funded by the Canadian Institutes of Health Research and other national Canadian health alliances. Dr. Meyer said he has no financial conflicts with regard to the work.

MADRID – Beefing up a pregnant woman’s diet with tryptophan and tyrosine might one day help avoid the "baby blues" – or even a downward slide into postpartum depression.

The proteins – found naturally in eggs, poultry, milk products, and some nuts and seeds – are important precursors of the mood-regulating brain monoamines dopamine, serotonin, and norepinephrine. Boosting them before giving birth could provide just enough cushion to counteract the effects of increased monoamine oxidase A (MAO-A). MAO-A rises sharply in the week after childbirth, metabolizing these neurotransmitters at a highly increased rate, which probably plays a key role in the emotional dysregulation many women experience, Dr. Jeffrey Meyer said March 17 at the World Conference on Women’s Mental Health .

"What we are emphasizing now in our research is trying to compensate for this increased MAO-A metabolism of serotonin, norepinephrine, and dopamine," he said. "Giving these precursor proteins might be a potential strategy to lower the intensity of the postpartum ‘blues’ and possibly lead to a treatment for postpartum depression."

Recent work in humans shows that MAO-A in postpartum women is inversely related to estrogen. This relationship, in which estrogen declines as MAO-A rises, could underlie the feelings of sadness that affect up to 75% of women around postpartum days 3-6, said Dr. Meyer, an associate professor in the psychiatry department at the University of Toronto.

Since he and his colleagues published their initial work on the MAO-A/estrogen connection last May (Arch. Gen. Psychiatry 2010;67:468-74), Dr. Meyer has begun to investigate whether nutritional supplementation with the precursor proteins could boost a woman’s mood-regulating neurotransmitters enough to ward off the enzyme’s postpartum effects.

The first step of that research is to examine how tyrosine and tryptophan – the proteins under investigation – affect breast milk. "If we see that there is a negligible level in milk relative to plasma, our next step will be to investigate whether their administration could attenuate postpartum blues," he said.

The ultimate goal, however, would not be yet another prenatal supplement. "Ideally, instead of giving a powder as we’re doing now [during research], we could offer some specific dietary recommendations – maybe recommending that a pregnant woman should have a diet rich in tryptophan and tyrosine."

Such an intervention would probably be more acceptable than a medication, because it would circumvent concerns about drug excretion into breast milk, he added.

Dr. Meyer’s research is based on previous animal studies – including his own – that show a precipitous drop in plasma estrogen within 48 hours of birth. Almost simultaneously and nearly in concert, Dr. Meyer said, MAO-A levels begin to rise. Plasma estrogen reaches its nadir around day 3, while MAO-A peaks around day 4. "Coincidentally, this is the typical time of postpartum sadness– this period of low mood, irritability, and sleeplessness," Dr. Meyer said. He also said that his work represents the only MAO-A/estrogen investigation in humans.

That study looked at 15 immediately postpartum women and 15 age-matched controls, all of whom underwent positron emission tomography with the radiotracer carbon 11–labeled harmine. The compound is extremely reliable for identifying brain levels of MAO-A, and has a 20-minute half-life, making it a good choice for lactating women, he noted. To further allay safety concerns, breast feeding was delayed for 12 half-lives of the radiotracer, with a test sample confirming that the milk was clear. Geiger counters placed on the mothers’ chests also ensured that background radiation was normal.

The new mothers all were scanned on postpartum days 4-6 – the most common time for symptoms of postpartum sadness to appear. The scans revealed 43% more MAO-A bound to the radiotracer in the postpartum group than in the controls, with significant differences seen in all the brain regions measured (prefrontal cortex, anterior cingulate cortex, anterior temporal cortex, thalamus, dorsal putamen, hippocampus, and midbrain).

The findings mesh with a wealth of literature confirming the relationship between depression, low neurotransmitter levels, and MAO-A levels, Dr. Meyer noted, as well as with an entire class of antidepressants aimed at inhibiting the enzyme.

"I’m not saying this is the only mechanism" underlying postpartum mood changes, he noted. "But this is an important one, because there is a strong magnitude of effect, and MAO-A is a target that directly affects mood. This is something we should be looking at.

"We give women all kinds of recommendations during pregnancy," such as iron to prevent anemia and folate to prevent neural tube defects. "But no one has ever said to a woman, ‘Look, there is a biological underpinning for the sadness you might feel after delivery, and here is something we might be able to do about it.’ "

The initial study was funded by the Canadian Institutes of Health Research and other national Canadian health alliances. Dr. Meyer said he has no financial conflicts with regard to the work.

MADRID – Beefing up a pregnant woman’s diet with tryptophan and tyrosine might one day help avoid the "baby blues" – or even a downward slide into postpartum depression.

The proteins – found naturally in eggs, poultry, milk products, and some nuts and seeds – are important precursors of the mood-regulating brain monoamines dopamine, serotonin, and norepinephrine. Boosting them before giving birth could provide just enough cushion to counteract the effects of increased monoamine oxidase A (MAO-A). MAO-A rises sharply in the week after childbirth, metabolizing these neurotransmitters at a highly increased rate, which probably plays a key role in the emotional dysregulation many women experience, Dr. Jeffrey Meyer said March 17 at the World Conference on Women’s Mental Health .

"What we are emphasizing now in our research is trying to compensate for this increased MAO-A metabolism of serotonin, norepinephrine, and dopamine," he said. "Giving these precursor proteins might be a potential strategy to lower the intensity of the postpartum ‘blues’ and possibly lead to a treatment for postpartum depression."

Recent work in humans shows that MAO-A in postpartum women is inversely related to estrogen. This relationship, in which estrogen declines as MAO-A rises, could underlie the feelings of sadness that affect up to 75% of women around postpartum days 3-6, said Dr. Meyer, an associate professor in the psychiatry department at the University of Toronto.

Since he and his colleagues published their initial work on the MAO-A/estrogen connection last May (Arch. Gen. Psychiatry 2010;67:468-74), Dr. Meyer has begun to investigate whether nutritional supplementation with the precursor proteins could boost a woman’s mood-regulating neurotransmitters enough to ward off the enzyme’s postpartum effects.

The first step of that research is to examine how tyrosine and tryptophan – the proteins under investigation – affect breast milk. "If we see that there is a negligible level in milk relative to plasma, our next step will be to investigate whether their administration could attenuate postpartum blues," he said.

The ultimate goal, however, would not be yet another prenatal supplement. "Ideally, instead of giving a powder as we’re doing now [during research], we could offer some specific dietary recommendations – maybe recommending that a pregnant woman should have a diet rich in tryptophan and tyrosine."

Such an intervention would probably be more acceptable than a medication, because it would circumvent concerns about drug excretion into breast milk, he added.

Dr. Meyer’s research is based on previous animal studies – including his own – that show a precipitous drop in plasma estrogen within 48 hours of birth. Almost simultaneously and nearly in concert, Dr. Meyer said, MAO-A levels begin to rise. Plasma estrogen reaches its nadir around day 3, while MAO-A peaks around day 4. "Coincidentally, this is the typical time of postpartum sadness– this period of low mood, irritability, and sleeplessness," Dr. Meyer said. He also said that his work represents the only MAO-A/estrogen investigation in humans.

That study looked at 15 immediately postpartum women and 15 age-matched controls, all of whom underwent positron emission tomography with the radiotracer carbon 11–labeled harmine. The compound is extremely reliable for identifying brain levels of MAO-A, and has a 20-minute half-life, making it a good choice for lactating women, he noted. To further allay safety concerns, breast feeding was delayed for 12 half-lives of the radiotracer, with a test sample confirming that the milk was clear. Geiger counters placed on the mothers’ chests also ensured that background radiation was normal.

The new mothers all were scanned on postpartum days 4-6 – the most common time for symptoms of postpartum sadness to appear. The scans revealed 43% more MAO-A bound to the radiotracer in the postpartum group than in the controls, with significant differences seen in all the brain regions measured (prefrontal cortex, anterior cingulate cortex, anterior temporal cortex, thalamus, dorsal putamen, hippocampus, and midbrain).

The findings mesh with a wealth of literature confirming the relationship between depression, low neurotransmitter levels, and MAO-A levels, Dr. Meyer noted, as well as with an entire class of antidepressants aimed at inhibiting the enzyme.

"I’m not saying this is the only mechanism" underlying postpartum mood changes, he noted. "But this is an important one, because there is a strong magnitude of effect, and MAO-A is a target that directly affects mood. This is something we should be looking at.

"We give women all kinds of recommendations during pregnancy," such as iron to prevent anemia and folate to prevent neural tube defects. "But no one has ever said to a woman, ‘Look, there is a biological underpinning for the sadness you might feel after delivery, and here is something we might be able to do about it.’ "

The initial study was funded by the Canadian Institutes of Health Research and other national Canadian health alliances. Dr. Meyer said he has no financial conflicts with regard to the work.

MADRID – Beefing up a pregnant woman’s diet with tryptophan and tyrosine might one day help avoid the "baby blues" – or even a downward slide into postpartum depression.

The proteins – found naturally in eggs, poultry, milk products, and some nuts and seeds – are important precursors of the mood-regulating brain monoamines dopamine, serotonin, and norepinephrine. Boosting them before giving birth could provide just enough cushion to counteract the effects of increased monoamine oxidase A (MAO-A). MAO-A rises sharply in the week after childbirth, metabolizing these neurotransmitters at a highly increased rate, which probably plays a key role in the emotional dysregulation many women experience, Dr. Jeffrey Meyer said March 17 at the World Conference on Women’s Mental Health .

"What we are emphasizing now in our research is trying to compensate for this increased MAO-A metabolism of serotonin, norepinephrine, and dopamine," he said. "Giving these precursor proteins might be a potential strategy to lower the intensity of the postpartum ‘blues’ and possibly lead to a treatment for postpartum depression."

Recent work in humans shows that MAO-A in postpartum women is inversely related to estrogen. This relationship, in which estrogen declines as MAO-A rises, could underlie the feelings of sadness that affect up to 75% of women around postpartum days 3-6, said Dr. Meyer, an associate professor in the psychiatry department at the University of Toronto.

Since he and his colleagues published their initial work on the MAO-A/estrogen connection last May (Arch. Gen. Psychiatry 2010;67:468-74), Dr. Meyer has begun to investigate whether nutritional supplementation with the precursor proteins could boost a woman’s mood-regulating neurotransmitters enough to ward off the enzyme’s postpartum effects.

The first step of that research is to examine how tyrosine and tryptophan – the proteins under investigation – affect breast milk. "If we see that there is a negligible level in milk relative to plasma, our next step will be to investigate whether their administration could attenuate postpartum blues," he said.

The ultimate goal, however, would not be yet another prenatal supplement. "Ideally, instead of giving a powder as we’re doing now [during research], we could offer some specific dietary recommendations – maybe recommending that a pregnant woman should have a diet rich in tryptophan and tyrosine."

Such an intervention would probably be more acceptable than a medication, because it would circumvent concerns about drug excretion into breast milk, he added.

Dr. Meyer’s research is based on previous animal studies – including his own – that show a precipitous drop in plasma estrogen within 48 hours of birth. Almost simultaneously and nearly in concert, Dr. Meyer said, MAO-A levels begin to rise. Plasma estrogen reaches its nadir around day 3, while MAO-A peaks around day 4. "Coincidentally, this is the typical time of postpartum sadness– this period of low mood, irritability, and sleeplessness," Dr. Meyer said. He also said that his work represents the only MAO-A/estrogen investigation in humans.

That study looked at 15 immediately postpartum women and 15 age-matched controls, all of whom underwent positron emission tomography with the radiotracer carbon 11–labeled harmine. The compound is extremely reliable for identifying brain levels of MAO-A, and has a 20-minute half-life, making it a good choice for lactating women, he noted. To further allay safety concerns, breast feeding was delayed for 12 half-lives of the radiotracer, with a test sample confirming that the milk was clear. Geiger counters placed on the mothers’ chests also ensured that background radiation was normal.

The new mothers all were scanned on postpartum days 4-6 – the most common time for symptoms of postpartum sadness to appear. The scans revealed 43% more MAO-A bound to the radiotracer in the postpartum group than in the controls, with significant differences seen in all the brain regions measured (prefrontal cortex, anterior cingulate cortex, anterior temporal cortex, thalamus, dorsal putamen, hippocampus, and midbrain).

The findings mesh with a wealth of literature confirming the relationship between depression, low neurotransmitter levels, and MAO-A levels, Dr. Meyer noted, as well as with an entire class of antidepressants aimed at inhibiting the enzyme.

"I’m not saying this is the only mechanism" underlying postpartum mood changes, he noted. "But this is an important one, because there is a strong magnitude of effect, and MAO-A is a target that directly affects mood. This is something we should be looking at.

"We give women all kinds of recommendations during pregnancy," such as iron to prevent anemia and folate to prevent neural tube defects. "But no one has ever said to a woman, ‘Look, there is a biological underpinning for the sadness you might feel after delivery, and here is something we might be able to do about it.’ "

The initial study was funded by the Canadian Institutes of Health Research and other national Canadian health alliances. Dr. Meyer said he has no financial conflicts with regard to the work.

MADRID – Beefing up a pregnant woman’s diet with tryptophan and tyrosine might one day help avoid the "baby blues" – or even a downward slide into postpartum depression.

The proteins – found naturally in eggs, poultry, milk products, and some nuts and seeds – are important precursors of the mood-regulating brain monoamines dopamine, serotonin, and norepinephrine. Boosting them before giving birth could provide just enough cushion to counteract the effects of increased monoamine oxidase A (MAO-A). MAO-A rises sharply in the week after childbirth, metabolizing these neurotransmitters at a highly increased rate, which probably plays a key role in the emotional dysregulation many women experience, Dr. Jeffrey Meyer said March 17 at the World Conference on Women’s Mental Health .

"What we are emphasizing now in our research is trying to compensate for this increased MAO-A metabolism of serotonin, norepinephrine, and dopamine," he said. "Giving these precursor proteins might be a potential strategy to lower the intensity of the postpartum ‘blues’ and possibly lead to a treatment for postpartum depression."

Recent work in humans shows that MAO-A in postpartum women is inversely related to estrogen. This relationship, in which estrogen declines as MAO-A rises, could underlie the feelings of sadness that affect up to 75% of women around postpartum days 3-6, said Dr. Meyer, an associate professor in the psychiatry department at the University of Toronto.

Since he and his colleagues published their initial work on the MAO-A/estrogen connection last May (Arch. Gen. Psychiatry 2010;67:468-74), Dr. Meyer has begun to investigate whether nutritional supplementation with the precursor proteins could boost a woman’s mood-regulating neurotransmitters enough to ward off the enzyme’s postpartum effects.

The first step of that research is to examine how tyrosine and tryptophan – the proteins under investigation – affect breast milk. "If we see that there is a negligible level in milk relative to plasma, our next step will be to investigate whether their administration could attenuate postpartum blues," he said.

The ultimate goal, however, would not be yet another prenatal supplement. "Ideally, instead of giving a powder as we’re doing now [during research], we could offer some specific dietary recommendations – maybe recommending that a pregnant woman should have a diet rich in tryptophan and tyrosine."

Such an intervention would probably be more acceptable than a medication, because it would circumvent concerns about drug excretion into breast milk, he added.

Dr. Meyer’s research is based on previous animal studies – including his own – that show a precipitous drop in plasma estrogen within 48 hours of birth. Almost simultaneously and nearly in concert, Dr. Meyer said, MAO-A levels begin to rise. Plasma estrogen reaches its nadir around day 3, while MAO-A peaks around day 4. "Coincidentally, this is the typical time of postpartum sadness– this period of low mood, irritability, and sleeplessness," Dr. Meyer said. He also said that his work represents the only MAO-A/estrogen investigation in humans.

That study looked at 15 immediately postpartum women and 15 age-matched controls, all of whom underwent positron emission tomography with the radiotracer carbon 11–labeled harmine. The compound is extremely reliable for identifying brain levels of MAO-A, and has a 20-minute half-life, making it a good choice for lactating women, he noted. To further allay safety concerns, breast feeding was delayed for 12 half-lives of the radiotracer, with a test sample confirming that the milk was clear. Geiger counters placed on the mothers’ chests also ensured that background radiation was normal.

The new mothers all were scanned on postpartum days 4-6 – the most common time for symptoms of postpartum sadness to appear. The scans revealed 43% more MAO-A bound to the radiotracer in the postpartum group than in the controls, with significant differences seen in all the brain regions measured (prefrontal cortex, anterior cingulate cortex, anterior temporal cortex, thalamus, dorsal putamen, hippocampus, and midbrain).

The findings mesh with a wealth of literature confirming the relationship between depression, low neurotransmitter levels, and MAO-A levels, Dr. Meyer noted, as well as with an entire class of antidepressants aimed at inhibiting the enzyme.

"I’m not saying this is the only mechanism" underlying postpartum mood changes, he noted. "But this is an important one, because there is a strong magnitude of effect, and MAO-A is a target that directly affects mood. This is something we should be looking at.

"We give women all kinds of recommendations during pregnancy," such as iron to prevent anemia and folate to prevent neural tube defects. "But no one has ever said to a woman, ‘Look, there is a biological underpinning for the sadness you might feel after delivery, and here is something we might be able to do about it.’ "

The initial study was funded by the Canadian Institutes of Health Research and other national Canadian health alliances. Dr. Meyer said he has no financial conflicts with regard to the work.

BARCELONA – The pathologic changes of Alzheimer’s disease may begin as early as 20 years before the expected onset of disease, at least in people whose families carry a high-risk gene, preliminary data from a 6-year longitudinal study suggested.

These first findings from the Dominantly Inherited Alzheimer Network (DIAN) study, a 6-year, cross-sectional, longitudinal study indicate that the use of PET and cerebrospinal fluid biomarkers of beta-amyloid and tau protein may allow researchers to select enriched pools of subjects for the testing of potential drug treatments, and, someday, allow clinicians to target patients with incipient disease for preventive treatment, Dr. John Morris said at the International Conference on Alzheimer’s and Parkinson’s Diseases.

"I have not yet had sufficient sample size or follow-up to predict this completely," said Dr. Morris, DIAN’s principal investigator. "However, I think there are data both from Europe and the U.S. showing that low beta-amyloid 42 [Abeta 42] and high tau in the cerebrospinal fluid together will reach a hazard ratio of 5.2 for becoming demented within 3-4 years. We are just beginning to get these same data for amyloid imaging and the hazard ratio is about the same."

Dr. Morris, professor of neurology at Washington University, St. Louis, said the DIAN study hopes to recruit 400 subjects who are the children of a parent with a known autosomal-dominant Alzheimer’s gene. Currently, three of those genes are known: amyloid precursor protein (APP), presenilin 1, and presenilin 2. He expects that about half the group will carry one of the mutations, while the other half will be unaffected siblings, who will serve as controls. The study involves 10 research institutions in the United States, United Kingdom, and Australia.

Each participant will undergo genetic analysis and the same periodic assessments, including cognitive and clinical testing; brain imaging with Pittsburgh imaging compound B, which binds to Abeta 42 plaques; ¹⁸fluorodeoxyglucose positron emission tomography; MRI; and lumbar punctures to test levels of Abeta 42 and tau. If subjects die during the study, their brains will be autopsied.

"The goals are to try and determine when the pathologic process begins in asymptomatic mutation carriers," Dr. Morris said. "We know, based on the parent’s age of onset, approximately when these carriers will become symptomatic. We want to see the changes, the rates of these changes, and determine to what extent the changes resemble those seen in sporadic Alzheimer’s."

As of last fall, DIAN had collected 106 volunteers, Dr. Morris said. About 70% of those are asymptomatic carriers, with an average age of 37 years, although that varies from 19 to 56 years. The average age of parental onset of dementia symptoms is 47 years, "so we have these folks an average of 10 years before their expected age of onset."

The presenilin 1 mutation is the most common in the group, occurring in 75%; presenilin 2 is present in 10%, and the APP mutation, in 15%.

Comparing the carriers with the noncarriers, the study’s "very preliminary" data indicate that cognitive decline begins as early as 10 years before the expected onset of symptoms, while neuropathologic changes start up to 20 years before.

But scores on the Mini-Mental State Exam (MMSE) for noncarrier siblings of these volunteers "have remained very clearly at 30," which is a normal score, Dr. Morrison said. The noncarriers also had normal scores on the Clinical Dementia Rating Scale (pdf) sum of boxes (CDR-SOB), another test used to identify Alzheimer’s-related cognitive changes.

This was not the case "for carriers, in whom we begin to see declines in the MMSE and the CDR about 10 years before the expected age of onset," Dr. Morris said.

The cerebrospinal fluid biomarkers followed a similar pattern. A decrease in spinal fluid Abeta 42 suggests that the protein is aggregating somewhere else in the body – probably in the characteristic brain plaques. These changes could be seen in carriers 20 years before the expected age of onset. Tau protein levels in the cerebrospinal fluid (CSF) of carriers begin to rise around 20 years before the onset of symptoms, "with a clear acceleration at the time they are changing from asymptomatic to symptomatic," he said.

However, noncarriers have stable levels of both proteins in the CSF at the same ages.

Imaging in the precuneus and caudate with Pittsburgh imaging compound B shows no Abeta 42 accumulation in noncarriers, but in carriers, the protein begins to appear in those regions about the same time that the CSF biomarkers start to change – 20 years before the expected appearance of symptomatic disease.

If these findings can be confirmed, they prove the existence of a long prodromal stage in subjects who are genetically destined to develop Alzheimer’s disease. This has several important applications in both drug research and potential treatment, Dr. Morris noted.

First, the neuropsychological testing scores currently in use, which define normal cognitive function, may be incorrect, because they could be based on cohorts that included individuals who had already experienced cognitive decline, but still fell within the "normal" range.

To illustrate this problem, Dr. Morris referred to the cognitive testing of two subjects. One began with cognitive functioning at the mean of normal, while the other began at 2 standard deviations above the mean. Over a period of years, the first person remained stable at the mean, while the second declined to the mean – showing that this subject was experiencing significant cognitive decline on an individual basis, while still being considered cognitively normal. The patient quickly developed mild cognitive impairment and then Alzheimer’s disease.

"This interferes with the ability to detect very early stages of symptomatic Alzheimer’s based on neuropsychological testing, because the test norms are contaminated by the inclusion of subjects who may have preclinical disease," Dr. Morris said.

Comparative testing or the report of a close companion could detect change in a high-functioning individual, but the majority of people never undergo neuropsychological testing unless a problem is suspected.

Biomarkers, on the other hand, appear to predict decline very objectively. "People [with altered biomarkers] should be considered the real treatment target so we are not focusing all of our efforts on curing people who already have the symptoms of Alzheimer’s dementia, but rather on trying to prevent those symptoms from appearing," Dr. Morris said.

"I would hope I’m wrong about this, but I would say it’s possible that amyloid monotherapies used after the symptomatic stage has begun will not be effective," he said. "At the point when we can make the diagnosis, when symptoms begin, up to 60% of the neurons in layer 2 of the entorhinal cortex are already lost; we are treating a damaged brain. Ideally, we need to treat when the lesions are just beginning, when an intervention might be effective."

DIAN is funded by a multiple-year research grant from the National Institute on Aging. Dr. Morris declared that he had received research grant funding from multiple drug companies.

BARCELONA – The pathologic changes of Alzheimer’s disease may begin as early as 20 years before the expected onset of disease, at least in people whose families carry a high-risk gene, preliminary data from a 6-year longitudinal study suggested.

These first findings from the Dominantly Inherited Alzheimer Network (DIAN) study, a 6-year, cross-sectional, longitudinal study indicate that the use of PET and cerebrospinal fluid biomarkers of beta-amyloid and tau protein may allow researchers to select enriched pools of subjects for the testing of potential drug treatments, and, someday, allow clinicians to target patients with incipient disease for preventive treatment, Dr. John Morris said at the International Conference on Alzheimer’s and Parkinson’s Diseases.

"I have not yet had sufficient sample size or follow-up to predict this completely," said Dr. Morris, DIAN’s principal investigator. "However, I think there are data both from Europe and the U.S. showing that low beta-amyloid 42 [Abeta 42] and high tau in the cerebrospinal fluid together will reach a hazard ratio of 5.2 for becoming demented within 3-4 years. We are just beginning to get these same data for amyloid imaging and the hazard ratio is about the same."

Dr. Morris, professor of neurology at Washington University, St. Louis, said the DIAN study hopes to recruit 400 subjects who are the children of a parent with a known autosomal-dominant Alzheimer’s gene. Currently, three of those genes are known: amyloid precursor protein (APP), presenilin 1, and presenilin 2. He expects that about half the group will carry one of the mutations, while the other half will be unaffected siblings, who will serve as controls. The study involves 10 research institutions in the United States, United Kingdom, and Australia.

Each participant will undergo genetic analysis and the same periodic assessments, including cognitive and clinical testing; brain imaging with Pittsburgh imaging compound B, which binds to Abeta 42 plaques; ¹⁸fluorodeoxyglucose positron emission tomography; MRI; and lumbar punctures to test levels of Abeta 42 and tau. If subjects die during the study, their brains will be autopsied.

"The goals are to try and determine when the pathologic process begins in asymptomatic mutation carriers," Dr. Morris said. "We know, based on the parent’s age of onset, approximately when these carriers will become symptomatic. We want to see the changes, the rates of these changes, and determine to what extent the changes resemble those seen in sporadic Alzheimer’s."

As of last fall, DIAN had collected 106 volunteers, Dr. Morris said. About 70% of those are asymptomatic carriers, with an average age of 37 years, although that varies from 19 to 56 years. The average age of parental onset of dementia symptoms is 47 years, "so we have these folks an average of 10 years before their expected age of onset."

The presenilin 1 mutation is the most common in the group, occurring in 75%; presenilin 2 is present in 10%, and the APP mutation, in 15%.

Comparing the carriers with the noncarriers, the study’s "very preliminary" data indicate that cognitive decline begins as early as 10 years before the expected onset of symptoms, while neuropathologic changes start up to 20 years before.

But scores on the Mini-Mental State Exam (MMSE) for noncarrier siblings of these volunteers "have remained very clearly at 30," which is a normal score, Dr. Morrison said. The noncarriers also had normal scores on the Clinical Dementia Rating Scale (pdf) sum of boxes (CDR-SOB), another test used to identify Alzheimer’s-related cognitive changes.

This was not the case "for carriers, in whom we begin to see declines in the MMSE and the CDR about 10 years before the expected age of onset," Dr. Morris said.

The cerebrospinal fluid biomarkers followed a similar pattern. A decrease in spinal fluid Abeta 42 suggests that the protein is aggregating somewhere else in the body – probably in the characteristic brain plaques. These changes could be seen in carriers 20 years before the expected age of onset. Tau protein levels in the cerebrospinal fluid (CSF) of carriers begin to rise around 20 years before the onset of symptoms, "with a clear acceleration at the time they are changing from asymptomatic to symptomatic," he said.

However, noncarriers have stable levels of both proteins in the CSF at the same ages.

Imaging in the precuneus and caudate with Pittsburgh imaging compound B shows no Abeta 42 accumulation in noncarriers, but in carriers, the protein begins to appear in those regions about the same time that the CSF biomarkers start to change – 20 years before the expected appearance of symptomatic disease.

If these findings can be confirmed, they prove the existence of a long prodromal stage in subjects who are genetically destined to develop Alzheimer’s disease. This has several important applications in both drug research and potential treatment, Dr. Morris noted.

First, the neuropsychological testing scores currently in use, which define normal cognitive function, may be incorrect, because they could be based on cohorts that included individuals who had already experienced cognitive decline, but still fell within the "normal" range.

To illustrate this problem, Dr. Morris referred to the cognitive testing of two subjects. One began with cognitive functioning at the mean of normal, while the other began at 2 standard deviations above the mean. Over a period of years, the first person remained stable at the mean, while the second declined to the mean – showing that this subject was experiencing significant cognitive decline on an individual basis, while still being considered cognitively normal. The patient quickly developed mild cognitive impairment and then Alzheimer’s disease.

"This interferes with the ability to detect very early stages of symptomatic Alzheimer’s based on neuropsychological testing, because the test norms are contaminated by the inclusion of subjects who may have preclinical disease," Dr. Morris said.

Comparative testing or the report of a close companion could detect change in a high-functioning individual, but the majority of people never undergo neuropsychological testing unless a problem is suspected.

Biomarkers, on the other hand, appear to predict decline very objectively. "People [with altered biomarkers] should be considered the real treatment target so we are not focusing all of our efforts on curing people who already have the symptoms of Alzheimer’s dementia, but rather on trying to prevent those symptoms from appearing," Dr. Morris said.

"I would hope I’m wrong about this, but I would say it’s possible that amyloid monotherapies used after the symptomatic stage has begun will not be effective," he said. "At the point when we can make the diagnosis, when symptoms begin, up to 60% of the neurons in layer 2 of the entorhinal cortex are already lost; we are treating a damaged brain. Ideally, we need to treat when the lesions are just beginning, when an intervention might be effective."

DIAN is funded by a multiple-year research grant from the National Institute on Aging. Dr. Morris declared that he had received research grant funding from multiple drug companies.

BARCELONA – The pathologic changes of Alzheimer’s disease may begin as early as 20 years before the expected onset of disease, at least in people whose families carry a high-risk gene, preliminary data from a 6-year longitudinal study suggested.

These first findings from the Dominantly Inherited Alzheimer Network (DIAN) study, a 6-year, cross-sectional, longitudinal study indicate that the use of PET and cerebrospinal fluid biomarkers of beta-amyloid and tau protein may allow researchers to select enriched pools of subjects for the testing of potential drug treatments, and, someday, allow clinicians to target patients with incipient disease for preventive treatment, Dr. John Morris said at the International Conference on Alzheimer’s and Parkinson’s Diseases.

"I have not yet had sufficient sample size or follow-up to predict this completely," said Dr. Morris, DIAN’s principal investigator. "However, I think there are data both from Europe and the U.S. showing that low beta-amyloid 42 [Abeta 42] and high tau in the cerebrospinal fluid together will reach a hazard ratio of 5.2 for becoming demented within 3-4 years. We are just beginning to get these same data for amyloid imaging and the hazard ratio is about the same."

Dr. Morris, professor of neurology at Washington University, St. Louis, said the DIAN study hopes to recruit 400 subjects who are the children of a parent with a known autosomal-dominant Alzheimer’s gene. Currently, three of those genes are known: amyloid precursor protein (APP), presenilin 1, and presenilin 2. He expects that about half the group will carry one of the mutations, while the other half will be unaffected siblings, who will serve as controls. The study involves 10 research institutions in the United States, United Kingdom, and Australia.

Each participant will undergo genetic analysis and the same periodic assessments, including cognitive and clinical testing; brain imaging with Pittsburgh imaging compound B, which binds to Abeta 42 plaques; ¹⁸fluorodeoxyglucose positron emission tomography; MRI; and lumbar punctures to test levels of Abeta 42 and tau. If subjects die during the study, their brains will be autopsied.

"The goals are to try and determine when the pathologic process begins in asymptomatic mutation carriers," Dr. Morris said. "We know, based on the parent’s age of onset, approximately when these carriers will become symptomatic. We want to see the changes, the rates of these changes, and determine to what extent the changes resemble those seen in sporadic Alzheimer’s."

As of last fall, DIAN had collected 106 volunteers, Dr. Morris said. About 70% of those are asymptomatic carriers, with an average age of 37 years, although that varies from 19 to 56 years. The average age of parental onset of dementia symptoms is 47 years, "so we have these folks an average of 10 years before their expected age of onset."

The presenilin 1 mutation is the most common in the group, occurring in 75%; presenilin 2 is present in 10%, and the APP mutation, in 15%.

Comparing the carriers with the noncarriers, the study’s "very preliminary" data indicate that cognitive decline begins as early as 10 years before the expected onset of symptoms, while neuropathologic changes start up to 20 years before.

But scores on the Mini-Mental State Exam (MMSE) for noncarrier siblings of these volunteers "have remained very clearly at 30," which is a normal score, Dr. Morrison said. The noncarriers also had normal scores on the Clinical Dementia Rating Scale (pdf) sum of boxes (CDR-SOB), another test used to identify Alzheimer’s-related cognitive changes.

This was not the case "for carriers, in whom we begin to see declines in the MMSE and the CDR about 10 years before the expected age of onset," Dr. Morris said.

The cerebrospinal fluid biomarkers followed a similar pattern. A decrease in spinal fluid Abeta 42 suggests that the protein is aggregating somewhere else in the body – probably in the characteristic brain plaques. These changes could be seen in carriers 20 years before the expected age of onset. Tau protein levels in the cerebrospinal fluid (CSF) of carriers begin to rise around 20 years before the onset of symptoms, "with a clear acceleration at the time they are changing from asymptomatic to symptomatic," he said.

However, noncarriers have stable levels of both proteins in the CSF at the same ages.

Imaging in the precuneus and caudate with Pittsburgh imaging compound B shows no Abeta 42 accumulation in noncarriers, but in carriers, the protein begins to appear in those regions about the same time that the CSF biomarkers start to change – 20 years before the expected appearance of symptomatic disease.

If these findings can be confirmed, they prove the existence of a long prodromal stage in subjects who are genetically destined to develop Alzheimer’s disease. This has several important applications in both drug research and potential treatment, Dr. Morris noted.

First, the neuropsychological testing scores currently in use, which define normal cognitive function, may be incorrect, because they could be based on cohorts that included individuals who had already experienced cognitive decline, but still fell within the "normal" range.

To illustrate this problem, Dr. Morris referred to the cognitive testing of two subjects. One began with cognitive functioning at the mean of normal, while the other began at 2 standard deviations above the mean. Over a period of years, the first person remained stable at the mean, while the second declined to the mean – showing that this subject was experiencing significant cognitive decline on an individual basis, while still being considered cognitively normal. The patient quickly developed mild cognitive impairment and then Alzheimer’s disease.

"This interferes with the ability to detect very early stages of symptomatic Alzheimer’s based on neuropsychological testing, because the test norms are contaminated by the inclusion of subjects who may have preclinical disease," Dr. Morris said.

Comparative testing or the report of a close companion could detect change in a high-functioning individual, but the majority of people never undergo neuropsychological testing unless a problem is suspected.

Biomarkers, on the other hand, appear to predict decline very objectively. "People [with altered biomarkers] should be considered the real treatment target so we are not focusing all of our efforts on curing people who already have the symptoms of Alzheimer’s dementia, but rather on trying to prevent those symptoms from appearing," Dr. Morris said.

"I would hope I’m wrong about this, but I would say it’s possible that amyloid monotherapies used after the symptomatic stage has begun will not be effective," he said. "At the point when we can make the diagnosis, when symptoms begin, up to 60% of the neurons in layer 2 of the entorhinal cortex are already lost; we are treating a damaged brain. Ideally, we need to treat when the lesions are just beginning, when an intervention might be effective."

DIAN is funded by a multiple-year research grant from the National Institute on Aging. Dr. Morris declared that he had received research grant funding from multiple drug companies.

BARCELONA – The pathologic changes of Alzheimer’s disease may begin as early as 20 years before the expected onset of disease, at least in people whose families carry a high-risk gene, preliminary data from a 6-year longitudinal study suggested.

These first findings from the Dominantly Inherited Alzheimer Network (DIAN) study, a 6-year, cross-sectional, longitudinal study indicate that the use of PET and cerebrospinal fluid biomarkers of beta-amyloid and tau protein may allow researchers to select enriched pools of subjects for the testing of potential drug treatments, and, someday, allow clinicians to target patients with incipient disease for preventive treatment, Dr. John Morris said at the International Conference on Alzheimer’s and Parkinson’s Diseases.

"I have not yet had sufficient sample size or follow-up to predict this completely," said Dr. Morris, DIAN’s principal investigator. "However, I think there are data both from Europe and the U.S. showing that low beta-amyloid 42 [Abeta 42] and high tau in the cerebrospinal fluid together will reach a hazard ratio of 5.2 for becoming demented within 3-4 years. We are just beginning to get these same data for amyloid imaging and the hazard ratio is about the same."

Dr. Morris, professor of neurology at Washington University, St. Louis, said the DIAN study hopes to recruit 400 subjects who are the children of a parent with a known autosomal-dominant Alzheimer’s gene. Currently, three of those genes are known: amyloid precursor protein (APP), presenilin 1, and presenilin 2. He expects that about half the group will carry one of the mutations, while the other half will be unaffected siblings, who will serve as controls. The study involves 10 research institutions in the United States, United Kingdom, and Australia.

Each participant will undergo genetic analysis and the same periodic assessments, including cognitive and clinical testing; brain imaging with Pittsburgh imaging compound B, which binds to Abeta 42 plaques; ¹⁸fluorodeoxyglucose positron emission tomography; MRI; and lumbar punctures to test levels of Abeta 42 and tau. If subjects die during the study, their brains will be autopsied.

"The goals are to try and determine when the pathologic process begins in asymptomatic mutation carriers," Dr. Morris said. "We know, based on the parent’s age of onset, approximately when these carriers will become symptomatic. We want to see the changes, the rates of these changes, and determine to what extent the changes resemble those seen in sporadic Alzheimer’s."

As of last fall, DIAN had collected 106 volunteers, Dr. Morris said. About 70% of those are asymptomatic carriers, with an average age of 37 years, although that varies from 19 to 56 years. The average age of parental onset of dementia symptoms is 47 years, "so we have these folks an average of 10 years before their expected age of onset."

The presenilin 1 mutation is the most common in the group, occurring in 75%; presenilin 2 is present in 10%, and the APP mutation, in 15%.

Comparing the carriers with the noncarriers, the study’s "very preliminary" data indicate that cognitive decline begins as early as 10 years before the expected onset of symptoms, while neuropathologic changes start up to 20 years before.

But scores on the Mini-Mental State Exam (MMSE) for noncarrier siblings of these volunteers "have remained very clearly at 30," which is a normal score, Dr. Morrison said. The noncarriers also had normal scores on the Clinical Dementia Rating Scale (pdf) sum of boxes (CDR-SOB), another test used to identify Alzheimer’s-related cognitive changes.

This was not the case "for carriers, in whom we begin to see declines in the MMSE and the CDR about 10 years before the expected age of onset," Dr. Morris said.

The cerebrospinal fluid biomarkers followed a similar pattern. A decrease in spinal fluid Abeta 42 suggests that the protein is aggregating somewhere else in the body – probably in the characteristic brain plaques. These changes could be seen in carriers 20 years before the expected age of onset. Tau protein levels in the cerebrospinal fluid (CSF) of carriers begin to rise around 20 years before the onset of symptoms, "with a clear acceleration at the time they are changing from asymptomatic to symptomatic," he said.

However, noncarriers have stable levels of both proteins in the CSF at the same ages.

Imaging in the precuneus and caudate with Pittsburgh imaging compound B shows no Abeta 42 accumulation in noncarriers, but in carriers, the protein begins to appear in those regions about the same time that the CSF biomarkers start to change – 20 years before the expected appearance of symptomatic disease.

If these findings can be confirmed, they prove the existence of a long prodromal stage in subjects who are genetically destined to develop Alzheimer’s disease. This has several important applications in both drug research and potential treatment, Dr. Morris noted.

First, the neuropsychological testing scores currently in use, which define normal cognitive function, may be incorrect, because they could be based on cohorts that included individuals who had already experienced cognitive decline, but still fell within the "normal" range.

To illustrate this problem, Dr. Morris referred to the cognitive testing of two subjects. One began with cognitive functioning at the mean of normal, while the other began at 2 standard deviations above the mean. Over a period of years, the first person remained stable at the mean, while the second declined to the mean – showing that this subject was experiencing significant cognitive decline on an individual basis, while still being considered cognitively normal. The patient quickly developed mild cognitive impairment and then Alzheimer’s disease.

"This interferes with the ability to detect very early stages of symptomatic Alzheimer’s based on neuropsychological testing, because the test norms are contaminated by the inclusion of subjects who may have preclinical disease," Dr. Morris said.

Comparative testing or the report of a close companion could detect change in a high-functioning individual, but the majority of people never undergo neuropsychological testing unless a problem is suspected.

Biomarkers, on the other hand, appear to predict decline very objectively. "People [with altered biomarkers] should be considered the real treatment target so we are not focusing all of our efforts on curing people who already have the symptoms of Alzheimer’s dementia, but rather on trying to prevent those symptoms from appearing," Dr. Morris said.

"I would hope I’m wrong about this, but I would say it’s possible that amyloid monotherapies used after the symptomatic stage has begun will not be effective," he said. "At the point when we can make the diagnosis, when symptoms begin, up to 60% of the neurons in layer 2 of the entorhinal cortex are already lost; we are treating a damaged brain. Ideally, we need to treat when the lesions are just beginning, when an intervention might be effective."

DIAN is funded by a multiple-year research grant from the National Institute on Aging. Dr. Morris declared that he had received research grant funding from multiple drug companies.

BARCELONA – The pathologic changes of Alzheimer’s disease may begin as early as 20 years before the expected onset of disease, at least in people whose families carry a high-risk gene, preliminary data from a 6-year longitudinal study suggested.

These first findings from the Dominantly Inherited Alzheimer Network (DIAN) study, a 6-year, cross-sectional, longitudinal study indicate that the use of PET and cerebrospinal fluid biomarkers of beta-amyloid and tau protein may allow researchers to select enriched pools of subjects for the testing of potential drug treatments, and, someday, allow clinicians to target patients with incipient disease for preventive treatment, Dr. John Morris said at the International Conference on Alzheimer’s and Parkinson’s Diseases.

"I have not yet had sufficient sample size or follow-up to predict this completely," said Dr. Morris, DIAN’s principal investigator. "However, I think there are data both from Europe and the U.S. showing that low beta-amyloid 42 [Abeta 42] and high tau in the cerebrospinal fluid together will reach a hazard ratio of 5.2 for becoming demented within 3-4 years. We are just beginning to get these same data for amyloid imaging and the hazard ratio is about the same."

Dr. Morris, professor of neurology at Washington University, St. Louis, said the DIAN study hopes to recruit 400 subjects who are the children of a parent with a known autosomal-dominant Alzheimer’s gene. Currently, three of those genes are known: amyloid precursor protein (APP), presenilin 1, and presenilin 2. He expects that about half the group will carry one of the mutations, while the other half will be unaffected siblings, who will serve as controls. The study involves 10 research institutions in the United States, United Kingdom, and Australia.

Each participant will undergo genetic analysis and the same periodic assessments, including cognitive and clinical testing; brain imaging with Pittsburgh imaging compound B, which binds to Abeta 42 plaques; ¹⁸fluorodeoxyglucose positron emission tomography; MRI; and lumbar punctures to test levels of Abeta 42 and tau. If subjects die during the study, their brains will be autopsied.

"The goals are to try and determine when the pathologic process begins in asymptomatic mutation carriers," Dr. Morris said. "We know, based on the parent’s age of onset, approximately when these carriers will become symptomatic. We want to see the changes, the rates of these changes, and determine to what extent the changes resemble those seen in sporadic Alzheimer’s."

As of last fall, DIAN had collected 106 volunteers, Dr. Morris said. About 70% of those are asymptomatic carriers, with an average age of 37 years, although that varies from 19 to 56 years. The average age of parental onset of dementia symptoms is 47 years, "so we have these folks an average of 10 years before their expected age of onset."

The presenilin 1 mutation is the most common in the group, occurring in 75%; presenilin 2 is present in 10%, and the APP mutation, in 15%.

Comparing the carriers with the noncarriers, the study’s "very preliminary" data indicate that cognitive decline begins as early as 10 years before the expected onset of symptoms, while neuropathologic changes start up to 20 years before.

But scores on the Mini-Mental State Exam (MMSE) for noncarrier siblings of these volunteers "have remained very clearly at 30," which is a normal score, Dr. Morrison said. The noncarriers also had normal scores on the Clinical Dementia Rating Scale (pdf) sum of boxes (CDR-SOB), another test used to identify Alzheimer’s-related cognitive changes.

This was not the case "for carriers, in whom we begin to see declines in the MMSE and the CDR about 10 years before the expected age of onset," Dr. Morris said.

The cerebrospinal fluid biomarkers followed a similar pattern. A decrease in spinal fluid Abeta 42 suggests that the protein is aggregating somewhere else in the body – probably in the characteristic brain plaques. These changes could be seen in carriers 20 years before the expected age of onset. Tau protein levels in the cerebrospinal fluid (CSF) of carriers begin to rise around 20 years before the onset of symptoms, "with a clear acceleration at the time they are changing from asymptomatic to symptomatic," he said.

However, noncarriers have stable levels of both proteins in the CSF at the same ages.

Imaging in the precuneus and caudate with Pittsburgh imaging compound B shows no Abeta 42 accumulation in noncarriers, but in carriers, the protein begins to appear in those regions about the same time that the CSF biomarkers start to change – 20 years before the expected appearance of symptomatic disease.

If these findings can be confirmed, they prove the existence of a long prodromal stage in subjects who are genetically destined to develop Alzheimer’s disease. This has several important applications in both drug research and potential treatment, Dr. Morris noted.

First, the neuropsychological testing scores currently in use, which define normal cognitive function, may be incorrect, because they could be based on cohorts that included individuals who had already experienced cognitive decline, but still fell within the "normal" range.

To illustrate this problem, Dr. Morris referred to the cognitive testing of two subjects. One began with cognitive functioning at the mean of normal, while the other began at 2 standard deviations above the mean. Over a period of years, the first person remained stable at the mean, while the second declined to the mean – showing that this subject was experiencing significant cognitive decline on an individual basis, while still being considered cognitively normal. The patient quickly developed mild cognitive impairment and then Alzheimer’s disease.

"This interferes with the ability to detect very early stages of symptomatic Alzheimer’s based on neuropsychological testing, because the test norms are contaminated by the inclusion of subjects who may have preclinical disease," Dr. Morris said.

Comparative testing or the report of a close companion could detect change in a high-functioning individual, but the majority of people never undergo neuropsychological testing unless a problem is suspected.

Biomarkers, on the other hand, appear to predict decline very objectively. "People [with altered biomarkers] should be considered the real treatment target so we are not focusing all of our efforts on curing people who already have the symptoms of Alzheimer’s dementia, but rather on trying to prevent those symptoms from appearing," Dr. Morris said.

"I would hope I’m wrong about this, but I would say it’s possible that amyloid monotherapies used after the symptomatic stage has begun will not be effective," he said. "At the point when we can make the diagnosis, when symptoms begin, up to 60% of the neurons in layer 2 of the entorhinal cortex are already lost; we are treating a damaged brain. Ideally, we need to treat when the lesions are just beginning, when an intervention might be effective."

DIAN is funded by a multiple-year research grant from the National Institute on Aging. Dr. Morris declared that he had received research grant funding from multiple drug companies.

BARCELONA – The pathologic changes of Alzheimer’s disease may begin as early as 20 years before the expected onset of disease, at least in people whose families carry a high-risk gene, preliminary data from a 6-year longitudinal study suggested.

These first findings from the Dominantly Inherited Alzheimer Network (DIAN) study, a 6-year, cross-sectional, longitudinal study indicate that the use of PET and cerebrospinal fluid biomarkers of beta-amyloid and tau protein may allow researchers to select enriched pools of subjects for the testing of potential drug treatments, and, someday, allow clinicians to target patients with incipient disease for preventive treatment, Dr. John Morris said at the International Conference on Alzheimer’s and Parkinson’s Diseases.

"I have not yet had sufficient sample size or follow-up to predict this completely," said Dr. Morris, DIAN’s principal investigator. "However, I think there are data both from Europe and the U.S. showing that low beta-amyloid 42 [Abeta 42] and high tau in the cerebrospinal fluid together will reach a hazard ratio of 5.2 for becoming demented within 3-4 years. We are just beginning to get these same data for amyloid imaging and the hazard ratio is about the same."

Dr. Morris, professor of neurology at Washington University, St. Louis, said the DIAN study hopes to recruit 400 subjects who are the children of a parent with a known autosomal-dominant Alzheimer’s gene. Currently, three of those genes are known: amyloid precursor protein (APP), presenilin 1, and presenilin 2. He expects that about half the group will carry one of the mutations, while the other half will be unaffected siblings, who will serve as controls. The study involves 10 research institutions in the United States, United Kingdom, and Australia.

Each participant will undergo genetic analysis and the same periodic assessments, including cognitive and clinical testing; brain imaging with Pittsburgh imaging compound B, which binds to Abeta 42 plaques; ¹⁸fluorodeoxyglucose positron emission tomography; MRI; and lumbar punctures to test levels of Abeta 42 and tau. If subjects die during the study, their brains will be autopsied.

"The goals are to try and determine when the pathologic process begins in asymptomatic mutation carriers," Dr. Morris said. "We know, based on the parent’s age of onset, approximately when these carriers will become symptomatic. We want to see the changes, the rates of these changes, and determine to what extent the changes resemble those seen in sporadic Alzheimer’s."

As of last fall, DIAN had collected 106 volunteers, Dr. Morris said. About 70% of those are asymptomatic carriers, with an average age of 37 years, although that varies from 19 to 56 years. The average age of parental onset of dementia symptoms is 47 years, "so we have these folks an average of 10 years before their expected age of onset."

The presenilin 1 mutation is the most common in the group, occurring in 75%; presenilin 2 is present in 10%, and the APP mutation, in 15%.

Comparing the carriers with the noncarriers, the study’s "very preliminary" data indicate that cognitive decline begins as early as 10 years before the expected onset of symptoms, while neuropathologic changes start up to 20 years before.

But scores on the Mini-Mental State Exam (MMSE) for noncarrier siblings of these volunteers "have remained very clearly at 30," which is a normal score, Dr. Morrison said. The noncarriers also had normal scores on the Clinical Dementia Rating Scale (pdf) sum of boxes (CDR-SOB), another test used to identify Alzheimer’s-related cognitive changes.

This was not the case "for carriers, in whom we begin to see declines in the MMSE and the CDR about 10 years before the expected age of onset," Dr. Morris said.

The cerebrospinal fluid biomarkers followed a similar pattern. A decrease in spinal fluid Abeta 42 suggests that the protein is aggregating somewhere else in the body – probably in the characteristic brain plaques. These changes could be seen in carriers 20 years before the expected age of onset. Tau protein levels in the cerebrospinal fluid (CSF) of carriers begin to rise around 20 years before the onset of symptoms, "with a clear acceleration at the time they are changing from asymptomatic to symptomatic," he said.

However, noncarriers have stable levels of both proteins in the CSF at the same ages.

Imaging in the precuneus and caudate with Pittsburgh imaging compound B shows no Abeta 42 accumulation in noncarriers, but in carriers, the protein begins to appear in those regions about the same time that the CSF biomarkers start to change – 20 years before the expected appearance of symptomatic disease.

If these findings can be confirmed, they prove the existence of a long prodromal stage in subjects who are genetically destined to develop Alzheimer’s disease. This has several important applications in both drug research and potential treatment, Dr. Morris noted.

First, the neuropsychological testing scores currently in use, which define normal cognitive function, may be incorrect, because they could be based on cohorts that included individuals who had already experienced cognitive decline, but still fell within the "normal" range.

To illustrate this problem, Dr. Morris referred to the cognitive testing of two subjects. One began with cognitive functioning at the mean of normal, while the other began at 2 standard deviations above the mean. Over a period of years, the first person remained stable at the mean, while the second declined to the mean – showing that this subject was experiencing significant cognitive decline on an individual basis, while still being considered cognitively normal. The patient quickly developed mild cognitive impairment and then Alzheimer’s disease.

"This interferes with the ability to detect very early stages of symptomatic Alzheimer’s based on neuropsychological testing, because the test norms are contaminated by the inclusion of subjects who may have preclinical disease," Dr. Morris said.

Comparative testing or the report of a close companion could detect change in a high-functioning individual, but the majority of people never undergo neuropsychological testing unless a problem is suspected.

Biomarkers, on the other hand, appear to predict decline very objectively. "People [with altered biomarkers] should be considered the real treatment target so we are not focusing all of our efforts on curing people who already have the symptoms of Alzheimer’s dementia, but rather on trying to prevent those symptoms from appearing," Dr. Morris said.

"I would hope I’m wrong about this, but I would say it’s possible that amyloid monotherapies used after the symptomatic stage has begun will not be effective," he said. "At the point when we can make the diagnosis, when symptoms begin, up to 60% of the neurons in layer 2 of the entorhinal cortex are already lost; we are treating a damaged brain. Ideally, we need to treat when the lesions are just beginning, when an intervention might be effective."

DIAN is funded by a multiple-year research grant from the National Institute on Aging. Dr. Morris declared that he had received research grant funding from multiple drug companies.