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Social isolation linked to lower brain volume
Further, the association between social isolation and reduced brain volume appears to be at least partly mediated by depressive symptoms.
“We believe that efforts should be made to reduce social isolation among the elderly as much as possible,” investigator Toshiharu Ninomiya, MD, PhD, professor of epidemiology and public health at Kyushu University in Fukuoka, Japan, said in an interview.
The study was published online in Neurology.
A dementia prevention strategy
Dr. Ninomiya noted there have been several studies suggesting that social interaction is beneficial in preventing cognitive decline and the onset of dementia.
In addition, recent epidemiological studies have shown social isolation is associated with a risk for cognitive decline and dementia.
Although the investigators note that very little is known about the link between the two, some studies have shown that social isolation is linked with depressive symptoms in older adults, and late-life depression has been associated with brain atrophy.
To explore the potential link between social isolation and brain atrophy, as well as the role of depression as a potential mediator, the investigators studied nearly 9,000 citizens aged 65 and older as part of the Japan Prospective Studies Collaboration for Aging and Dementia (JPSC-AD), an ongoing, community-based nationwide cohort study of dementia in Japan.
Participants were recruited from eight research sites across Japan, and each had a baseline MRI scan between 2016 and 2018. The investigators excluded those with a dementia diagnosis at baseline. Self-reported frequency of social contact was categorized as every day, several times a week, several times a month, or seldom.
Participants also answered questions about medical history and treatment, antihypertensive or antidiabetic medications, exercise, current alcohol intake, and smoking habits. Depressive symptoms were assessed with the Geriatric Depression Scale. Of the participants, 57% were women, and the mean age was 73 years.
Lower brain volume
Total brain volume was lower in those with the lowest frequency of social contact vs. those with the highest frequency (67.3% vs. 67.8%). Less social contact was also linked to smaller temporal lobe, occipital lobe, cingulum, hippocampus, and amygdala volumes.
White matter lesion volume increased with fewer social interactions, from 0.26% in the most social group to 0.30% in the least.
Cognitive function was higher in participants who had daily social contact, compared with those who had the least contact (28 vs. 27 on the Mini-Mental State Examination; P < .001). Scores between 25 and 30 are considered normal.
Depressive symptoms were lower in the daily contact group, compared with the seldom-contact group (P < .001).
The team also found that lower frequency of social contact was significantly associated with the smaller superior, middle, or inferior temporal gyrus; and a smaller fusiform gyrus, transverse temporal gyrus, temporal pole, and entorhinal cortex, among other subregions.
Mediation analyses indicated that depressive symptoms accounted for only 15%-29% of the associations of lower frequency of social contact with each regional volume.
Worse physical health
The results also showed that socially isolated participants were more likely to have diabetes, to have hypertension, to smoke, and to be physically inactive.
“Cardiovascular risk factors have been reported to cause endothelial dysfunction in the brain, which could in turn lead to problems in maintaining microcirculation and blood-brain barrier function,” the investigators write.
Some epidemiological studies have associated cardiovascular risk factors with brain atrophy, they noted, which could have been one of the underlying mechanisms.
Another possibility is that reduced cognitive stimulation due to social isolation may cause brain atrophy, they add.
“Ultimately,” Dr. Ninomiya said, “the detailed mechanism of the relationship between social isolation and brain volume is not yet clear.”
He also said more research is needed to know whether the findings would apply to people in other countries.
In an accompanying editorial, Alexa Walter, PhD, and Danielle Sandsmark, MD, PhD, from the University of Pennsylvania, Philadelphia, note that isolation has been associated with many adverse health outcomes, including increased risk of heart disease, stroke, and premature death.
“Given these findings, future work considering social health factors in the context of neurological disease is an important area of research to consider. Additionally, leveraging other existing longitudinal studies could provide us with an opportunity to better understand these relationships within populations and inform public policy to address these issues,” Dr. Walter and Dr. Sandsmark write.
The study was funded by the Japan Agency for Medical Research and Development and Suntory Holdings Limited. Dr. Ninomiya reports receiving grants from Suntory Holdings Limited.
A version of this article first appeared on Medscape.com.
Further, the association between social isolation and reduced brain volume appears to be at least partly mediated by depressive symptoms.
“We believe that efforts should be made to reduce social isolation among the elderly as much as possible,” investigator Toshiharu Ninomiya, MD, PhD, professor of epidemiology and public health at Kyushu University in Fukuoka, Japan, said in an interview.
The study was published online in Neurology.
A dementia prevention strategy
Dr. Ninomiya noted there have been several studies suggesting that social interaction is beneficial in preventing cognitive decline and the onset of dementia.
In addition, recent epidemiological studies have shown social isolation is associated with a risk for cognitive decline and dementia.
Although the investigators note that very little is known about the link between the two, some studies have shown that social isolation is linked with depressive symptoms in older adults, and late-life depression has been associated with brain atrophy.
To explore the potential link between social isolation and brain atrophy, as well as the role of depression as a potential mediator, the investigators studied nearly 9,000 citizens aged 65 and older as part of the Japan Prospective Studies Collaboration for Aging and Dementia (JPSC-AD), an ongoing, community-based nationwide cohort study of dementia in Japan.
Participants were recruited from eight research sites across Japan, and each had a baseline MRI scan between 2016 and 2018. The investigators excluded those with a dementia diagnosis at baseline. Self-reported frequency of social contact was categorized as every day, several times a week, several times a month, or seldom.
Participants also answered questions about medical history and treatment, antihypertensive or antidiabetic medications, exercise, current alcohol intake, and smoking habits. Depressive symptoms were assessed with the Geriatric Depression Scale. Of the participants, 57% were women, and the mean age was 73 years.
Lower brain volume
Total brain volume was lower in those with the lowest frequency of social contact vs. those with the highest frequency (67.3% vs. 67.8%). Less social contact was also linked to smaller temporal lobe, occipital lobe, cingulum, hippocampus, and amygdala volumes.
White matter lesion volume increased with fewer social interactions, from 0.26% in the most social group to 0.30% in the least.
Cognitive function was higher in participants who had daily social contact, compared with those who had the least contact (28 vs. 27 on the Mini-Mental State Examination; P < .001). Scores between 25 and 30 are considered normal.
Depressive symptoms were lower in the daily contact group, compared with the seldom-contact group (P < .001).
The team also found that lower frequency of social contact was significantly associated with the smaller superior, middle, or inferior temporal gyrus; and a smaller fusiform gyrus, transverse temporal gyrus, temporal pole, and entorhinal cortex, among other subregions.
Mediation analyses indicated that depressive symptoms accounted for only 15%-29% of the associations of lower frequency of social contact with each regional volume.
Worse physical health
The results also showed that socially isolated participants were more likely to have diabetes, to have hypertension, to smoke, and to be physically inactive.
“Cardiovascular risk factors have been reported to cause endothelial dysfunction in the brain, which could in turn lead to problems in maintaining microcirculation and blood-brain barrier function,” the investigators write.
Some epidemiological studies have associated cardiovascular risk factors with brain atrophy, they noted, which could have been one of the underlying mechanisms.
Another possibility is that reduced cognitive stimulation due to social isolation may cause brain atrophy, they add.
“Ultimately,” Dr. Ninomiya said, “the detailed mechanism of the relationship between social isolation and brain volume is not yet clear.”
He also said more research is needed to know whether the findings would apply to people in other countries.
In an accompanying editorial, Alexa Walter, PhD, and Danielle Sandsmark, MD, PhD, from the University of Pennsylvania, Philadelphia, note that isolation has been associated with many adverse health outcomes, including increased risk of heart disease, stroke, and premature death.
“Given these findings, future work considering social health factors in the context of neurological disease is an important area of research to consider. Additionally, leveraging other existing longitudinal studies could provide us with an opportunity to better understand these relationships within populations and inform public policy to address these issues,” Dr. Walter and Dr. Sandsmark write.
The study was funded by the Japan Agency for Medical Research and Development and Suntory Holdings Limited. Dr. Ninomiya reports receiving grants from Suntory Holdings Limited.
A version of this article first appeared on Medscape.com.
Further, the association between social isolation and reduced brain volume appears to be at least partly mediated by depressive symptoms.
“We believe that efforts should be made to reduce social isolation among the elderly as much as possible,” investigator Toshiharu Ninomiya, MD, PhD, professor of epidemiology and public health at Kyushu University in Fukuoka, Japan, said in an interview.
The study was published online in Neurology.
A dementia prevention strategy
Dr. Ninomiya noted there have been several studies suggesting that social interaction is beneficial in preventing cognitive decline and the onset of dementia.
In addition, recent epidemiological studies have shown social isolation is associated with a risk for cognitive decline and dementia.
Although the investigators note that very little is known about the link between the two, some studies have shown that social isolation is linked with depressive symptoms in older adults, and late-life depression has been associated with brain atrophy.
To explore the potential link between social isolation and brain atrophy, as well as the role of depression as a potential mediator, the investigators studied nearly 9,000 citizens aged 65 and older as part of the Japan Prospective Studies Collaboration for Aging and Dementia (JPSC-AD), an ongoing, community-based nationwide cohort study of dementia in Japan.
Participants were recruited from eight research sites across Japan, and each had a baseline MRI scan between 2016 and 2018. The investigators excluded those with a dementia diagnosis at baseline. Self-reported frequency of social contact was categorized as every day, several times a week, several times a month, or seldom.
Participants also answered questions about medical history and treatment, antihypertensive or antidiabetic medications, exercise, current alcohol intake, and smoking habits. Depressive symptoms were assessed with the Geriatric Depression Scale. Of the participants, 57% were women, and the mean age was 73 years.
Lower brain volume
Total brain volume was lower in those with the lowest frequency of social contact vs. those with the highest frequency (67.3% vs. 67.8%). Less social contact was also linked to smaller temporal lobe, occipital lobe, cingulum, hippocampus, and amygdala volumes.
White matter lesion volume increased with fewer social interactions, from 0.26% in the most social group to 0.30% in the least.
Cognitive function was higher in participants who had daily social contact, compared with those who had the least contact (28 vs. 27 on the Mini-Mental State Examination; P < .001). Scores between 25 and 30 are considered normal.
Depressive symptoms were lower in the daily contact group, compared with the seldom-contact group (P < .001).
The team also found that lower frequency of social contact was significantly associated with the smaller superior, middle, or inferior temporal gyrus; and a smaller fusiform gyrus, transverse temporal gyrus, temporal pole, and entorhinal cortex, among other subregions.
Mediation analyses indicated that depressive symptoms accounted for only 15%-29% of the associations of lower frequency of social contact with each regional volume.
Worse physical health
The results also showed that socially isolated participants were more likely to have diabetes, to have hypertension, to smoke, and to be physically inactive.
“Cardiovascular risk factors have been reported to cause endothelial dysfunction in the brain, which could in turn lead to problems in maintaining microcirculation and blood-brain barrier function,” the investigators write.
Some epidemiological studies have associated cardiovascular risk factors with brain atrophy, they noted, which could have been one of the underlying mechanisms.
Another possibility is that reduced cognitive stimulation due to social isolation may cause brain atrophy, they add.
“Ultimately,” Dr. Ninomiya said, “the detailed mechanism of the relationship between social isolation and brain volume is not yet clear.”
He also said more research is needed to know whether the findings would apply to people in other countries.
In an accompanying editorial, Alexa Walter, PhD, and Danielle Sandsmark, MD, PhD, from the University of Pennsylvania, Philadelphia, note that isolation has been associated with many adverse health outcomes, including increased risk of heart disease, stroke, and premature death.
“Given these findings, future work considering social health factors in the context of neurological disease is an important area of research to consider. Additionally, leveraging other existing longitudinal studies could provide us with an opportunity to better understand these relationships within populations and inform public policy to address these issues,” Dr. Walter and Dr. Sandsmark write.
The study was funded by the Japan Agency for Medical Research and Development and Suntory Holdings Limited. Dr. Ninomiya reports receiving grants from Suntory Holdings Limited.
A version of this article first appeared on Medscape.com.
FROM NEUROLOGY
New Alzheimer’s drugs: Setting realistic expectations
With the Food and Drug Administration’s full stamp of approval in hand, Leqembi (lecanemab) is poised to catapult us into a new era of treatment for Alzheimer’s disease. And now that the donanemab trial data are out, there’s another antiamyloid drug waiting in the wings.
To finally have true disease-modifying therapies for Alzheimer’s disease is a massive step forward for a field that’s been plagued with disappointment. But these drugs come with serious concerns and unknowns. They will require complex decision-making, putting doctors, patients, and their families in a medical quandary.
Striking the right balance between cautious optimism and realistic expectations will be a formidable challenge.
Managing patient and family expectations
These drugs are no magic bullet. They slow down the dementia’s progression, buying patients more time (on the order of months) before they begin to experience significant worsening. We’ll need a lot more information from research and clinical experience before we can understand how meaningful that treatment effect is. Right now, it is unclear whether eligible patients and their families will even perceive tangible differences.
In the CLARITY-AD trial, participants on lecanemab experienced a 27% slowing in the rate of cognitive decline over 18 months. Donanemab was shown to slow decline in memory and cognition by about 35% over the same time frame in the TRAILBLAZER-ALZ 2 trial. That translates to more time for patients and their families to enjoy independence, maintain normal life, and stave off the most distressing parts of the disease.
But what happens after 18 months of treatment – will the treatment effect magnify or dissipate? How much time are we really buying in the long run? Counseling patients and their families is made all the more difficult when the answers to important questions like these remain to be seen.
Only a sliver of Alzheimer’s patients are current candidates
The fact is that most patients living with Alzheimer’s disease will not qualify for treatment with these drugs. Lecanemab is approved for people with early-stage disease, meaning their dementia is mild or they have mild cognitive impairment, which is a precursor to full-blown Alzheimer’s disease. Of the 6 million people in the United States living with Alzheimer’s, about 1.5 million are estimated to fall into that category. We can expect to see a similar qualifier for donanemab if it receives FDA approval, especially because that trial suggested a more pronounced treatment effect for patients in the earliest stages of the disease.
Even if a patient hits the sweet spot where they have just enough cognitive impairment, but not too much, they aren’t technically therapeutic candidates until prerequisite testing confirms amyloid protein accumulation in the brain via PET scan or cerebrospinal fluid analysis.
Even then, the FDA’s boxed warning for lecanemab recommends that patients undergo genetic testing for the apo E4 mutation to identify those at a particularly high risk for severe adverse effects including brain bleeding and swelling. This recommendation is not unreasonable considering that 15% of the Alzheimer’s population has two copies of the apo E4 mutation and fall into that high-risk group.
Significant risks
Antiamyloid drugs are well-known to cause serious side effects. In the lecanemab trial, 13% of participants receiving Leqembi experienced brain swelling (vs. 2% of participants receiving placebo) and 17% of participants had brain bleeding (vs. 9% of participants on placebo). In the donanemab trial, brain bleeding occurred in 31.4% of participants on the drug (vs. 13.6% on placebo) and swelling occurred in 24% (vs. 2.1% receiving placebo). Thankfully, in both trials, most of these adverse events did not produce significant symptoms, but in rare cases these events caused severe or catastrophic neurologic injury, including death.
How can we best guide patients and their families to weigh the uncertain benefits against potentially serious risks? We can start by considering the patient characteristics most likely to portend increased risk for serious side effects: apo E4 mutations, blood thinner use, and the presence of microhemorrhages on brain imaging. But after that, we’re left with a lot of uncertainty in terms of which patients are most likely to see meaningful clinical improvements from the drug and unknown factors that may increase the risks of treatment.
A costly therapy
Medicare plans to cover 80% of lecanemab’s steep cost of $26,500 per year. Still, that will leave many patients with a hefty copay, potentially over $6,000 per year. But that only scratches the surface. Consider the frequent medical visits, repeated brain scans, laboratory tests, and infusion center appointments. It’s been estimated that all-in, the treatment will actually cost about $90,000 per year.
Yes, Medicare will reimburse a large portion of that cost, but it adds up to an estimated $2 billion per year for about 85,000 patients. This will probably spur increases to Medicare premiums, among other economic consequences for the health care system.
We’ll probably have to wait for an FDA approval decision before we know where donanemab will be priced.
Logistical challenges could be a rate-limiting step
Ask anyone who’s tried to see a neurologist recently, and they’ll tell you that the wait for a new patient appointment is months long. The shortage of neurologists in the United States is already a crisis, and there are even fewer cognitive neurologists. How long will patients be forced to wait for their diagnosis?
Many geriatricians will get comfortable prescribing these drugs, but will our already overburdened primary care providers have the bandwidth to do the same? It’s a tall order.
A new world of Alzheimer’s treatments also means that the infrastructure of our health care systems will need to be ramped up. Lecanemab infusions are administered every 2 weeks and donanemab every 4 weeks. Infusion centers will need to accommodate a lot more patients. And those patients will need frequent brain scans, so neuroimaging centers will need to increase their capacity to perform many more brain MRI and PET scans.
Antiamyloid drugs: An exciting first step
The bottom line is that these drugs aren’t the Alzheimer’s holy grail: An accessible treatment that could stop the disease in its tracks or reverse cognitive impairment. They are, however, a very promising breakthrough.
Yes, there are a ton of kinks to work out here, but this is an exciting start. Alzheimer’s research is entering a renaissance era that will hopefully bring more groundbreaking developments. Better biomarkers to facilitate faster, easier diagnosis. More drugs that go beyond amyloid proteins for their therapeutic targets. Treatments for later-stage disease. Drugs that prevent dementia altogether.
Ultimately, these new antiamyloid beta drugs are an exciting indication that we will eventually have a toolkit of Alzheimer’s drugs to choose from. For now, we’ve taken a solid step forward and there is ample reason to be hopeful for the future.
Dr. Croll is assistant professor of neurology at Temple University, Philadelphia. She reported no relevant conflicts of interest.
A version of this article first appeared on Medscape.com.
With the Food and Drug Administration’s full stamp of approval in hand, Leqembi (lecanemab) is poised to catapult us into a new era of treatment for Alzheimer’s disease. And now that the donanemab trial data are out, there’s another antiamyloid drug waiting in the wings.
To finally have true disease-modifying therapies for Alzheimer’s disease is a massive step forward for a field that’s been plagued with disappointment. But these drugs come with serious concerns and unknowns. They will require complex decision-making, putting doctors, patients, and their families in a medical quandary.
Striking the right balance between cautious optimism and realistic expectations will be a formidable challenge.
Managing patient and family expectations
These drugs are no magic bullet. They slow down the dementia’s progression, buying patients more time (on the order of months) before they begin to experience significant worsening. We’ll need a lot more information from research and clinical experience before we can understand how meaningful that treatment effect is. Right now, it is unclear whether eligible patients and their families will even perceive tangible differences.
In the CLARITY-AD trial, participants on lecanemab experienced a 27% slowing in the rate of cognitive decline over 18 months. Donanemab was shown to slow decline in memory and cognition by about 35% over the same time frame in the TRAILBLAZER-ALZ 2 trial. That translates to more time for patients and their families to enjoy independence, maintain normal life, and stave off the most distressing parts of the disease.
But what happens after 18 months of treatment – will the treatment effect magnify or dissipate? How much time are we really buying in the long run? Counseling patients and their families is made all the more difficult when the answers to important questions like these remain to be seen.
Only a sliver of Alzheimer’s patients are current candidates
The fact is that most patients living with Alzheimer’s disease will not qualify for treatment with these drugs. Lecanemab is approved for people with early-stage disease, meaning their dementia is mild or they have mild cognitive impairment, which is a precursor to full-blown Alzheimer’s disease. Of the 6 million people in the United States living with Alzheimer’s, about 1.5 million are estimated to fall into that category. We can expect to see a similar qualifier for donanemab if it receives FDA approval, especially because that trial suggested a more pronounced treatment effect for patients in the earliest stages of the disease.
Even if a patient hits the sweet spot where they have just enough cognitive impairment, but not too much, they aren’t technically therapeutic candidates until prerequisite testing confirms amyloid protein accumulation in the brain via PET scan or cerebrospinal fluid analysis.
Even then, the FDA’s boxed warning for lecanemab recommends that patients undergo genetic testing for the apo E4 mutation to identify those at a particularly high risk for severe adverse effects including brain bleeding and swelling. This recommendation is not unreasonable considering that 15% of the Alzheimer’s population has two copies of the apo E4 mutation and fall into that high-risk group.
Significant risks
Antiamyloid drugs are well-known to cause serious side effects. In the lecanemab trial, 13% of participants receiving Leqembi experienced brain swelling (vs. 2% of participants receiving placebo) and 17% of participants had brain bleeding (vs. 9% of participants on placebo). In the donanemab trial, brain bleeding occurred in 31.4% of participants on the drug (vs. 13.6% on placebo) and swelling occurred in 24% (vs. 2.1% receiving placebo). Thankfully, in both trials, most of these adverse events did not produce significant symptoms, but in rare cases these events caused severe or catastrophic neurologic injury, including death.
How can we best guide patients and their families to weigh the uncertain benefits against potentially serious risks? We can start by considering the patient characteristics most likely to portend increased risk for serious side effects: apo E4 mutations, blood thinner use, and the presence of microhemorrhages on brain imaging. But after that, we’re left with a lot of uncertainty in terms of which patients are most likely to see meaningful clinical improvements from the drug and unknown factors that may increase the risks of treatment.
A costly therapy
Medicare plans to cover 80% of lecanemab’s steep cost of $26,500 per year. Still, that will leave many patients with a hefty copay, potentially over $6,000 per year. But that only scratches the surface. Consider the frequent medical visits, repeated brain scans, laboratory tests, and infusion center appointments. It’s been estimated that all-in, the treatment will actually cost about $90,000 per year.
Yes, Medicare will reimburse a large portion of that cost, but it adds up to an estimated $2 billion per year for about 85,000 patients. This will probably spur increases to Medicare premiums, among other economic consequences for the health care system.
We’ll probably have to wait for an FDA approval decision before we know where donanemab will be priced.
Logistical challenges could be a rate-limiting step
Ask anyone who’s tried to see a neurologist recently, and they’ll tell you that the wait for a new patient appointment is months long. The shortage of neurologists in the United States is already a crisis, and there are even fewer cognitive neurologists. How long will patients be forced to wait for their diagnosis?
Many geriatricians will get comfortable prescribing these drugs, but will our already overburdened primary care providers have the bandwidth to do the same? It’s a tall order.
A new world of Alzheimer’s treatments also means that the infrastructure of our health care systems will need to be ramped up. Lecanemab infusions are administered every 2 weeks and donanemab every 4 weeks. Infusion centers will need to accommodate a lot more patients. And those patients will need frequent brain scans, so neuroimaging centers will need to increase their capacity to perform many more brain MRI and PET scans.
Antiamyloid drugs: An exciting first step
The bottom line is that these drugs aren’t the Alzheimer’s holy grail: An accessible treatment that could stop the disease in its tracks or reverse cognitive impairment. They are, however, a very promising breakthrough.
Yes, there are a ton of kinks to work out here, but this is an exciting start. Alzheimer’s research is entering a renaissance era that will hopefully bring more groundbreaking developments. Better biomarkers to facilitate faster, easier diagnosis. More drugs that go beyond amyloid proteins for their therapeutic targets. Treatments for later-stage disease. Drugs that prevent dementia altogether.
Ultimately, these new antiamyloid beta drugs are an exciting indication that we will eventually have a toolkit of Alzheimer’s drugs to choose from. For now, we’ve taken a solid step forward and there is ample reason to be hopeful for the future.
Dr. Croll is assistant professor of neurology at Temple University, Philadelphia. She reported no relevant conflicts of interest.
A version of this article first appeared on Medscape.com.
With the Food and Drug Administration’s full stamp of approval in hand, Leqembi (lecanemab) is poised to catapult us into a new era of treatment for Alzheimer’s disease. And now that the donanemab trial data are out, there’s another antiamyloid drug waiting in the wings.
To finally have true disease-modifying therapies for Alzheimer’s disease is a massive step forward for a field that’s been plagued with disappointment. But these drugs come with serious concerns and unknowns. They will require complex decision-making, putting doctors, patients, and their families in a medical quandary.
Striking the right balance between cautious optimism and realistic expectations will be a formidable challenge.
Managing patient and family expectations
These drugs are no magic bullet. They slow down the dementia’s progression, buying patients more time (on the order of months) before they begin to experience significant worsening. We’ll need a lot more information from research and clinical experience before we can understand how meaningful that treatment effect is. Right now, it is unclear whether eligible patients and their families will even perceive tangible differences.
In the CLARITY-AD trial, participants on lecanemab experienced a 27% slowing in the rate of cognitive decline over 18 months. Donanemab was shown to slow decline in memory and cognition by about 35% over the same time frame in the TRAILBLAZER-ALZ 2 trial. That translates to more time for patients and their families to enjoy independence, maintain normal life, and stave off the most distressing parts of the disease.
But what happens after 18 months of treatment – will the treatment effect magnify or dissipate? How much time are we really buying in the long run? Counseling patients and their families is made all the more difficult when the answers to important questions like these remain to be seen.
Only a sliver of Alzheimer’s patients are current candidates
The fact is that most patients living with Alzheimer’s disease will not qualify for treatment with these drugs. Lecanemab is approved for people with early-stage disease, meaning their dementia is mild or they have mild cognitive impairment, which is a precursor to full-blown Alzheimer’s disease. Of the 6 million people in the United States living with Alzheimer’s, about 1.5 million are estimated to fall into that category. We can expect to see a similar qualifier for donanemab if it receives FDA approval, especially because that trial suggested a more pronounced treatment effect for patients in the earliest stages of the disease.
Even if a patient hits the sweet spot where they have just enough cognitive impairment, but not too much, they aren’t technically therapeutic candidates until prerequisite testing confirms amyloid protein accumulation in the brain via PET scan or cerebrospinal fluid analysis.
Even then, the FDA’s boxed warning for lecanemab recommends that patients undergo genetic testing for the apo E4 mutation to identify those at a particularly high risk for severe adverse effects including brain bleeding and swelling. This recommendation is not unreasonable considering that 15% of the Alzheimer’s population has two copies of the apo E4 mutation and fall into that high-risk group.
Significant risks
Antiamyloid drugs are well-known to cause serious side effects. In the lecanemab trial, 13% of participants receiving Leqembi experienced brain swelling (vs. 2% of participants receiving placebo) and 17% of participants had brain bleeding (vs. 9% of participants on placebo). In the donanemab trial, brain bleeding occurred in 31.4% of participants on the drug (vs. 13.6% on placebo) and swelling occurred in 24% (vs. 2.1% receiving placebo). Thankfully, in both trials, most of these adverse events did not produce significant symptoms, but in rare cases these events caused severe or catastrophic neurologic injury, including death.
How can we best guide patients and their families to weigh the uncertain benefits against potentially serious risks? We can start by considering the patient characteristics most likely to portend increased risk for serious side effects: apo E4 mutations, blood thinner use, and the presence of microhemorrhages on brain imaging. But after that, we’re left with a lot of uncertainty in terms of which patients are most likely to see meaningful clinical improvements from the drug and unknown factors that may increase the risks of treatment.
A costly therapy
Medicare plans to cover 80% of lecanemab’s steep cost of $26,500 per year. Still, that will leave many patients with a hefty copay, potentially over $6,000 per year. But that only scratches the surface. Consider the frequent medical visits, repeated brain scans, laboratory tests, and infusion center appointments. It’s been estimated that all-in, the treatment will actually cost about $90,000 per year.
Yes, Medicare will reimburse a large portion of that cost, but it adds up to an estimated $2 billion per year for about 85,000 patients. This will probably spur increases to Medicare premiums, among other economic consequences for the health care system.
We’ll probably have to wait for an FDA approval decision before we know where donanemab will be priced.
Logistical challenges could be a rate-limiting step
Ask anyone who’s tried to see a neurologist recently, and they’ll tell you that the wait for a new patient appointment is months long. The shortage of neurologists in the United States is already a crisis, and there are even fewer cognitive neurologists. How long will patients be forced to wait for their diagnosis?
Many geriatricians will get comfortable prescribing these drugs, but will our already overburdened primary care providers have the bandwidth to do the same? It’s a tall order.
A new world of Alzheimer’s treatments also means that the infrastructure of our health care systems will need to be ramped up. Lecanemab infusions are administered every 2 weeks and donanemab every 4 weeks. Infusion centers will need to accommodate a lot more patients. And those patients will need frequent brain scans, so neuroimaging centers will need to increase their capacity to perform many more brain MRI and PET scans.
Antiamyloid drugs: An exciting first step
The bottom line is that these drugs aren’t the Alzheimer’s holy grail: An accessible treatment that could stop the disease in its tracks or reverse cognitive impairment. They are, however, a very promising breakthrough.
Yes, there are a ton of kinks to work out here, but this is an exciting start. Alzheimer’s research is entering a renaissance era that will hopefully bring more groundbreaking developments. Better biomarkers to facilitate faster, easier diagnosis. More drugs that go beyond amyloid proteins for their therapeutic targets. Treatments for later-stage disease. Drugs that prevent dementia altogether.
Ultimately, these new antiamyloid beta drugs are an exciting indication that we will eventually have a toolkit of Alzheimer’s drugs to choose from. For now, we’ve taken a solid step forward and there is ample reason to be hopeful for the future.
Dr. Croll is assistant professor of neurology at Temple University, Philadelphia. She reported no relevant conflicts of interest.
A version of this article first appeared on Medscape.com.
No cognitive benefit from meditation, learning a language?
The findings are similar to results from another study published last year but are contrary to previous findings showing cognitive benefits for practicing meditation and learning a new language later in life.
“Based on existing literature, which has provided support for the efficacy of meditation and foreign language training in promoting cognition among older adults, perhaps the most surprising outcome of our study was the lack of evidence indicating cognitive benefits after 18 months of either intervention,” lead author Harriet Demnitz-King, MSc, a doctoral candidate at University College London, said in an interview. The findings were published online in JAMA Network Open.
Contradictory findings
For the study, 135 French-speaking, cognitively healthy people were randomized to English-language training, meditation, or a control group. All participants were aged 65 years or older, had been retired for at least 1 year, and had completed at least 7 years of education.
The meditation and English-language training interventions were both 18 months long and included a 2-hour weekly group session, daily home practice of at least 20 minutes, and 1-day intensive 5-hour practice.
Researchers found no significant changes in global cognition, episodic memory, executive function, or attention with either intervention, compared with the control group or to each other.
The findings contradict the researchers’ earlier work that found mindfulness meditation boosted cognitive function in older adults with subjective cognitive decline.
“We are still trying to reconcile these findings,” senior author Natalie Marchant, PhD, associate professor in the division of psychiatry at University College London, said. “It may be that mindfulness meditation may not improve cognition beyond normally functioning levels but may help to preserve cognition in the face of cognitive decline.”
This study was the longest randomized controlled trial in older adults to investigate the effects of non-native language learning on cognition, Dr. Marchant said.
“It may be that language-learning may buffer against age-related cognitive decline but does not boost cognition in high-functioning individuals,” Dr. Marchant said. “While language learning may not improve cognition, we do not want to discard the other possibility without first examining it.”
Dr. Marchant plans to follow participants for years to come to study that very question.
More to learn
The results harken to those of a study last year with a similar participant group and similar results. In that work, mindfulness meditation and exercise also failed to boost cognition in healthy adults. But that may not be the whole story, according to Eric Lenze, MD, professor and chair of psychiatry at Washington University School of Medicine, St. Louis.
Dr. Lenze was a lead author on that earlier research, known as the MEDEX trial, but was not involved with this study. He commented on the new findings for this news organization.
“People may read these results, and ours that were published in JAMA in December, as suggesting that lifestyle and cognitive interventions don’t work in older adults, but that’s not what this shows, in my opinion,” Dr. Lenze said. “It shows that we don’t understand the science of the aging brain as much as we would like to.”
Participants in most of these studies were mostly White, highly educated, and in good cognitive health, all characteristics that could have skewed these findings, he added.
“It may be that interventions to improve cognitive function in older adults would be more likely to help people who have more room to benefit,” Dr. Lenze said. “If you’re already highly educated, healthy, and cognitively normal, why should we expect that you could do even better than that?”
The Age-Well study was funded by European Union in Horizon 2020 program and Inserm, Région Normandie, Fondation d’entreprise MMA des Entrepreneurs du Futur. Dr. Marchant reports grants from Alzheimer’s Society and the U.K. Medical Research Council. Dr. Lenze reports funding from Takeda pharmaceuticals and has been a consultant for Pritikin Intensive Cardiac Rehabilitation.
A version of this article first appeared on Medscape.com.
The findings are similar to results from another study published last year but are contrary to previous findings showing cognitive benefits for practicing meditation and learning a new language later in life.
“Based on existing literature, which has provided support for the efficacy of meditation and foreign language training in promoting cognition among older adults, perhaps the most surprising outcome of our study was the lack of evidence indicating cognitive benefits after 18 months of either intervention,” lead author Harriet Demnitz-King, MSc, a doctoral candidate at University College London, said in an interview. The findings were published online in JAMA Network Open.
Contradictory findings
For the study, 135 French-speaking, cognitively healthy people were randomized to English-language training, meditation, or a control group. All participants were aged 65 years or older, had been retired for at least 1 year, and had completed at least 7 years of education.
The meditation and English-language training interventions were both 18 months long and included a 2-hour weekly group session, daily home practice of at least 20 minutes, and 1-day intensive 5-hour practice.
Researchers found no significant changes in global cognition, episodic memory, executive function, or attention with either intervention, compared with the control group or to each other.
The findings contradict the researchers’ earlier work that found mindfulness meditation boosted cognitive function in older adults with subjective cognitive decline.
“We are still trying to reconcile these findings,” senior author Natalie Marchant, PhD, associate professor in the division of psychiatry at University College London, said. “It may be that mindfulness meditation may not improve cognition beyond normally functioning levels but may help to preserve cognition in the face of cognitive decline.”
This study was the longest randomized controlled trial in older adults to investigate the effects of non-native language learning on cognition, Dr. Marchant said.
“It may be that language-learning may buffer against age-related cognitive decline but does not boost cognition in high-functioning individuals,” Dr. Marchant said. “While language learning may not improve cognition, we do not want to discard the other possibility without first examining it.”
Dr. Marchant plans to follow participants for years to come to study that very question.
More to learn
The results harken to those of a study last year with a similar participant group and similar results. In that work, mindfulness meditation and exercise also failed to boost cognition in healthy adults. But that may not be the whole story, according to Eric Lenze, MD, professor and chair of psychiatry at Washington University School of Medicine, St. Louis.
Dr. Lenze was a lead author on that earlier research, known as the MEDEX trial, but was not involved with this study. He commented on the new findings for this news organization.
“People may read these results, and ours that were published in JAMA in December, as suggesting that lifestyle and cognitive interventions don’t work in older adults, but that’s not what this shows, in my opinion,” Dr. Lenze said. “It shows that we don’t understand the science of the aging brain as much as we would like to.”
Participants in most of these studies were mostly White, highly educated, and in good cognitive health, all characteristics that could have skewed these findings, he added.
“It may be that interventions to improve cognitive function in older adults would be more likely to help people who have more room to benefit,” Dr. Lenze said. “If you’re already highly educated, healthy, and cognitively normal, why should we expect that you could do even better than that?”
The Age-Well study was funded by European Union in Horizon 2020 program and Inserm, Région Normandie, Fondation d’entreprise MMA des Entrepreneurs du Futur. Dr. Marchant reports grants from Alzheimer’s Society and the U.K. Medical Research Council. Dr. Lenze reports funding from Takeda pharmaceuticals and has been a consultant for Pritikin Intensive Cardiac Rehabilitation.
A version of this article first appeared on Medscape.com.
The findings are similar to results from another study published last year but are contrary to previous findings showing cognitive benefits for practicing meditation and learning a new language later in life.
“Based on existing literature, which has provided support for the efficacy of meditation and foreign language training in promoting cognition among older adults, perhaps the most surprising outcome of our study was the lack of evidence indicating cognitive benefits after 18 months of either intervention,” lead author Harriet Demnitz-King, MSc, a doctoral candidate at University College London, said in an interview. The findings were published online in JAMA Network Open.
Contradictory findings
For the study, 135 French-speaking, cognitively healthy people were randomized to English-language training, meditation, or a control group. All participants were aged 65 years or older, had been retired for at least 1 year, and had completed at least 7 years of education.
The meditation and English-language training interventions were both 18 months long and included a 2-hour weekly group session, daily home practice of at least 20 minutes, and 1-day intensive 5-hour practice.
Researchers found no significant changes in global cognition, episodic memory, executive function, or attention with either intervention, compared with the control group or to each other.
The findings contradict the researchers’ earlier work that found mindfulness meditation boosted cognitive function in older adults with subjective cognitive decline.
“We are still trying to reconcile these findings,” senior author Natalie Marchant, PhD, associate professor in the division of psychiatry at University College London, said. “It may be that mindfulness meditation may not improve cognition beyond normally functioning levels but may help to preserve cognition in the face of cognitive decline.”
This study was the longest randomized controlled trial in older adults to investigate the effects of non-native language learning on cognition, Dr. Marchant said.
“It may be that language-learning may buffer against age-related cognitive decline but does not boost cognition in high-functioning individuals,” Dr. Marchant said. “While language learning may not improve cognition, we do not want to discard the other possibility without first examining it.”
Dr. Marchant plans to follow participants for years to come to study that very question.
More to learn
The results harken to those of a study last year with a similar participant group and similar results. In that work, mindfulness meditation and exercise also failed to boost cognition in healthy adults. But that may not be the whole story, according to Eric Lenze, MD, professor and chair of psychiatry at Washington University School of Medicine, St. Louis.
Dr. Lenze was a lead author on that earlier research, known as the MEDEX trial, but was not involved with this study. He commented on the new findings for this news organization.
“People may read these results, and ours that were published in JAMA in December, as suggesting that lifestyle and cognitive interventions don’t work in older adults, but that’s not what this shows, in my opinion,” Dr. Lenze said. “It shows that we don’t understand the science of the aging brain as much as we would like to.”
Participants in most of these studies were mostly White, highly educated, and in good cognitive health, all characteristics that could have skewed these findings, he added.
“It may be that interventions to improve cognitive function in older adults would be more likely to help people who have more room to benefit,” Dr. Lenze said. “If you’re already highly educated, healthy, and cognitively normal, why should we expect that you could do even better than that?”
The Age-Well study was funded by European Union in Horizon 2020 program and Inserm, Région Normandie, Fondation d’entreprise MMA des Entrepreneurs du Futur. Dr. Marchant reports grants from Alzheimer’s Society and the U.K. Medical Research Council. Dr. Lenze reports funding from Takeda pharmaceuticals and has been a consultant for Pritikin Intensive Cardiac Rehabilitation.
A version of this article first appeared on Medscape.com.
FROM JAMA Network Open
Oral tau inhibitor continues to show promise in Alzheimer’s
in the LUCIDITY phase 3 trial.
Blood concentrations of neurofilament light chain (NfL) showed a 93% reduction in change over 12 months in participants receiving HMTM at the target dose of 16 mg/day relative to the control group, which correlated significantly with a tau biomarker (p-tau 181) in blood and changes in cognitive test scores.
“This is the first tau aggregation inhibitor to reach the phase 3 stage of development and to produce results like this,” Claude Wischik, PhD, executive chairman of TauRx Therapeutics, which is developing the drug, noted in an interview.
“NfL is one of the best studied biomarkers in the business because it goes off the rails in a range of neurodegenerative disorders. In AD, it correlates with disease severity, and it tracks ongoing damage to neurons,” Dr. Wischik explained.
Oral HMTM was designed to reduce tau pathology in AD, and the noted changes in NfL concentration by HMTM indicate a “direct impact on disease pathology,” Dr. Wischik said.
The findings, from a prespecified blood biomarker analysis of the LUCIDITY phase 3 trial, were presented at the annual Alzheimer’s Association International Conference.
Support for tau inhibitor
Topline results from the LUCIDITY trial showed improvement in cognition over 18 months in participants with mild cognitive impairment (MCI) caused by AD who were treated with a 16-mg/day dose of HMTM.
However, in an odd twist, participants in the control group who received a low dose of methylthioninium chloride (MTC) also showed cognitive improvement.
As a result, HMTM 16 mg/day failed to reach its two primary endpoints – change from baseline on the Alzheimer’s Disease Assessment Scale–Cognitive Subscale (ADAS-Cog11) and the Alzheimer’s Disease Cooperative Study/Activities of Daily Living Inventory (ADCS-ADL23) – relative to the MTC control group.
That’s likely because treatment with MTC, which is a variant of HMTM, unexpectedly achieved blood levels of active drug above the threshold needed to produce a clinical effect.
For the prespecified biomarker analysis reported at AAIC 2023, baseline and 12-month NfL plasma levels were available in 161 of 185 participants receiving HMTM 16 mg/day, 38 of 48 receiving HMTM 8 mg/day and 136 of 185 receiving MTC 8 mg/week.
Blood concentrations of NfL showed a statistically significant 93% reduction in change over 12 months in participants receiving HMTM at a dose of 16 mg/day relative to the control group (P = .0278), Dr. Wischik reported.
In addition, the p-tau 181 increase over 12 months “reduced to zero” with HMTM 16 mg/day and there was significant correlation between change in NfL and p-tau 181 concentration, he noted.
NfL reductions were significantly correlated with change in ADAS-Cog11 (P = .0038) and whole brain volume (P = .0359) over 24 months.
‘Exciting’ biomarker data
Commenting on the new data in an interview, Christopher Weber, PhD, director of global science initiatives at the Alzheimer’s Association, said the phase 3 LUCIDITY results “suggest that HMTM could be a potential therapeutic for slowing down neurodegenerative processes in Alzheimer’s disease.”
“Plasma NfL is an interesting biomarker which is used more and more in clinical trials because it’s noninvasive, accessible, and can assist in diagnosing and monitoring the disease in the early stages. Elevated NfL levels suggest that neurons are being affected in the brain, which could indicate the presence or progression of Alzheimer’s disease,” Dr. Weber said in an interview.
He said the biomarker data from the LUCIDITY study are “exciting.”
“However, due to the relatively small sample size, we look forward to seeing additional research on HMTM in larger, and even more diverse cohorts to better understand the performance of this treatment and the role of NfL in Alzheimer’s disease,” Dr. Weber said.
Also providing outside perspective, Howard Fillit, MD, founding executive director of the Alzheimer’s Drug Discovery Foundation, noted that currently “there is a lot of effort in trying to address the abnormal tau that occurs in Alzheimer’s disease.”
The biomarker data from LUCIDITY show that HMTM “seems to markedly decrease the amount of NfL in plasma and there is some correlation with cognitive scores. The obvious unknown is whether these changes in plasma NfL will predict clinical benefit,” Dr. Fillit said in an interview.
“This is an oral drug that has a good safety profile, and the mechanism of action makes sense, but we need to see the clinical data,” Dr. Fillit said.
Final 2-year data from the LUCIDITY trial are expected to be released later in 2023.
In the United Kingdom, TauRx has entered an accelerated approval process for the drug, and the company said it plans to seek regulatory approval in the United States and Canada in 2023.
The study was funded by TauRx Therapeutics. Dr. Wischik is an employee of the University of Aberdeen (Scotland), and TauRx Therapeutics. Dr. Weber and Dr. Fillit reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
in the LUCIDITY phase 3 trial.
Blood concentrations of neurofilament light chain (NfL) showed a 93% reduction in change over 12 months in participants receiving HMTM at the target dose of 16 mg/day relative to the control group, which correlated significantly with a tau biomarker (p-tau 181) in blood and changes in cognitive test scores.
“This is the first tau aggregation inhibitor to reach the phase 3 stage of development and to produce results like this,” Claude Wischik, PhD, executive chairman of TauRx Therapeutics, which is developing the drug, noted in an interview.
“NfL is one of the best studied biomarkers in the business because it goes off the rails in a range of neurodegenerative disorders. In AD, it correlates with disease severity, and it tracks ongoing damage to neurons,” Dr. Wischik explained.
Oral HMTM was designed to reduce tau pathology in AD, and the noted changes in NfL concentration by HMTM indicate a “direct impact on disease pathology,” Dr. Wischik said.
The findings, from a prespecified blood biomarker analysis of the LUCIDITY phase 3 trial, were presented at the annual Alzheimer’s Association International Conference.
Support for tau inhibitor
Topline results from the LUCIDITY trial showed improvement in cognition over 18 months in participants with mild cognitive impairment (MCI) caused by AD who were treated with a 16-mg/day dose of HMTM.
However, in an odd twist, participants in the control group who received a low dose of methylthioninium chloride (MTC) also showed cognitive improvement.
As a result, HMTM 16 mg/day failed to reach its two primary endpoints – change from baseline on the Alzheimer’s Disease Assessment Scale–Cognitive Subscale (ADAS-Cog11) and the Alzheimer’s Disease Cooperative Study/Activities of Daily Living Inventory (ADCS-ADL23) – relative to the MTC control group.
That’s likely because treatment with MTC, which is a variant of HMTM, unexpectedly achieved blood levels of active drug above the threshold needed to produce a clinical effect.
For the prespecified biomarker analysis reported at AAIC 2023, baseline and 12-month NfL plasma levels were available in 161 of 185 participants receiving HMTM 16 mg/day, 38 of 48 receiving HMTM 8 mg/day and 136 of 185 receiving MTC 8 mg/week.
Blood concentrations of NfL showed a statistically significant 93% reduction in change over 12 months in participants receiving HMTM at a dose of 16 mg/day relative to the control group (P = .0278), Dr. Wischik reported.
In addition, the p-tau 181 increase over 12 months “reduced to zero” with HMTM 16 mg/day and there was significant correlation between change in NfL and p-tau 181 concentration, he noted.
NfL reductions were significantly correlated with change in ADAS-Cog11 (P = .0038) and whole brain volume (P = .0359) over 24 months.
‘Exciting’ biomarker data
Commenting on the new data in an interview, Christopher Weber, PhD, director of global science initiatives at the Alzheimer’s Association, said the phase 3 LUCIDITY results “suggest that HMTM could be a potential therapeutic for slowing down neurodegenerative processes in Alzheimer’s disease.”
“Plasma NfL is an interesting biomarker which is used more and more in clinical trials because it’s noninvasive, accessible, and can assist in diagnosing and monitoring the disease in the early stages. Elevated NfL levels suggest that neurons are being affected in the brain, which could indicate the presence or progression of Alzheimer’s disease,” Dr. Weber said in an interview.
He said the biomarker data from the LUCIDITY study are “exciting.”
“However, due to the relatively small sample size, we look forward to seeing additional research on HMTM in larger, and even more diverse cohorts to better understand the performance of this treatment and the role of NfL in Alzheimer’s disease,” Dr. Weber said.
Also providing outside perspective, Howard Fillit, MD, founding executive director of the Alzheimer’s Drug Discovery Foundation, noted that currently “there is a lot of effort in trying to address the abnormal tau that occurs in Alzheimer’s disease.”
The biomarker data from LUCIDITY show that HMTM “seems to markedly decrease the amount of NfL in plasma and there is some correlation with cognitive scores. The obvious unknown is whether these changes in plasma NfL will predict clinical benefit,” Dr. Fillit said in an interview.
“This is an oral drug that has a good safety profile, and the mechanism of action makes sense, but we need to see the clinical data,” Dr. Fillit said.
Final 2-year data from the LUCIDITY trial are expected to be released later in 2023.
In the United Kingdom, TauRx has entered an accelerated approval process for the drug, and the company said it plans to seek regulatory approval in the United States and Canada in 2023.
The study was funded by TauRx Therapeutics. Dr. Wischik is an employee of the University of Aberdeen (Scotland), and TauRx Therapeutics. Dr. Weber and Dr. Fillit reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
in the LUCIDITY phase 3 trial.
Blood concentrations of neurofilament light chain (NfL) showed a 93% reduction in change over 12 months in participants receiving HMTM at the target dose of 16 mg/day relative to the control group, which correlated significantly with a tau biomarker (p-tau 181) in blood and changes in cognitive test scores.
“This is the first tau aggregation inhibitor to reach the phase 3 stage of development and to produce results like this,” Claude Wischik, PhD, executive chairman of TauRx Therapeutics, which is developing the drug, noted in an interview.
“NfL is one of the best studied biomarkers in the business because it goes off the rails in a range of neurodegenerative disorders. In AD, it correlates with disease severity, and it tracks ongoing damage to neurons,” Dr. Wischik explained.
Oral HMTM was designed to reduce tau pathology in AD, and the noted changes in NfL concentration by HMTM indicate a “direct impact on disease pathology,” Dr. Wischik said.
The findings, from a prespecified blood biomarker analysis of the LUCIDITY phase 3 trial, were presented at the annual Alzheimer’s Association International Conference.
Support for tau inhibitor
Topline results from the LUCIDITY trial showed improvement in cognition over 18 months in participants with mild cognitive impairment (MCI) caused by AD who were treated with a 16-mg/day dose of HMTM.
However, in an odd twist, participants in the control group who received a low dose of methylthioninium chloride (MTC) also showed cognitive improvement.
As a result, HMTM 16 mg/day failed to reach its two primary endpoints – change from baseline on the Alzheimer’s Disease Assessment Scale–Cognitive Subscale (ADAS-Cog11) and the Alzheimer’s Disease Cooperative Study/Activities of Daily Living Inventory (ADCS-ADL23) – relative to the MTC control group.
That’s likely because treatment with MTC, which is a variant of HMTM, unexpectedly achieved blood levels of active drug above the threshold needed to produce a clinical effect.
For the prespecified biomarker analysis reported at AAIC 2023, baseline and 12-month NfL plasma levels were available in 161 of 185 participants receiving HMTM 16 mg/day, 38 of 48 receiving HMTM 8 mg/day and 136 of 185 receiving MTC 8 mg/week.
Blood concentrations of NfL showed a statistically significant 93% reduction in change over 12 months in participants receiving HMTM at a dose of 16 mg/day relative to the control group (P = .0278), Dr. Wischik reported.
In addition, the p-tau 181 increase over 12 months “reduced to zero” with HMTM 16 mg/day and there was significant correlation between change in NfL and p-tau 181 concentration, he noted.
NfL reductions were significantly correlated with change in ADAS-Cog11 (P = .0038) and whole brain volume (P = .0359) over 24 months.
‘Exciting’ biomarker data
Commenting on the new data in an interview, Christopher Weber, PhD, director of global science initiatives at the Alzheimer’s Association, said the phase 3 LUCIDITY results “suggest that HMTM could be a potential therapeutic for slowing down neurodegenerative processes in Alzheimer’s disease.”
“Plasma NfL is an interesting biomarker which is used more and more in clinical trials because it’s noninvasive, accessible, and can assist in diagnosing and monitoring the disease in the early stages. Elevated NfL levels suggest that neurons are being affected in the brain, which could indicate the presence or progression of Alzheimer’s disease,” Dr. Weber said in an interview.
He said the biomarker data from the LUCIDITY study are “exciting.”
“However, due to the relatively small sample size, we look forward to seeing additional research on HMTM in larger, and even more diverse cohorts to better understand the performance of this treatment and the role of NfL in Alzheimer’s disease,” Dr. Weber said.
Also providing outside perspective, Howard Fillit, MD, founding executive director of the Alzheimer’s Drug Discovery Foundation, noted that currently “there is a lot of effort in trying to address the abnormal tau that occurs in Alzheimer’s disease.”
The biomarker data from LUCIDITY show that HMTM “seems to markedly decrease the amount of NfL in plasma and there is some correlation with cognitive scores. The obvious unknown is whether these changes in plasma NfL will predict clinical benefit,” Dr. Fillit said in an interview.
“This is an oral drug that has a good safety profile, and the mechanism of action makes sense, but we need to see the clinical data,” Dr. Fillit said.
Final 2-year data from the LUCIDITY trial are expected to be released later in 2023.
In the United Kingdom, TauRx has entered an accelerated approval process for the drug, and the company said it plans to seek regulatory approval in the United States and Canada in 2023.
The study was funded by TauRx Therapeutics. Dr. Wischik is an employee of the University of Aberdeen (Scotland), and TauRx Therapeutics. Dr. Weber and Dr. Fillit reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM AAIC 2023
Cognitive benefit of highly touted MIND diet questioned
in healthy adults at risk for dementia, results of a new randomized trial show.
Given the strong base of evidence from observational studies that demonstrate the benefits of the MIND diet on cognitive decline, Alzheimer’s disease (AD), and neuropathologic changes such as reduced beta amyloid and tau associated with AD, the study’s results were “unexpected,” study investigator Lisa L. Barnes, PhD, with the Rush Alzheimer’s Disease Center, Chicago, said in an interview.
“One possibility is the trial may not have been long enough to see an effect. It’s also possible that participants in the control diet group benefited just as much as those in the MIND diet group because they also improved their diets to focus on weight loss,” Dr. Barnes said.
“Although we did not see a specific effect of the MIND diet, people in both groups improved their cognitive function, suggesting that a healthy diet in general is good for cognitive function,” she added.
The findings were presented at the annual Alzheimer’s Association International Conference and simultaneously published online in the New England Journal of Medicine.
Randomized trial
A hybrid of the Dietary Approaches to Stop Hypertension (DASH) and Mediterranean diet, the MIND diet includes foods and nutrients that have been putatively associated with a decreased risk of dementia.
To further investigate, the researchers conducted a randomized trial that included 604 older adults without cognitive impairment who had a family history of dementia, a body mass index greater than 25, and a suboptimal diet determined via a 14-item questionnaire.
For 3 years, 301 were randomly assigned to follow the MIND-diet with mild calorie restriction and 303 to follow a control diet with mild calorie restriction only. All participants received counseling to help them adhere to their assigned diet, plus support to promote weight loss of 3%-5% by year 3.
The primary endpoint was the change from baseline in global cognition and in specific cognitive domains through year 3. Cognition was assessed with an established battery of 12 publicly available cognitive function tests.
The secondary endpoint was the change from baseline in MRI-derived measures of brain characteristics in a nonrandom sample of participants.
“We had good adherence to the assigned diets and both groups lost weight, on average about 5 kilograms in both groups,” Dr. Barnes noted in her presentation.
From baseline through 3 years, small improvements in global cognition scores were observed in both groups, with increases of 0.205 standardized units in the MIND-diet group versus 0.170 standardized units in the control-diet group.
However, in intention-to-treat analysis, the mean change in score did not differ significantly between groups, with an estimated mean difference at the end of the trial of 0.035 standardized units (P = .23).
At the trial’s conclusion, there were also no between-group differences in change in white-matter hyperintensities, hippocampal volumes, and total gray- and white-matter volumes on MRI.
Dr. Barnes noted that the trial was limited to well-educated, older adults, mostly of European descent. Other limitations include the small sample size of those who received MRI and follow-up that was shorter than a typical observational study.
Dr. Barnes noted that this is a single study and that there needs to be more randomized trials of the MIND diet that, as with the observational research, follow participants for a longer period of time.
More to brain health than diet
Reached for comment, Majid Fotuhi, MD, PhD, adjunct professor of neuroscience at George Washington University, Washington, noted that participants who enroll in clinical trials that focus on diet become more aware of their eating habits and shift toward a healthier diet.
“This may explain the reason why both groups of participants in this study improved,” said Dr. Fotuhi, medical director of NeuroGrow Brain Fitness Center, McLean, Va.
However, he believes that better brain health requires a multipronged approach.
“In order to see significant results, people need to improve their diet, become physically fit, sleep well, reduce their stress, engage in cognitively challenging activities, and develop a positive mind set,” said Dr. Fotuhi.
“Interventions that target only one of these goals may not produce results that are as remarkable as multimodal programs, which target all of these goals,” Dr. Fotuhi said.
Dr. Fotuhi developed a multidimensional “brain fitness program” that has shown to provide multiple benefits for individuals with memory loss, attention deficit hyperactivity disorder, and post-concussion syndrome.
“Having provided our 12-week program for thousands of patients in the past 10 years, I have noticed a synergistic effect in patients who incorporate all of these changes in their day-to-day life and maintain it over time. They often become sharper and feel better overall,” Dr. Fotuhi told this news organization.
The study was supported by the National Institute on Aging. Disclosures for study authors are listed with the original article. Dr. Fotuhi has disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
in healthy adults at risk for dementia, results of a new randomized trial show.
Given the strong base of evidence from observational studies that demonstrate the benefits of the MIND diet on cognitive decline, Alzheimer’s disease (AD), and neuropathologic changes such as reduced beta amyloid and tau associated with AD, the study’s results were “unexpected,” study investigator Lisa L. Barnes, PhD, with the Rush Alzheimer’s Disease Center, Chicago, said in an interview.
“One possibility is the trial may not have been long enough to see an effect. It’s also possible that participants in the control diet group benefited just as much as those in the MIND diet group because they also improved their diets to focus on weight loss,” Dr. Barnes said.
“Although we did not see a specific effect of the MIND diet, people in both groups improved their cognitive function, suggesting that a healthy diet in general is good for cognitive function,” she added.
The findings were presented at the annual Alzheimer’s Association International Conference and simultaneously published online in the New England Journal of Medicine.
Randomized trial
A hybrid of the Dietary Approaches to Stop Hypertension (DASH) and Mediterranean diet, the MIND diet includes foods and nutrients that have been putatively associated with a decreased risk of dementia.
To further investigate, the researchers conducted a randomized trial that included 604 older adults without cognitive impairment who had a family history of dementia, a body mass index greater than 25, and a suboptimal diet determined via a 14-item questionnaire.
For 3 years, 301 were randomly assigned to follow the MIND-diet with mild calorie restriction and 303 to follow a control diet with mild calorie restriction only. All participants received counseling to help them adhere to their assigned diet, plus support to promote weight loss of 3%-5% by year 3.
The primary endpoint was the change from baseline in global cognition and in specific cognitive domains through year 3. Cognition was assessed with an established battery of 12 publicly available cognitive function tests.
The secondary endpoint was the change from baseline in MRI-derived measures of brain characteristics in a nonrandom sample of participants.
“We had good adherence to the assigned diets and both groups lost weight, on average about 5 kilograms in both groups,” Dr. Barnes noted in her presentation.
From baseline through 3 years, small improvements in global cognition scores were observed in both groups, with increases of 0.205 standardized units in the MIND-diet group versus 0.170 standardized units in the control-diet group.
However, in intention-to-treat analysis, the mean change in score did not differ significantly between groups, with an estimated mean difference at the end of the trial of 0.035 standardized units (P = .23).
At the trial’s conclusion, there were also no between-group differences in change in white-matter hyperintensities, hippocampal volumes, and total gray- and white-matter volumes on MRI.
Dr. Barnes noted that the trial was limited to well-educated, older adults, mostly of European descent. Other limitations include the small sample size of those who received MRI and follow-up that was shorter than a typical observational study.
Dr. Barnes noted that this is a single study and that there needs to be more randomized trials of the MIND diet that, as with the observational research, follow participants for a longer period of time.
More to brain health than diet
Reached for comment, Majid Fotuhi, MD, PhD, adjunct professor of neuroscience at George Washington University, Washington, noted that participants who enroll in clinical trials that focus on diet become more aware of their eating habits and shift toward a healthier diet.
“This may explain the reason why both groups of participants in this study improved,” said Dr. Fotuhi, medical director of NeuroGrow Brain Fitness Center, McLean, Va.
However, he believes that better brain health requires a multipronged approach.
“In order to see significant results, people need to improve their diet, become physically fit, sleep well, reduce their stress, engage in cognitively challenging activities, and develop a positive mind set,” said Dr. Fotuhi.
“Interventions that target only one of these goals may not produce results that are as remarkable as multimodal programs, which target all of these goals,” Dr. Fotuhi said.
Dr. Fotuhi developed a multidimensional “brain fitness program” that has shown to provide multiple benefits for individuals with memory loss, attention deficit hyperactivity disorder, and post-concussion syndrome.
“Having provided our 12-week program for thousands of patients in the past 10 years, I have noticed a synergistic effect in patients who incorporate all of these changes in their day-to-day life and maintain it over time. They often become sharper and feel better overall,” Dr. Fotuhi told this news organization.
The study was supported by the National Institute on Aging. Disclosures for study authors are listed with the original article. Dr. Fotuhi has disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
in healthy adults at risk for dementia, results of a new randomized trial show.
Given the strong base of evidence from observational studies that demonstrate the benefits of the MIND diet on cognitive decline, Alzheimer’s disease (AD), and neuropathologic changes such as reduced beta amyloid and tau associated with AD, the study’s results were “unexpected,” study investigator Lisa L. Barnes, PhD, with the Rush Alzheimer’s Disease Center, Chicago, said in an interview.
“One possibility is the trial may not have been long enough to see an effect. It’s also possible that participants in the control diet group benefited just as much as those in the MIND diet group because they also improved their diets to focus on weight loss,” Dr. Barnes said.
“Although we did not see a specific effect of the MIND diet, people in both groups improved their cognitive function, suggesting that a healthy diet in general is good for cognitive function,” she added.
The findings were presented at the annual Alzheimer’s Association International Conference and simultaneously published online in the New England Journal of Medicine.
Randomized trial
A hybrid of the Dietary Approaches to Stop Hypertension (DASH) and Mediterranean diet, the MIND diet includes foods and nutrients that have been putatively associated with a decreased risk of dementia.
To further investigate, the researchers conducted a randomized trial that included 604 older adults without cognitive impairment who had a family history of dementia, a body mass index greater than 25, and a suboptimal diet determined via a 14-item questionnaire.
For 3 years, 301 were randomly assigned to follow the MIND-diet with mild calorie restriction and 303 to follow a control diet with mild calorie restriction only. All participants received counseling to help them adhere to their assigned diet, plus support to promote weight loss of 3%-5% by year 3.
The primary endpoint was the change from baseline in global cognition and in specific cognitive domains through year 3. Cognition was assessed with an established battery of 12 publicly available cognitive function tests.
The secondary endpoint was the change from baseline in MRI-derived measures of brain characteristics in a nonrandom sample of participants.
“We had good adherence to the assigned diets and both groups lost weight, on average about 5 kilograms in both groups,” Dr. Barnes noted in her presentation.
From baseline through 3 years, small improvements in global cognition scores were observed in both groups, with increases of 0.205 standardized units in the MIND-diet group versus 0.170 standardized units in the control-diet group.
However, in intention-to-treat analysis, the mean change in score did not differ significantly between groups, with an estimated mean difference at the end of the trial of 0.035 standardized units (P = .23).
At the trial’s conclusion, there were also no between-group differences in change in white-matter hyperintensities, hippocampal volumes, and total gray- and white-matter volumes on MRI.
Dr. Barnes noted that the trial was limited to well-educated, older adults, mostly of European descent. Other limitations include the small sample size of those who received MRI and follow-up that was shorter than a typical observational study.
Dr. Barnes noted that this is a single study and that there needs to be more randomized trials of the MIND diet that, as with the observational research, follow participants for a longer period of time.
More to brain health than diet
Reached for comment, Majid Fotuhi, MD, PhD, adjunct professor of neuroscience at George Washington University, Washington, noted that participants who enroll in clinical trials that focus on diet become more aware of their eating habits and shift toward a healthier diet.
“This may explain the reason why both groups of participants in this study improved,” said Dr. Fotuhi, medical director of NeuroGrow Brain Fitness Center, McLean, Va.
However, he believes that better brain health requires a multipronged approach.
“In order to see significant results, people need to improve their diet, become physically fit, sleep well, reduce their stress, engage in cognitively challenging activities, and develop a positive mind set,” said Dr. Fotuhi.
“Interventions that target only one of these goals may not produce results that are as remarkable as multimodal programs, which target all of these goals,” Dr. Fotuhi said.
Dr. Fotuhi developed a multidimensional “brain fitness program” that has shown to provide multiple benefits for individuals with memory loss, attention deficit hyperactivity disorder, and post-concussion syndrome.
“Having provided our 12-week program for thousands of patients in the past 10 years, I have noticed a synergistic effect in patients who incorporate all of these changes in their day-to-day life and maintain it over time. They often become sharper and feel better overall,” Dr. Fotuhi told this news organization.
The study was supported by the National Institute on Aging. Disclosures for study authors are listed with the original article. Dr. Fotuhi has disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM AAIC 2023
Chronic constipation linked to cognitive decline
Compared with individuals who have a bowel movement once daily, adults with constipation who have a bowel movement every 3 days or more had significantly worse cognition that was commensurate with an additional 3 years of chronological cognitive aging, the investigators found.
“We should watch for symptoms of abnormal intestinal function, especially constipation, in older individuals, as these symptoms may hint at a higher risk of cognitive decline in the future,” study investigator Chaoran Ma, MD, PhD, former research fellow at Brigham and Women’s Hospital and Harvard Medical School, both in Boston, and current assistant professor at the University of Massachusetts Amherst, said in an interview.
The findings were presented at the Alzheimer’s Association International Conference.
Prevent constipation, improve brain health?
It’s estimated that 16% of the world’s population suffers from constipation. The problem is more common in older adults, owing to age-related factors such as a lack of dietary fiber and exercise and the use of constipating drugs to treat other medical conditions.
Chronic constipation – defined as having bowel movements every 3 days or more – has been associated with long-term health problems, such as inflammation, hormonal imbalances, anxiety, and depression.
However, few studies have investigated variations in intestinal motility and cognitive function.
“Our study provides first-of-its-kind evidence that examined a wide spectrum of bowel movement frequency, especially an analysis of the more frequent end, in relation to cognitive function,” Dr. Ma said.
The analysis involved data from 112,753 women and men from the Nurses’ Health Study (aged 30-55 years), the Nurses’ Health Study II (aged 25-42), and the Health Professionals Follow-up Study (aged 40-75).
Data on participants’ bowel movement frequency was collected between 2012 and 2013, and self-assessments of cognitive function were obtained from 2014 to 2017. A subgroup of 12,696 participants completed a standard neuropsychological test battery for objective cognitive assessment between 2014 and 2018.
The results show that bowel movement frequency was associated with overall objective cognitive function and learning and working memory in an inverse J-shape dose-response manner (both P for nonlinearity < .05).
Compared with adults who had one bowel movement daily, those who only had a bowel movement every 3 or more days had significantly worse cognition, equivalent to 3 years of additional aging (95% confidence interval, 1.2-4.7).
The researchers also observed similar J-shape dose-response relationships of bowel movement frequency with the odds of subjective cognitive decline and the likelihood of having more subjective cognitive complaints over time.
Compared with once-daily bowel movements, having bowel movements every 3 or more days was associated with a greater likelihood of subjective cognitive decline (odds ratio, 1.73; 95% CI, 1.60-1.86).
These relationships were generally consistent across the three cohorts and subgroups.
“These results stress the importance of clinicians discussing gut health, especially constipation, with their older patients,” senior investigator Dong Wang, MD, ScD, with Harvard Medical School and Brigham and Women’s Hospital, said in a conference statement.
“Interventions for preventing constipation and improving gut health include adopting healthy diets enriched with high-fiber and high-polyphenol foods such as fruits, vegetables, and whole grains; taking fiber supplementation; drinking plenty of water every day; and having regular physical activity,” Dr. Wang added.
The researchers also explored the role of the gut microbiome in the association between bowel movement frequency and cognitive function in a subgroup of 515 women and men.
They found that bowel movement frequency and subjective cognition were significantly associated with the overall variation of the gut microbiome (both P < .005) and specific microbial species.
“This research adds further evidence for a link between the microbiome and gastrointestinal function with cognitive function,” Dr. Ma said in an interview.
Interconnected systems
Commenting on the study in a conference statement, Heather M. Snyder, PhD, vice president of medical and scientific relations at the Alzheimer’s Association, noted that “our body systems are all interconnected. When one system is malfunctioning, it impacts other systems. When that dysfunction isn’t addressed, it can create a waterfall of consequences for the rest of the body.”
Dr. Snyder cautioned, however, that “there are a lot of unanswered questions about the connection between the health of our digestive system and our long-term cognitive function. Answering these questions may uncover novel therapeutic and risk-reduction approaches for Alzheimer’s and other dementias.”
In an interview, Percy Griffin, PhD, director of scientific engagement at the Alzheimer’s Association, noted that the U.S. Study to Protect Brain Health Through Lifestyle Intervention to Reduce Risk, is evaluating the impact of behavioral interventions on the gut-brain axis.
“We want to better understand how engaging in healthier habits can impact microorganisms in the gut and how changes in gut bacteria relate to brain health,” Dr. Griffin said.
The study was funded by the National Institutes of Health. Dr. Ma, Dr. Wang, Dr. Snyder, and Dr. Griffin have no relevant disclosures.
A version of this article first appeared on Medscape.com.
Compared with individuals who have a bowel movement once daily, adults with constipation who have a bowel movement every 3 days or more had significantly worse cognition that was commensurate with an additional 3 years of chronological cognitive aging, the investigators found.
“We should watch for symptoms of abnormal intestinal function, especially constipation, in older individuals, as these symptoms may hint at a higher risk of cognitive decline in the future,” study investigator Chaoran Ma, MD, PhD, former research fellow at Brigham and Women’s Hospital and Harvard Medical School, both in Boston, and current assistant professor at the University of Massachusetts Amherst, said in an interview.
The findings were presented at the Alzheimer’s Association International Conference.
Prevent constipation, improve brain health?
It’s estimated that 16% of the world’s population suffers from constipation. The problem is more common in older adults, owing to age-related factors such as a lack of dietary fiber and exercise and the use of constipating drugs to treat other medical conditions.
Chronic constipation – defined as having bowel movements every 3 days or more – has been associated with long-term health problems, such as inflammation, hormonal imbalances, anxiety, and depression.
However, few studies have investigated variations in intestinal motility and cognitive function.
“Our study provides first-of-its-kind evidence that examined a wide spectrum of bowel movement frequency, especially an analysis of the more frequent end, in relation to cognitive function,” Dr. Ma said.
The analysis involved data from 112,753 women and men from the Nurses’ Health Study (aged 30-55 years), the Nurses’ Health Study II (aged 25-42), and the Health Professionals Follow-up Study (aged 40-75).
Data on participants’ bowel movement frequency was collected between 2012 and 2013, and self-assessments of cognitive function were obtained from 2014 to 2017. A subgroup of 12,696 participants completed a standard neuropsychological test battery for objective cognitive assessment between 2014 and 2018.
The results show that bowel movement frequency was associated with overall objective cognitive function and learning and working memory in an inverse J-shape dose-response manner (both P for nonlinearity < .05).
Compared with adults who had one bowel movement daily, those who only had a bowel movement every 3 or more days had significantly worse cognition, equivalent to 3 years of additional aging (95% confidence interval, 1.2-4.7).
The researchers also observed similar J-shape dose-response relationships of bowel movement frequency with the odds of subjective cognitive decline and the likelihood of having more subjective cognitive complaints over time.
Compared with once-daily bowel movements, having bowel movements every 3 or more days was associated with a greater likelihood of subjective cognitive decline (odds ratio, 1.73; 95% CI, 1.60-1.86).
These relationships were generally consistent across the three cohorts and subgroups.
“These results stress the importance of clinicians discussing gut health, especially constipation, with their older patients,” senior investigator Dong Wang, MD, ScD, with Harvard Medical School and Brigham and Women’s Hospital, said in a conference statement.
“Interventions for preventing constipation and improving gut health include adopting healthy diets enriched with high-fiber and high-polyphenol foods such as fruits, vegetables, and whole grains; taking fiber supplementation; drinking plenty of water every day; and having regular physical activity,” Dr. Wang added.
The researchers also explored the role of the gut microbiome in the association between bowel movement frequency and cognitive function in a subgroup of 515 women and men.
They found that bowel movement frequency and subjective cognition were significantly associated with the overall variation of the gut microbiome (both P < .005) and specific microbial species.
“This research adds further evidence for a link between the microbiome and gastrointestinal function with cognitive function,” Dr. Ma said in an interview.
Interconnected systems
Commenting on the study in a conference statement, Heather M. Snyder, PhD, vice president of medical and scientific relations at the Alzheimer’s Association, noted that “our body systems are all interconnected. When one system is malfunctioning, it impacts other systems. When that dysfunction isn’t addressed, it can create a waterfall of consequences for the rest of the body.”
Dr. Snyder cautioned, however, that “there are a lot of unanswered questions about the connection between the health of our digestive system and our long-term cognitive function. Answering these questions may uncover novel therapeutic and risk-reduction approaches for Alzheimer’s and other dementias.”
In an interview, Percy Griffin, PhD, director of scientific engagement at the Alzheimer’s Association, noted that the U.S. Study to Protect Brain Health Through Lifestyle Intervention to Reduce Risk, is evaluating the impact of behavioral interventions on the gut-brain axis.
“We want to better understand how engaging in healthier habits can impact microorganisms in the gut and how changes in gut bacteria relate to brain health,” Dr. Griffin said.
The study was funded by the National Institutes of Health. Dr. Ma, Dr. Wang, Dr. Snyder, and Dr. Griffin have no relevant disclosures.
A version of this article first appeared on Medscape.com.
Compared with individuals who have a bowel movement once daily, adults with constipation who have a bowel movement every 3 days or more had significantly worse cognition that was commensurate with an additional 3 years of chronological cognitive aging, the investigators found.
“We should watch for symptoms of abnormal intestinal function, especially constipation, in older individuals, as these symptoms may hint at a higher risk of cognitive decline in the future,” study investigator Chaoran Ma, MD, PhD, former research fellow at Brigham and Women’s Hospital and Harvard Medical School, both in Boston, and current assistant professor at the University of Massachusetts Amherst, said in an interview.
The findings were presented at the Alzheimer’s Association International Conference.
Prevent constipation, improve brain health?
It’s estimated that 16% of the world’s population suffers from constipation. The problem is more common in older adults, owing to age-related factors such as a lack of dietary fiber and exercise and the use of constipating drugs to treat other medical conditions.
Chronic constipation – defined as having bowel movements every 3 days or more – has been associated with long-term health problems, such as inflammation, hormonal imbalances, anxiety, and depression.
However, few studies have investigated variations in intestinal motility and cognitive function.
“Our study provides first-of-its-kind evidence that examined a wide spectrum of bowel movement frequency, especially an analysis of the more frequent end, in relation to cognitive function,” Dr. Ma said.
The analysis involved data from 112,753 women and men from the Nurses’ Health Study (aged 30-55 years), the Nurses’ Health Study II (aged 25-42), and the Health Professionals Follow-up Study (aged 40-75).
Data on participants’ bowel movement frequency was collected between 2012 and 2013, and self-assessments of cognitive function were obtained from 2014 to 2017. A subgroup of 12,696 participants completed a standard neuropsychological test battery for objective cognitive assessment between 2014 and 2018.
The results show that bowel movement frequency was associated with overall objective cognitive function and learning and working memory in an inverse J-shape dose-response manner (both P for nonlinearity < .05).
Compared with adults who had one bowel movement daily, those who only had a bowel movement every 3 or more days had significantly worse cognition, equivalent to 3 years of additional aging (95% confidence interval, 1.2-4.7).
The researchers also observed similar J-shape dose-response relationships of bowel movement frequency with the odds of subjective cognitive decline and the likelihood of having more subjective cognitive complaints over time.
Compared with once-daily bowel movements, having bowel movements every 3 or more days was associated with a greater likelihood of subjective cognitive decline (odds ratio, 1.73; 95% CI, 1.60-1.86).
These relationships were generally consistent across the three cohorts and subgroups.
“These results stress the importance of clinicians discussing gut health, especially constipation, with their older patients,” senior investigator Dong Wang, MD, ScD, with Harvard Medical School and Brigham and Women’s Hospital, said in a conference statement.
“Interventions for preventing constipation and improving gut health include adopting healthy diets enriched with high-fiber and high-polyphenol foods such as fruits, vegetables, and whole grains; taking fiber supplementation; drinking plenty of water every day; and having regular physical activity,” Dr. Wang added.
The researchers also explored the role of the gut microbiome in the association between bowel movement frequency and cognitive function in a subgroup of 515 women and men.
They found that bowel movement frequency and subjective cognition were significantly associated with the overall variation of the gut microbiome (both P < .005) and specific microbial species.
“This research adds further evidence for a link between the microbiome and gastrointestinal function with cognitive function,” Dr. Ma said in an interview.
Interconnected systems
Commenting on the study in a conference statement, Heather M. Snyder, PhD, vice president of medical and scientific relations at the Alzheimer’s Association, noted that “our body systems are all interconnected. When one system is malfunctioning, it impacts other systems. When that dysfunction isn’t addressed, it can create a waterfall of consequences for the rest of the body.”
Dr. Snyder cautioned, however, that “there are a lot of unanswered questions about the connection between the health of our digestive system and our long-term cognitive function. Answering these questions may uncover novel therapeutic and risk-reduction approaches for Alzheimer’s and other dementias.”
In an interview, Percy Griffin, PhD, director of scientific engagement at the Alzheimer’s Association, noted that the U.S. Study to Protect Brain Health Through Lifestyle Intervention to Reduce Risk, is evaluating the impact of behavioral interventions on the gut-brain axis.
“We want to better understand how engaging in healthier habits can impact microorganisms in the gut and how changes in gut bacteria relate to brain health,” Dr. Griffin said.
The study was funded by the National Institutes of Health. Dr. Ma, Dr. Wang, Dr. Snyder, and Dr. Griffin have no relevant disclosures.
A version of this article first appeared on Medscape.com.
FROM AAIC 2023
Verbal working memory deterioration predicts relapse in remitted psychosis
Previous research has suggested that cognitive impairments may predict recurrent psychotic episodes, but data on the association between specific cognitive deficits and relapse of psychosis over time are limited, wrote Tiffany J. Tao, MPhil, a PhD candidate at the University of Hong Kong, and colleagues.
In a naturalistic 1-year follow-up study published in Psychiatry Research , the researchers recruited psychosis patients with full remission for a least 6 months from two outpatient psychiatric clinics. The study population included adults aged 18-55 years, with an average age of 29.2 years; 62% were women. Relapse, defined as a recurrence of psychotic symptoms measured by the Positive and Negative Syndrome Scale (PANSS) and the Clinical Global Impression Scale, was assessed monthly via phone interviews with the use of a smartphone app. Cognitive decline was based on working memory deterioration, assessed monthly via the Visual Patterns Test (VPT) and the Letter-Number Sequencing (LNS) test, respectively, for visual and verbal working memory.
Overall, 18 patients (16%) experienced a relapse at 1 year. One-third of these (six patients) required hospitalization, with a median hospital stay of 23 days.
In a multivariate analysis, independent and significant predictors of relapse were verbal working memory deterioration 2 months prior to relapse (P = .029), worse medication adherence (P = .018), and less resilience (P = .014) with odds ratios of 9.445, 0.051, and 0.769, respectively.
“Specifically, declines in verbal working memory were observed beginning at 2 months prior to the relapse episode in both the univariate and multivariate models after controlling for other significant predictors,” the researchers wrote in their discussion.
The mechanism of action for the association remains unclear, but cognitive impairment might reflect dopamine dysregulation or other processes in the prefrontal cortex that could contribute to psychotic relapse, they said.
Other factors include the associations between cognitive impairment and medication nonadherence, and the impact of cognitive impairment on a patient’s ability to manage the stresses of daily living that could trigger a psychotic relapse, they added.
Notably, the current study identified verbal working memory, but not visual working memory, as a predictor of relapse, which is important given the different neurobiological bases for visual and verbal tasks, the researchers wrote.
The study findings were limited by several factors including the inability to identify weaker predictors of relapse given the low relapse rate, and potential lack of generalizability to other less homogeneous populations, and the exclusion of patients with illicit drug use, the researchers noted.
However, the results were strengthened by the prospective measurements that prevented recall bias, and the inclusion of other objective predictors of relapse. The findings highlight the potential for early intervention to prevent relapse based on cognitive assessment, which can be measured objectively in the clinical setting or remotely from home using digital technology, they concluded.
The study received no outside funding. Ms. Tao had no financial conflicts to disclose.
Previous research has suggested that cognitive impairments may predict recurrent psychotic episodes, but data on the association between specific cognitive deficits and relapse of psychosis over time are limited, wrote Tiffany J. Tao, MPhil, a PhD candidate at the University of Hong Kong, and colleagues.
In a naturalistic 1-year follow-up study published in Psychiatry Research , the researchers recruited psychosis patients with full remission for a least 6 months from two outpatient psychiatric clinics. The study population included adults aged 18-55 years, with an average age of 29.2 years; 62% were women. Relapse, defined as a recurrence of psychotic symptoms measured by the Positive and Negative Syndrome Scale (PANSS) and the Clinical Global Impression Scale, was assessed monthly via phone interviews with the use of a smartphone app. Cognitive decline was based on working memory deterioration, assessed monthly via the Visual Patterns Test (VPT) and the Letter-Number Sequencing (LNS) test, respectively, for visual and verbal working memory.
Overall, 18 patients (16%) experienced a relapse at 1 year. One-third of these (six patients) required hospitalization, with a median hospital stay of 23 days.
In a multivariate analysis, independent and significant predictors of relapse were verbal working memory deterioration 2 months prior to relapse (P = .029), worse medication adherence (P = .018), and less resilience (P = .014) with odds ratios of 9.445, 0.051, and 0.769, respectively.
“Specifically, declines in verbal working memory were observed beginning at 2 months prior to the relapse episode in both the univariate and multivariate models after controlling for other significant predictors,” the researchers wrote in their discussion.
The mechanism of action for the association remains unclear, but cognitive impairment might reflect dopamine dysregulation or other processes in the prefrontal cortex that could contribute to psychotic relapse, they said.
Other factors include the associations between cognitive impairment and medication nonadherence, and the impact of cognitive impairment on a patient’s ability to manage the stresses of daily living that could trigger a psychotic relapse, they added.
Notably, the current study identified verbal working memory, but not visual working memory, as a predictor of relapse, which is important given the different neurobiological bases for visual and verbal tasks, the researchers wrote.
The study findings were limited by several factors including the inability to identify weaker predictors of relapse given the low relapse rate, and potential lack of generalizability to other less homogeneous populations, and the exclusion of patients with illicit drug use, the researchers noted.
However, the results were strengthened by the prospective measurements that prevented recall bias, and the inclusion of other objective predictors of relapse. The findings highlight the potential for early intervention to prevent relapse based on cognitive assessment, which can be measured objectively in the clinical setting or remotely from home using digital technology, they concluded.
The study received no outside funding. Ms. Tao had no financial conflicts to disclose.
Previous research has suggested that cognitive impairments may predict recurrent psychotic episodes, but data on the association between specific cognitive deficits and relapse of psychosis over time are limited, wrote Tiffany J. Tao, MPhil, a PhD candidate at the University of Hong Kong, and colleagues.
In a naturalistic 1-year follow-up study published in Psychiatry Research , the researchers recruited psychosis patients with full remission for a least 6 months from two outpatient psychiatric clinics. The study population included adults aged 18-55 years, with an average age of 29.2 years; 62% were women. Relapse, defined as a recurrence of psychotic symptoms measured by the Positive and Negative Syndrome Scale (PANSS) and the Clinical Global Impression Scale, was assessed monthly via phone interviews with the use of a smartphone app. Cognitive decline was based on working memory deterioration, assessed monthly via the Visual Patterns Test (VPT) and the Letter-Number Sequencing (LNS) test, respectively, for visual and verbal working memory.
Overall, 18 patients (16%) experienced a relapse at 1 year. One-third of these (six patients) required hospitalization, with a median hospital stay of 23 days.
In a multivariate analysis, independent and significant predictors of relapse were verbal working memory deterioration 2 months prior to relapse (P = .029), worse medication adherence (P = .018), and less resilience (P = .014) with odds ratios of 9.445, 0.051, and 0.769, respectively.
“Specifically, declines in verbal working memory were observed beginning at 2 months prior to the relapse episode in both the univariate and multivariate models after controlling for other significant predictors,” the researchers wrote in their discussion.
The mechanism of action for the association remains unclear, but cognitive impairment might reflect dopamine dysregulation or other processes in the prefrontal cortex that could contribute to psychotic relapse, they said.
Other factors include the associations between cognitive impairment and medication nonadherence, and the impact of cognitive impairment on a patient’s ability to manage the stresses of daily living that could trigger a psychotic relapse, they added.
Notably, the current study identified verbal working memory, but not visual working memory, as a predictor of relapse, which is important given the different neurobiological bases for visual and verbal tasks, the researchers wrote.
The study findings were limited by several factors including the inability to identify weaker predictors of relapse given the low relapse rate, and potential lack of generalizability to other less homogeneous populations, and the exclusion of patients with illicit drug use, the researchers noted.
However, the results were strengthened by the prospective measurements that prevented recall bias, and the inclusion of other objective predictors of relapse. The findings highlight the potential for early intervention to prevent relapse based on cognitive assessment, which can be measured objectively in the clinical setting or remotely from home using digital technology, they concluded.
The study received no outside funding. Ms. Tao had no financial conflicts to disclose.
FROM PSYCHIATRY RESEARCH
Opioid initiation in dementia tied to an 11-fold increased risk of death
Opioid initiation for older adults with dementia is linked to a significantly increased risk of death, especially in the first 2 weeks, when the risk is elevated 11-fold, new research shows.
“We expected that opioids would be associated with an increased risk of death, but we are surprised by the magnitude,” study investigator Christina Jensen-Dahm, MD, PhD, with the Danish Dementia Research Centre, Copenhagen University Hospital, Rigshospitalet, Denmark, told this news organization.
“It’s important that physicians carefully evaluate the risk and benefits if considering initiating an opioid, and this is particularly important in elderly with dementia,” Dr. Jensen-Dahm added.
The findings were presented at the Alzheimer’s Association International Conference.
Risky business
Using Danish nationwide registries, the researchers analyzed data on all 75,471 adults in Denmark who were aged 65 and older and had been diagnosed with dementia between 2008 and 2018. A total of 31,619 individuals (42%) filled a prescription for an opioid. These “exposed” individuals were matched to 63,235 unexposed individuals.
Among the exposed group, 10,474 (33%) died within 180 days after starting opioid therapy, compared with 3,980 (6.4%) in the unexposed group.
After adjusting for potential differences between groups, new use of an opioid was associated with a greater than fourfold excess mortality risk (adjusted hazard ratio, 4.16; 95% confidence interval, 4.00-4.33).
New use of a strong opioid – defined as morphine, oxycodone, ketobemidone, hydromorphone, pethidine, buprenorphine, and fentanyl – was associated with a greater than sixfold increase in mortality risk (aHR, 6.42; 95% CI, 6.08-6.79).
Among those who used fentanyl patches as their first opioid, 65% died within the first 180 days, compared with 6.7% in the unexposed – an eightfold increased mortality risk (aHR, 8.04; 95% CI, 7.01-9.22).
For all opioids, the risk was greatest in the first 14 days, with a nearly 11-fold increased risk of mortality (aHR, 10.8; 95% CI, 9.74-11.99). However, there remained a twofold increase in risk after taking opioids for 90 days (aHR, 2.32; 95% CI, 2.17-2.48).
“Opioids are associated with severe and well-known side effects, such as sedation, confusion, respiratory depression, falls, and in the most severe cases, death. In the general population, opioids have been associated with an increased risk of death, and similar to ours, greatest in the first 14 days,” said Dr. Jensen-Dahm.
Need to weigh risks, benefits
Commenting on the study, Percy Griffin, PhD, director of scientific engagement at the Alzheimer’s Association, told this news organization that the use of strong opioids has “increased considerably over the past decade among older people with dementia. Opioid therapy should only be considered for pain if the benefits are anticipated to outweigh the risks in individuals who are living with dementia.”
“Opioids are very powerful drugs, and while we need to see additional research in more diverse populations, these initial findings indicate they may put older adults with dementia at much higher risk of death,” Nicole Purcell, DO, neurologist and senior director of clinical practice at the Alzheimer’s Association, added in a conference statement.
“Pain should not go undiagnosed or untreated, in particular in people living with dementia, who may not be able to effectively articulate the location and severity of the pain,” Dr. Purcell added.
These new findings further emphasize the need for discussion between patient, family, and physician. Decisions about prescribing pain medication should be thought through carefully, and if used, there needs to be careful monitoring of the patient, said Dr. Purcell.
The study was supported by a grant from the Capital Region of Denmark. Dr. Jensen-Dahm, Dr. Griffin, and Dr. Purcell have no relevant disclosures.
A version of this article first appeared on Medscape.com.
Opioid initiation for older adults with dementia is linked to a significantly increased risk of death, especially in the first 2 weeks, when the risk is elevated 11-fold, new research shows.
“We expected that opioids would be associated with an increased risk of death, but we are surprised by the magnitude,” study investigator Christina Jensen-Dahm, MD, PhD, with the Danish Dementia Research Centre, Copenhagen University Hospital, Rigshospitalet, Denmark, told this news organization.
“It’s important that physicians carefully evaluate the risk and benefits if considering initiating an opioid, and this is particularly important in elderly with dementia,” Dr. Jensen-Dahm added.
The findings were presented at the Alzheimer’s Association International Conference.
Risky business
Using Danish nationwide registries, the researchers analyzed data on all 75,471 adults in Denmark who were aged 65 and older and had been diagnosed with dementia between 2008 and 2018. A total of 31,619 individuals (42%) filled a prescription for an opioid. These “exposed” individuals were matched to 63,235 unexposed individuals.
Among the exposed group, 10,474 (33%) died within 180 days after starting opioid therapy, compared with 3,980 (6.4%) in the unexposed group.
After adjusting for potential differences between groups, new use of an opioid was associated with a greater than fourfold excess mortality risk (adjusted hazard ratio, 4.16; 95% confidence interval, 4.00-4.33).
New use of a strong opioid – defined as morphine, oxycodone, ketobemidone, hydromorphone, pethidine, buprenorphine, and fentanyl – was associated with a greater than sixfold increase in mortality risk (aHR, 6.42; 95% CI, 6.08-6.79).
Among those who used fentanyl patches as their first opioid, 65% died within the first 180 days, compared with 6.7% in the unexposed – an eightfold increased mortality risk (aHR, 8.04; 95% CI, 7.01-9.22).
For all opioids, the risk was greatest in the first 14 days, with a nearly 11-fold increased risk of mortality (aHR, 10.8; 95% CI, 9.74-11.99). However, there remained a twofold increase in risk after taking opioids for 90 days (aHR, 2.32; 95% CI, 2.17-2.48).
“Opioids are associated with severe and well-known side effects, such as sedation, confusion, respiratory depression, falls, and in the most severe cases, death. In the general population, opioids have been associated with an increased risk of death, and similar to ours, greatest in the first 14 days,” said Dr. Jensen-Dahm.
Need to weigh risks, benefits
Commenting on the study, Percy Griffin, PhD, director of scientific engagement at the Alzheimer’s Association, told this news organization that the use of strong opioids has “increased considerably over the past decade among older people with dementia. Opioid therapy should only be considered for pain if the benefits are anticipated to outweigh the risks in individuals who are living with dementia.”
“Opioids are very powerful drugs, and while we need to see additional research in more diverse populations, these initial findings indicate they may put older adults with dementia at much higher risk of death,” Nicole Purcell, DO, neurologist and senior director of clinical practice at the Alzheimer’s Association, added in a conference statement.
“Pain should not go undiagnosed or untreated, in particular in people living with dementia, who may not be able to effectively articulate the location and severity of the pain,” Dr. Purcell added.
These new findings further emphasize the need for discussion between patient, family, and physician. Decisions about prescribing pain medication should be thought through carefully, and if used, there needs to be careful monitoring of the patient, said Dr. Purcell.
The study was supported by a grant from the Capital Region of Denmark. Dr. Jensen-Dahm, Dr. Griffin, and Dr. Purcell have no relevant disclosures.
A version of this article first appeared on Medscape.com.
Opioid initiation for older adults with dementia is linked to a significantly increased risk of death, especially in the first 2 weeks, when the risk is elevated 11-fold, new research shows.
“We expected that opioids would be associated with an increased risk of death, but we are surprised by the magnitude,” study investigator Christina Jensen-Dahm, MD, PhD, with the Danish Dementia Research Centre, Copenhagen University Hospital, Rigshospitalet, Denmark, told this news organization.
“It’s important that physicians carefully evaluate the risk and benefits if considering initiating an opioid, and this is particularly important in elderly with dementia,” Dr. Jensen-Dahm added.
The findings were presented at the Alzheimer’s Association International Conference.
Risky business
Using Danish nationwide registries, the researchers analyzed data on all 75,471 adults in Denmark who were aged 65 and older and had been diagnosed with dementia between 2008 and 2018. A total of 31,619 individuals (42%) filled a prescription for an opioid. These “exposed” individuals were matched to 63,235 unexposed individuals.
Among the exposed group, 10,474 (33%) died within 180 days after starting opioid therapy, compared with 3,980 (6.4%) in the unexposed group.
After adjusting for potential differences between groups, new use of an opioid was associated with a greater than fourfold excess mortality risk (adjusted hazard ratio, 4.16; 95% confidence interval, 4.00-4.33).
New use of a strong opioid – defined as morphine, oxycodone, ketobemidone, hydromorphone, pethidine, buprenorphine, and fentanyl – was associated with a greater than sixfold increase in mortality risk (aHR, 6.42; 95% CI, 6.08-6.79).
Among those who used fentanyl patches as their first opioid, 65% died within the first 180 days, compared with 6.7% in the unexposed – an eightfold increased mortality risk (aHR, 8.04; 95% CI, 7.01-9.22).
For all opioids, the risk was greatest in the first 14 days, with a nearly 11-fold increased risk of mortality (aHR, 10.8; 95% CI, 9.74-11.99). However, there remained a twofold increase in risk after taking opioids for 90 days (aHR, 2.32; 95% CI, 2.17-2.48).
“Opioids are associated with severe and well-known side effects, such as sedation, confusion, respiratory depression, falls, and in the most severe cases, death. In the general population, opioids have been associated with an increased risk of death, and similar to ours, greatest in the first 14 days,” said Dr. Jensen-Dahm.
Need to weigh risks, benefits
Commenting on the study, Percy Griffin, PhD, director of scientific engagement at the Alzheimer’s Association, told this news organization that the use of strong opioids has “increased considerably over the past decade among older people with dementia. Opioid therapy should only be considered for pain if the benefits are anticipated to outweigh the risks in individuals who are living with dementia.”
“Opioids are very powerful drugs, and while we need to see additional research in more diverse populations, these initial findings indicate they may put older adults with dementia at much higher risk of death,” Nicole Purcell, DO, neurologist and senior director of clinical practice at the Alzheimer’s Association, added in a conference statement.
“Pain should not go undiagnosed or untreated, in particular in people living with dementia, who may not be able to effectively articulate the location and severity of the pain,” Dr. Purcell added.
These new findings further emphasize the need for discussion between patient, family, and physician. Decisions about prescribing pain medication should be thought through carefully, and if used, there needs to be careful monitoring of the patient, said Dr. Purcell.
The study was supported by a grant from the Capital Region of Denmark. Dr. Jensen-Dahm, Dr. Griffin, and Dr. Purcell have no relevant disclosures.
A version of this article first appeared on Medscape.com.
From AAIC 2023
‘Brain fitness program’ may aid memory loss, concussion, ADHD
new research shows.
The program, which consists of targeted cognitive training and EEG-based neurofeedback, coupled with meditation and diet/lifestyle coaching, led to improvements in memory, attention, mood, alertness, and sleep.
The program promotes “neuroplasticity and was equally effective for patients with all three conditions,” program creator Majid Fotuhi, MD, PhD, said in an interview.
Patients with mild to moderate cognitive symptoms often see “remarkable” results within 3 months of consistently following the program, said Dr. Fotuhi, adjunct professor of neuroscience at George Washington University, Washington, and medical director of NeuroGrow Brain Fitness Center, McLean, Va.
“It actually makes intuitive sense that a healthier and stronger brain would function better and that patients of all ages with various cognitive or emotional symptoms would all benefit from improving the biology of their brain,” Dr. Fotuhi added.
The study was published online in the Journal of Alzheimer’s Disease Reports.
Personalized program
The findings are based on 223 children and adults who completed the 12-week NeuroGrow Brain Fitness Program (NeuroGrow BFP), including 71 with ADHD, 88 with PCS, and 64 with memory loss, defined as diagnosed mild cognitive impairment or subjective cognitive decline.
As part of the program, participants undergo a complete neurocognitive evaluation, including tests for verbal memory, complex attention, processing speed, executive functioning, and the Neurocognitive Index.
They also complete questionnaires regarding sleep, mood, diet, exercise, and anxiety/depression, and they undergo quantitative EEG at the beginning and end of the program.
A comparison of before and after neurocognitive test scores showed that all three patient subgroups experienced statistically significant improvements on most measures, the study team reports.
After completing the program, 60%-90% of patients scored higher on cognitive tests and reported having fewer cognitive, sleep, and emotional symptoms.
In all subgroups, the most significant improvement was observed in executive functioning.
“These preliminary findings appear to show that multimodal interventions which are known to increase neuroplasticity in the brain, when personalized, can have benefits for patients with cognitive symptoms from a variety of neurological conditions,” the investigators wrote.
The study’s strengths include a large, community-based sample of patients of different ages who had disruptive symptoms and abnormalities as determined using objective cognitive tests whose progress was monitored by objective and subjective measures.
The chief limitation is the lack of a control or placebo group.
“Though it is difficult to find a comparable group of patients with the exact same profile of cognitive deficits and brain-related symptoms, studying a larger group of patients – and comparing them with a wait-list group – may make it possible to do a more definitive assessment of the NeuroGrow BFP,” the researchers noted.
Dr. Fotuhi said the “secret to the success” of the program is that it involves a full assessment of all cognitive and neurobehavioral symptoms for each patient. This allows for individualized and targeted interventions for specific concerns and symptoms.
He said there is a need to recognize that patients who present to a neurology practice with a single complaint, such as a problem with memory or attention, often have other problems, such as anxiety/depression, stress, insomnia, sedentary lifestyle, obesity, diabetes, sleep apnea, or alcohol overuse.
“Each of these factors can affect their cognitive abilities and need a multimodal set of interventions in order to see full resolution of their cognitive symptoms,” Dr. Fotuhi said.
He has created a series of educational videos to demonstrate the program’s benefits.
The self-pay cost for the NeuroGrow BFP assessment and treatment sessions is approximately $7,000.
Dr. Fotuhi said all of the interventions included in the program are readily available at low cost.
He suggested that health care professionals who lack time or staff for conducting a comprehensive neurocognitive assessment for their patients can provide them with a copy of the Brain Health Index.
“Patients can then be instructed to work on the individual components of their brain health on their own – and measure their brain health index on a weekly basis,” Dr. Fotuhi said. “Private practices or academic centers can use the detailed information I have provided in my paper to develop their own brain fitness program.”
Not ready for prime time
Commenting on the study, Percy Griffin, PhD, director of scientific engagement for the Alzheimer’s Association, noted that “nonpharmacologic interventions can help alleviate some of the symptoms associated with dementia.
“The current study investigates nonpharmacologic interventions in a small number of patients with ADHD, postconcussion syndrome, or memory loss. The researchers found improvements on most measures following the brain rehabilitation program.
“While this is interesting, more work is needed in larger, more diverse cohorts before these programs can be applied broadly. Nonpharmacologic interventions are a helpful tool that need to be studied further in future studies,” Dr. Griffin added.
Funding for the study was provided by the NeuroGrow Brain Fitness Center. Dr. Fotuhi, the owner of NeuroGrow, was involved in data analysis, writing, editing, approval, and decision to publish. Dr. Griffin reported no disclosures.
A version of this article appeared on Medscape.com.
new research shows.
The program, which consists of targeted cognitive training and EEG-based neurofeedback, coupled with meditation and diet/lifestyle coaching, led to improvements in memory, attention, mood, alertness, and sleep.
The program promotes “neuroplasticity and was equally effective for patients with all three conditions,” program creator Majid Fotuhi, MD, PhD, said in an interview.
Patients with mild to moderate cognitive symptoms often see “remarkable” results within 3 months of consistently following the program, said Dr. Fotuhi, adjunct professor of neuroscience at George Washington University, Washington, and medical director of NeuroGrow Brain Fitness Center, McLean, Va.
“It actually makes intuitive sense that a healthier and stronger brain would function better and that patients of all ages with various cognitive or emotional symptoms would all benefit from improving the biology of their brain,” Dr. Fotuhi added.
The study was published online in the Journal of Alzheimer’s Disease Reports.
Personalized program
The findings are based on 223 children and adults who completed the 12-week NeuroGrow Brain Fitness Program (NeuroGrow BFP), including 71 with ADHD, 88 with PCS, and 64 with memory loss, defined as diagnosed mild cognitive impairment or subjective cognitive decline.
As part of the program, participants undergo a complete neurocognitive evaluation, including tests for verbal memory, complex attention, processing speed, executive functioning, and the Neurocognitive Index.
They also complete questionnaires regarding sleep, mood, diet, exercise, and anxiety/depression, and they undergo quantitative EEG at the beginning and end of the program.
A comparison of before and after neurocognitive test scores showed that all three patient subgroups experienced statistically significant improvements on most measures, the study team reports.
After completing the program, 60%-90% of patients scored higher on cognitive tests and reported having fewer cognitive, sleep, and emotional symptoms.
In all subgroups, the most significant improvement was observed in executive functioning.
“These preliminary findings appear to show that multimodal interventions which are known to increase neuroplasticity in the brain, when personalized, can have benefits for patients with cognitive symptoms from a variety of neurological conditions,” the investigators wrote.
The study’s strengths include a large, community-based sample of patients of different ages who had disruptive symptoms and abnormalities as determined using objective cognitive tests whose progress was monitored by objective and subjective measures.
The chief limitation is the lack of a control or placebo group.
“Though it is difficult to find a comparable group of patients with the exact same profile of cognitive deficits and brain-related symptoms, studying a larger group of patients – and comparing them with a wait-list group – may make it possible to do a more definitive assessment of the NeuroGrow BFP,” the researchers noted.
Dr. Fotuhi said the “secret to the success” of the program is that it involves a full assessment of all cognitive and neurobehavioral symptoms for each patient. This allows for individualized and targeted interventions for specific concerns and symptoms.
He said there is a need to recognize that patients who present to a neurology practice with a single complaint, such as a problem with memory or attention, often have other problems, such as anxiety/depression, stress, insomnia, sedentary lifestyle, obesity, diabetes, sleep apnea, or alcohol overuse.
“Each of these factors can affect their cognitive abilities and need a multimodal set of interventions in order to see full resolution of their cognitive symptoms,” Dr. Fotuhi said.
He has created a series of educational videos to demonstrate the program’s benefits.
The self-pay cost for the NeuroGrow BFP assessment and treatment sessions is approximately $7,000.
Dr. Fotuhi said all of the interventions included in the program are readily available at low cost.
He suggested that health care professionals who lack time or staff for conducting a comprehensive neurocognitive assessment for their patients can provide them with a copy of the Brain Health Index.
“Patients can then be instructed to work on the individual components of their brain health on their own – and measure their brain health index on a weekly basis,” Dr. Fotuhi said. “Private practices or academic centers can use the detailed information I have provided in my paper to develop their own brain fitness program.”
Not ready for prime time
Commenting on the study, Percy Griffin, PhD, director of scientific engagement for the Alzheimer’s Association, noted that “nonpharmacologic interventions can help alleviate some of the symptoms associated with dementia.
“The current study investigates nonpharmacologic interventions in a small number of patients with ADHD, postconcussion syndrome, or memory loss. The researchers found improvements on most measures following the brain rehabilitation program.
“While this is interesting, more work is needed in larger, more diverse cohorts before these programs can be applied broadly. Nonpharmacologic interventions are a helpful tool that need to be studied further in future studies,” Dr. Griffin added.
Funding for the study was provided by the NeuroGrow Brain Fitness Center. Dr. Fotuhi, the owner of NeuroGrow, was involved in data analysis, writing, editing, approval, and decision to publish. Dr. Griffin reported no disclosures.
A version of this article appeared on Medscape.com.
new research shows.
The program, which consists of targeted cognitive training and EEG-based neurofeedback, coupled with meditation and diet/lifestyle coaching, led to improvements in memory, attention, mood, alertness, and sleep.
The program promotes “neuroplasticity and was equally effective for patients with all three conditions,” program creator Majid Fotuhi, MD, PhD, said in an interview.
Patients with mild to moderate cognitive symptoms often see “remarkable” results within 3 months of consistently following the program, said Dr. Fotuhi, adjunct professor of neuroscience at George Washington University, Washington, and medical director of NeuroGrow Brain Fitness Center, McLean, Va.
“It actually makes intuitive sense that a healthier and stronger brain would function better and that patients of all ages with various cognitive or emotional symptoms would all benefit from improving the biology of their brain,” Dr. Fotuhi added.
The study was published online in the Journal of Alzheimer’s Disease Reports.
Personalized program
The findings are based on 223 children and adults who completed the 12-week NeuroGrow Brain Fitness Program (NeuroGrow BFP), including 71 with ADHD, 88 with PCS, and 64 with memory loss, defined as diagnosed mild cognitive impairment or subjective cognitive decline.
As part of the program, participants undergo a complete neurocognitive evaluation, including tests for verbal memory, complex attention, processing speed, executive functioning, and the Neurocognitive Index.
They also complete questionnaires regarding sleep, mood, diet, exercise, and anxiety/depression, and they undergo quantitative EEG at the beginning and end of the program.
A comparison of before and after neurocognitive test scores showed that all three patient subgroups experienced statistically significant improvements on most measures, the study team reports.
After completing the program, 60%-90% of patients scored higher on cognitive tests and reported having fewer cognitive, sleep, and emotional symptoms.
In all subgroups, the most significant improvement was observed in executive functioning.
“These preliminary findings appear to show that multimodal interventions which are known to increase neuroplasticity in the brain, when personalized, can have benefits for patients with cognitive symptoms from a variety of neurological conditions,” the investigators wrote.
The study’s strengths include a large, community-based sample of patients of different ages who had disruptive symptoms and abnormalities as determined using objective cognitive tests whose progress was monitored by objective and subjective measures.
The chief limitation is the lack of a control or placebo group.
“Though it is difficult to find a comparable group of patients with the exact same profile of cognitive deficits and brain-related symptoms, studying a larger group of patients – and comparing them with a wait-list group – may make it possible to do a more definitive assessment of the NeuroGrow BFP,” the researchers noted.
Dr. Fotuhi said the “secret to the success” of the program is that it involves a full assessment of all cognitive and neurobehavioral symptoms for each patient. This allows for individualized and targeted interventions for specific concerns and symptoms.
He said there is a need to recognize that patients who present to a neurology practice with a single complaint, such as a problem with memory or attention, often have other problems, such as anxiety/depression, stress, insomnia, sedentary lifestyle, obesity, diabetes, sleep apnea, or alcohol overuse.
“Each of these factors can affect their cognitive abilities and need a multimodal set of interventions in order to see full resolution of their cognitive symptoms,” Dr. Fotuhi said.
He has created a series of educational videos to demonstrate the program’s benefits.
The self-pay cost for the NeuroGrow BFP assessment and treatment sessions is approximately $7,000.
Dr. Fotuhi said all of the interventions included in the program are readily available at low cost.
He suggested that health care professionals who lack time or staff for conducting a comprehensive neurocognitive assessment for their patients can provide them with a copy of the Brain Health Index.
“Patients can then be instructed to work on the individual components of their brain health on their own – and measure their brain health index on a weekly basis,” Dr. Fotuhi said. “Private practices or academic centers can use the detailed information I have provided in my paper to develop their own brain fitness program.”
Not ready for prime time
Commenting on the study, Percy Griffin, PhD, director of scientific engagement for the Alzheimer’s Association, noted that “nonpharmacologic interventions can help alleviate some of the symptoms associated with dementia.
“The current study investigates nonpharmacologic interventions in a small number of patients with ADHD, postconcussion syndrome, or memory loss. The researchers found improvements on most measures following the brain rehabilitation program.
“While this is interesting, more work is needed in larger, more diverse cohorts before these programs can be applied broadly. Nonpharmacologic interventions are a helpful tool that need to be studied further in future studies,” Dr. Griffin added.
Funding for the study was provided by the NeuroGrow Brain Fitness Center. Dr. Fotuhi, the owner of NeuroGrow, was involved in data analysis, writing, editing, approval, and decision to publish. Dr. Griffin reported no disclosures.
A version of this article appeared on Medscape.com.
FROM THE JOURNAL OF ALZHEIMER’S DISEASE REPORTS
Promising phase 3 results for Alzheimer’s drug donanemab
results of a phase 3 study showed.
“This trial demonstrates that an antiamyloid drug significantly slows the disease and provides meaningful benefit to patients, and we’re hoping that with approval, we will be able to make that drug available,” said Mark Mintun, MD, VP, pain and neurodegeneration research, Eli Lilly.
At a press briefing highlighting the new results, Maria Carrillo, PhD, chief science officer, Alzheimer’s Association, noted the “palpable excitement” surrounding this new study, which follows on the heels of other promising antiamyloid research. “This is the decade of Alzheimer’s disease, and it will get better from here,” she said.
The findings were presented at the Alzheimer’s Association International Conference and were published online in JAMA.
Primary, secondary endpoints met
The TRAILBLAZER-ALZ 2 study included 1,736 patients with mild cognitive impairment (MCI) or mild dementia for whom PET showed evidence of amyloid and tau pathology. The mean age of the participants was 73 years, and most of the participants were White.
Participants were randomly assigned to receive either placebo or donanemab, an investigational IgG1 monoclonal antibody directed against an insoluble, modified, N-terminal, truncated form of beta-amyloid. Donanemab was administered at a dose of 700 mg for the first three doses and 1,400 mg thereafter. The drug was administered intravenously every 4 weeks for up to 72 weeks.
Researchers stratified patients on the basis of the amount of tau, a biomarker for Alzheimer’s disease progression, into a low/medium tau group and a combined tau group (low/medium and high tau).
The primary endpoint was change from baseline to 76 weeks on the integrated Alzheimer’s Disease Rating Scale (iADRS), which measures cognition and activities of daily living.
In those with low/medium tau levels, the least squares mean (LSM) change in iADRS score was −6.02 (95% confidence interval, −7.01 to −5.03) in the donanemab group and −9.27 (95% CI, −10.23 to −8.31) in the placebo group (difference, 3.25; 95% CI, 1.88 – 4.62; P < .001), representing a 35.1% slowing of disease progression.
In the combined (tau) population, LSM change in iADRS was −10.19 (95% CI, −11.22 to −9.16) in the donanemab group and −13.11 (95% CI, −14.10 to −12.13) in the placebo group (difference, 2.92; 95% CI, 1.51 – 4.33; P < .001), representing a 22.3% slowing of disease progression.
The study also met all secondary endpoints regarding measurements of cognitive and functional decline, including the Clinical Dementia Rating–Sum of Boxes (CDR-SB), which showed 36% slowing of decline (P < .0001) over 18 months.
The authors noted that the changes on these scales were clinically meaningful (considered to be > 20% slowing of clinical progression) for both the low/medium tau and combined populations.
Greater benefit with lower tau
However, patients with low/medium tau generally demonstrated effect size estimates that were larger than those of the overall population, which suggests there’s greater benefit when amyloid-lowering therapies are initiated at an earlier disease stage, the investigators noted.
Additional support for clinical relevance was a 38.6% risk reduction of disease progression, as measured on the CDR–Global Score.
In addition, participants who received the active drug benefited in terms of activities of daily living, as demonstrated by 40% less decline (P < .0001) on the Alzheimer’s Disease Cooperative Study–Instrumental Activities of Daily Living Inventory.
Donanemab significantly reduced brain amyloid plaque: 80% (low/medium tau population) and 76% (combined population) of participants achieved amyloid clearance at 76 weeks. The intervention was also associated with a greater decrease in whole-brain volume.
The treatment effect continued to widen after patients were switched to placebo, as evidenced on PET scan at 6 or 12 months, said Dr. Mintun.
The effects of the drug were similar among men and women but were especially pronounced among younger participants, with a 48% slowing on iADRS and a 45% slowing on CDR-SB in those younger than 75 years.
Safety issues
However, the drug is not without some safety concerns. Amyloid-related imaging abnormalities (ARIAs) occurred in 36.8% of the treatment group versus 14.9% of the placebo group, and in 40.6% of patients who were homozygous for apo E4 and received the drug. Microhemorrhage occurred in 26.8% in the donanemab group versus 12.5% in the placebo group.
Most ARIA cases were mild to moderate and resolved or stabilized with appropriate management. However, three deaths were determined to be drug related among participants who developed serious ARIAs or brain bleeding and swelling.
An important study limitation was that it enrolled primarily White patients (91.5%), which may limit generalizability to other populations, and the age limit was 85 years, which some believe is an inadequate representation of older adults. In addition, the 18-month treatment window limits the long-term understanding of donanemab’s benefits and side effects.
Eli Lilly has filed a submission to the Food and Drug Administration. If approved, donanemab will be the third antiamyloid monoclonal antibody to receive this status, following aducanumab (Aduhelm) and lecanemab (Leqembi).
Strongest data yet
Commenting on the study findings, Percy Griffin, PhD, director of scientific engagement, Alzheimer’s Association, said these new results are “very, very exciting” and represent “the strongest data to-date” for antiamyloid monoclonal antibodies in Alzheimer’s disease.
“A good percentage of individuals on the drug actually saw a complete clearance of amyloid, and some had to be taken off the drug, because if you’re on an antiamyloid drug and there’s no amyloid, what are you going for?”
He noted that the study had some unique aspects, including using tau-PET “to see whether or not the drug is more effective in subpopulations.”
Access to this and other antiamyloid therapies should be a priority, said Dr. Griffin. “We have to make sure people who have the potential to benefit from these treatments do.”
The Alzheimer’s Association is calling for Medicare beneficiaries who are living with the disease to receive the same coverage afforded to those with other diseases.
“The Centers for Medicare & Medicaid Services policy to block Medicare access to FDA-approved Alzheimer’s disease treatments is in stark contrast to scientific evidence, is unprecedented and must be reversed immediately,” Joanne Pike, DrPH, president and CEO of the Alzheimer’s Association, said in a press release.
Also important is tracking the longitudinal performance of these drugs outside of clinical trials, said Dr. Griffin. “Not everyone is going to be in that Goldilocks zone of being able to see a doctor whenever they want and have access to these PET and MRI tools and other things used in clinical trials.”
He noted that the Alzheimer’s Association is leading a network for diagnostics and therapeutics (ALZ-NET) that will track the performance of novel FDA-approved Alzheimer’s disease therapies “in the real world.”
While these are exciting findings for antiamyloid therapy, “we can’t take our foot off the gas, we need more therapies that target different aspects of the disease biology,” said Dr. Griffin.
A version of this article appeared on Medscape.com.
results of a phase 3 study showed.
“This trial demonstrates that an antiamyloid drug significantly slows the disease and provides meaningful benefit to patients, and we’re hoping that with approval, we will be able to make that drug available,” said Mark Mintun, MD, VP, pain and neurodegeneration research, Eli Lilly.
At a press briefing highlighting the new results, Maria Carrillo, PhD, chief science officer, Alzheimer’s Association, noted the “palpable excitement” surrounding this new study, which follows on the heels of other promising antiamyloid research. “This is the decade of Alzheimer’s disease, and it will get better from here,” she said.
The findings were presented at the Alzheimer’s Association International Conference and were published online in JAMA.
Primary, secondary endpoints met
The TRAILBLAZER-ALZ 2 study included 1,736 patients with mild cognitive impairment (MCI) or mild dementia for whom PET showed evidence of amyloid and tau pathology. The mean age of the participants was 73 years, and most of the participants were White.
Participants were randomly assigned to receive either placebo or donanemab, an investigational IgG1 monoclonal antibody directed against an insoluble, modified, N-terminal, truncated form of beta-amyloid. Donanemab was administered at a dose of 700 mg for the first three doses and 1,400 mg thereafter. The drug was administered intravenously every 4 weeks for up to 72 weeks.
Researchers stratified patients on the basis of the amount of tau, a biomarker for Alzheimer’s disease progression, into a low/medium tau group and a combined tau group (low/medium and high tau).
The primary endpoint was change from baseline to 76 weeks on the integrated Alzheimer’s Disease Rating Scale (iADRS), which measures cognition and activities of daily living.
In those with low/medium tau levels, the least squares mean (LSM) change in iADRS score was −6.02 (95% confidence interval, −7.01 to −5.03) in the donanemab group and −9.27 (95% CI, −10.23 to −8.31) in the placebo group (difference, 3.25; 95% CI, 1.88 – 4.62; P < .001), representing a 35.1% slowing of disease progression.
In the combined (tau) population, LSM change in iADRS was −10.19 (95% CI, −11.22 to −9.16) in the donanemab group and −13.11 (95% CI, −14.10 to −12.13) in the placebo group (difference, 2.92; 95% CI, 1.51 – 4.33; P < .001), representing a 22.3% slowing of disease progression.
The study also met all secondary endpoints regarding measurements of cognitive and functional decline, including the Clinical Dementia Rating–Sum of Boxes (CDR-SB), which showed 36% slowing of decline (P < .0001) over 18 months.
The authors noted that the changes on these scales were clinically meaningful (considered to be > 20% slowing of clinical progression) for both the low/medium tau and combined populations.
Greater benefit with lower tau
However, patients with low/medium tau generally demonstrated effect size estimates that were larger than those of the overall population, which suggests there’s greater benefit when amyloid-lowering therapies are initiated at an earlier disease stage, the investigators noted.
Additional support for clinical relevance was a 38.6% risk reduction of disease progression, as measured on the CDR–Global Score.
In addition, participants who received the active drug benefited in terms of activities of daily living, as demonstrated by 40% less decline (P < .0001) on the Alzheimer’s Disease Cooperative Study–Instrumental Activities of Daily Living Inventory.
Donanemab significantly reduced brain amyloid plaque: 80% (low/medium tau population) and 76% (combined population) of participants achieved amyloid clearance at 76 weeks. The intervention was also associated with a greater decrease in whole-brain volume.
The treatment effect continued to widen after patients were switched to placebo, as evidenced on PET scan at 6 or 12 months, said Dr. Mintun.
The effects of the drug were similar among men and women but were especially pronounced among younger participants, with a 48% slowing on iADRS and a 45% slowing on CDR-SB in those younger than 75 years.
Safety issues
However, the drug is not without some safety concerns. Amyloid-related imaging abnormalities (ARIAs) occurred in 36.8% of the treatment group versus 14.9% of the placebo group, and in 40.6% of patients who were homozygous for apo E4 and received the drug. Microhemorrhage occurred in 26.8% in the donanemab group versus 12.5% in the placebo group.
Most ARIA cases were mild to moderate and resolved or stabilized with appropriate management. However, three deaths were determined to be drug related among participants who developed serious ARIAs or brain bleeding and swelling.
An important study limitation was that it enrolled primarily White patients (91.5%), which may limit generalizability to other populations, and the age limit was 85 years, which some believe is an inadequate representation of older adults. In addition, the 18-month treatment window limits the long-term understanding of donanemab’s benefits and side effects.
Eli Lilly has filed a submission to the Food and Drug Administration. If approved, donanemab will be the third antiamyloid monoclonal antibody to receive this status, following aducanumab (Aduhelm) and lecanemab (Leqembi).
Strongest data yet
Commenting on the study findings, Percy Griffin, PhD, director of scientific engagement, Alzheimer’s Association, said these new results are “very, very exciting” and represent “the strongest data to-date” for antiamyloid monoclonal antibodies in Alzheimer’s disease.
“A good percentage of individuals on the drug actually saw a complete clearance of amyloid, and some had to be taken off the drug, because if you’re on an antiamyloid drug and there’s no amyloid, what are you going for?”
He noted that the study had some unique aspects, including using tau-PET “to see whether or not the drug is more effective in subpopulations.”
Access to this and other antiamyloid therapies should be a priority, said Dr. Griffin. “We have to make sure people who have the potential to benefit from these treatments do.”
The Alzheimer’s Association is calling for Medicare beneficiaries who are living with the disease to receive the same coverage afforded to those with other diseases.
“The Centers for Medicare & Medicaid Services policy to block Medicare access to FDA-approved Alzheimer’s disease treatments is in stark contrast to scientific evidence, is unprecedented and must be reversed immediately,” Joanne Pike, DrPH, president and CEO of the Alzheimer’s Association, said in a press release.
Also important is tracking the longitudinal performance of these drugs outside of clinical trials, said Dr. Griffin. “Not everyone is going to be in that Goldilocks zone of being able to see a doctor whenever they want and have access to these PET and MRI tools and other things used in clinical trials.”
He noted that the Alzheimer’s Association is leading a network for diagnostics and therapeutics (ALZ-NET) that will track the performance of novel FDA-approved Alzheimer’s disease therapies “in the real world.”
While these are exciting findings for antiamyloid therapy, “we can’t take our foot off the gas, we need more therapies that target different aspects of the disease biology,” said Dr. Griffin.
A version of this article appeared on Medscape.com.
results of a phase 3 study showed.
“This trial demonstrates that an antiamyloid drug significantly slows the disease and provides meaningful benefit to patients, and we’re hoping that with approval, we will be able to make that drug available,” said Mark Mintun, MD, VP, pain and neurodegeneration research, Eli Lilly.
At a press briefing highlighting the new results, Maria Carrillo, PhD, chief science officer, Alzheimer’s Association, noted the “palpable excitement” surrounding this new study, which follows on the heels of other promising antiamyloid research. “This is the decade of Alzheimer’s disease, and it will get better from here,” she said.
The findings were presented at the Alzheimer’s Association International Conference and were published online in JAMA.
Primary, secondary endpoints met
The TRAILBLAZER-ALZ 2 study included 1,736 patients with mild cognitive impairment (MCI) or mild dementia for whom PET showed evidence of amyloid and tau pathology. The mean age of the participants was 73 years, and most of the participants were White.
Participants were randomly assigned to receive either placebo or donanemab, an investigational IgG1 monoclonal antibody directed against an insoluble, modified, N-terminal, truncated form of beta-amyloid. Donanemab was administered at a dose of 700 mg for the first three doses and 1,400 mg thereafter. The drug was administered intravenously every 4 weeks for up to 72 weeks.
Researchers stratified patients on the basis of the amount of tau, a biomarker for Alzheimer’s disease progression, into a low/medium tau group and a combined tau group (low/medium and high tau).
The primary endpoint was change from baseline to 76 weeks on the integrated Alzheimer’s Disease Rating Scale (iADRS), which measures cognition and activities of daily living.
In those with low/medium tau levels, the least squares mean (LSM) change in iADRS score was −6.02 (95% confidence interval, −7.01 to −5.03) in the donanemab group and −9.27 (95% CI, −10.23 to −8.31) in the placebo group (difference, 3.25; 95% CI, 1.88 – 4.62; P < .001), representing a 35.1% slowing of disease progression.
In the combined (tau) population, LSM change in iADRS was −10.19 (95% CI, −11.22 to −9.16) in the donanemab group and −13.11 (95% CI, −14.10 to −12.13) in the placebo group (difference, 2.92; 95% CI, 1.51 – 4.33; P < .001), representing a 22.3% slowing of disease progression.
The study also met all secondary endpoints regarding measurements of cognitive and functional decline, including the Clinical Dementia Rating–Sum of Boxes (CDR-SB), which showed 36% slowing of decline (P < .0001) over 18 months.
The authors noted that the changes on these scales were clinically meaningful (considered to be > 20% slowing of clinical progression) for both the low/medium tau and combined populations.
Greater benefit with lower tau
However, patients with low/medium tau generally demonstrated effect size estimates that were larger than those of the overall population, which suggests there’s greater benefit when amyloid-lowering therapies are initiated at an earlier disease stage, the investigators noted.
Additional support for clinical relevance was a 38.6% risk reduction of disease progression, as measured on the CDR–Global Score.
In addition, participants who received the active drug benefited in terms of activities of daily living, as demonstrated by 40% less decline (P < .0001) on the Alzheimer’s Disease Cooperative Study–Instrumental Activities of Daily Living Inventory.
Donanemab significantly reduced brain amyloid plaque: 80% (low/medium tau population) and 76% (combined population) of participants achieved amyloid clearance at 76 weeks. The intervention was also associated with a greater decrease in whole-brain volume.
The treatment effect continued to widen after patients were switched to placebo, as evidenced on PET scan at 6 or 12 months, said Dr. Mintun.
The effects of the drug were similar among men and women but were especially pronounced among younger participants, with a 48% slowing on iADRS and a 45% slowing on CDR-SB in those younger than 75 years.
Safety issues
However, the drug is not without some safety concerns. Amyloid-related imaging abnormalities (ARIAs) occurred in 36.8% of the treatment group versus 14.9% of the placebo group, and in 40.6% of patients who were homozygous for apo E4 and received the drug. Microhemorrhage occurred in 26.8% in the donanemab group versus 12.5% in the placebo group.
Most ARIA cases were mild to moderate and resolved or stabilized with appropriate management. However, three deaths were determined to be drug related among participants who developed serious ARIAs or brain bleeding and swelling.
An important study limitation was that it enrolled primarily White patients (91.5%), which may limit generalizability to other populations, and the age limit was 85 years, which some believe is an inadequate representation of older adults. In addition, the 18-month treatment window limits the long-term understanding of donanemab’s benefits and side effects.
Eli Lilly has filed a submission to the Food and Drug Administration. If approved, donanemab will be the third antiamyloid monoclonal antibody to receive this status, following aducanumab (Aduhelm) and lecanemab (Leqembi).
Strongest data yet
Commenting on the study findings, Percy Griffin, PhD, director of scientific engagement, Alzheimer’s Association, said these new results are “very, very exciting” and represent “the strongest data to-date” for antiamyloid monoclonal antibodies in Alzheimer’s disease.
“A good percentage of individuals on the drug actually saw a complete clearance of amyloid, and some had to be taken off the drug, because if you’re on an antiamyloid drug and there’s no amyloid, what are you going for?”
He noted that the study had some unique aspects, including using tau-PET “to see whether or not the drug is more effective in subpopulations.”
Access to this and other antiamyloid therapies should be a priority, said Dr. Griffin. “We have to make sure people who have the potential to benefit from these treatments do.”
The Alzheimer’s Association is calling for Medicare beneficiaries who are living with the disease to receive the same coverage afforded to those with other diseases.
“The Centers for Medicare & Medicaid Services policy to block Medicare access to FDA-approved Alzheimer’s disease treatments is in stark contrast to scientific evidence, is unprecedented and must be reversed immediately,” Joanne Pike, DrPH, president and CEO of the Alzheimer’s Association, said in a press release.
Also important is tracking the longitudinal performance of these drugs outside of clinical trials, said Dr. Griffin. “Not everyone is going to be in that Goldilocks zone of being able to see a doctor whenever they want and have access to these PET and MRI tools and other things used in clinical trials.”
He noted that the Alzheimer’s Association is leading a network for diagnostics and therapeutics (ALZ-NET) that will track the performance of novel FDA-approved Alzheimer’s disease therapies “in the real world.”
While these are exciting findings for antiamyloid therapy, “we can’t take our foot off the gas, we need more therapies that target different aspects of the disease biology,” said Dr. Griffin.
A version of this article appeared on Medscape.com.
FROM AAIC 2023