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A new definition of Alzheimer’s disease based solely on biomarkers has the potential to strengthen clinical trials and change the way physicians talk to patients.
The paradigm recasts Alzheimer’s disease from a symptomatic syndrome validated by biomarkers to a strictly biologic construct defined by the presence of amyloid beta, tau, and neuronal damage.
Amyloid beta is the key to this classification paradigm—any patient with it is on the Alzheimer’s continuum. But only those with both amyloid and tau in the brain are classified as having Alzheimer’s disease. A third biomarker, neurodegeneration, may be either present or absent for an Alzheimer’s disease profile. Cognitive staging adds important details, but remains secondary to the biomarker classification.
Jointly created by the National Institute on Aging (NIA) and the Alzheimer’s Association (AA), the system—dubbed the NIA-AA Research Framework—represents a common language that researchers around the world may now use to generate and test Alzheimer’s hypotheses and to optimize epidemiologic studies and interventional trials. It will be especially important as Alzheimer’s disease prevention trials seek to target patients who are cognitively normal, yet harbor the neuropathologic hallmarks of the disease.
This recasting adds Alzheimer’s disease to the list of biomarker-defined disorders such as hypertension, diabetes, and hyperlipidemia. It is a timely and necessary reframing, said Clifford R. Jack Jr, MD, chair of the 20-member committee that created the paradigm, which was published in the April issue of Alzheimer’s & Dementia. 
Refining Research Cohorts
“This is a fundamental change in the definition of Alzheimer’s disease,” Dr. Jack said in an interview. “We are advocating that the disease be defined by its neuropathology [of plaques and tangles], which is specific to Alzheimer’s, and no longer by clinical symptoms which are not specific for any disease.”
One of the primary intents is to refine Alzheimer’s disease research cohorts, allowing pure stratification of patients who actually have the intended therapeutic targets of amyloid beta or tau. Without biomarker screening, as much as 30% of subjects who enroll in Alzheimer’s disease drug trials do not have the target pathologies—a situation that researchers say contributes to the long string of failed Alzheimer’s drug studies.
For now, the system is intended only for research settings, said Dr. Jack, an Alzheimer’s disease investigator at the Mayo Clinic in Rochester, Minnesota. But as biomarker testing comes of age and less expensive tests are discovered, the paradigm will likely be incorporated into clinical practice. The process can begin even now with a simple change in the way doctors talk to patients about Alzheimer’s disease, he said.
“We advocate that people stop using the terms ‘probable’ or ‘possible Alzheimer’s disease,’” Dr. Jack said. “A better term is ‘Alzheimer’s clinical syndrome.’ Without biomarkers, the clinical syndrome is the only thing you can know. What you can’t know is whether they do or do not have Alzheimer’s disease. When I am asked by physicians, ‘What do I tell my patients now?’ my very direct answer is ‘Tell them the truth.’ And the truth is that they have Alzheimer’s clinical syndrome and may or may not have Alzheimer’s disease.”
A Reflection of Evolving Science
The research framework reflects advances in Alzheimer’s disease science that have occurred since the NIA last updated its Alzheimer’s disease
Since the 2011 diagnostic criteria emergered, advances in understanding the biology and pathology of Alzheimer’s disease, as well as technical advances in biomarker measurements, have made it possible not only to measure amyloid beta and tau in CSF, but also to see these proteins in living brains with specialized PET ligands. It also became obvious that about a third of subjects in any given Alzheimer’s disease study did not have the disease-defining brain plaques and tangles—the therapeutic targets of all the largest drug studies to date. And while it is clear that none of the interventions in those studies have exerted a significant benefit yet, “treating people for a disease they don’t have can’t possibly help the results,” Dr. Jack said.
These research observations and biomarker advances have reshaped the way researchers think about Alzheimer’s disease. To maximize research potential and create a global classification standard to unify studies, the NIA and the Alzheimer’s Association convened several meetings to redefine Alzheimer’s disease biologically by pathologic brain changes, as measured by biomarkers. In this paradigm, cognitive dysfunction is a symptom of Alzheimer’s disease, not its primary classification driver.
“The way Alzheimer’s disease has historically been defined is by clinical symptoms. A progressive amnestic dementia was Alzheimer’s, and if there was no progressive amnestic dementia, it was not,” Dr. Jack said. “Well, it turns out that both of those statements are wrong. About 30% of people with progressive amnestic dementia have other things causing it.”
It makes much more sense, he said, to define the disease based on its unique neuropathologic signature: amyloid beta plaques and tau neurofibrillary tangles in the brain.
The Three-Part Key: AT(N)
The NIA-AA Research Framework yields eight biomarker profiles with different combinations of amyloid (A), tau (T), and neurodegeneration or neuronal injury (N).
“Different measures have different roles,” Dr. Jack and his colleagues said. “Amyloid beta biomarkers determine whether or not an individual is in the Alzheimer’s continuum. Pathologic tau biomarkers determine if someone who is in the Alzheimer’s continuum has Alzheimer’s disease, because both amyloid beta and tau are required for a neuropathologic diagnosis of the disease. Neurodegenerative/neuronal injury biomarkers and cognitive symptoms, neither of which is specific for Alzheimer’s disease, are used only to stage severity, not to define the presence of the Alzheimer’s continuum.”
The “N” category is not as cut and dried at the other biomarkers, the paper noted. “Biomarkers in the (N) group are indicators of neurodegeneration or neuronal injury resulting from many causes; they are not specific for neurodegeneration due to Alzheimer’s disease. In any individual, the proportion of observed neurodegeneration/injury that can be attributed to Alzheimer’s disease versus other possible comorbid conditions (most of which have no extant biomarker) is unknown.”
The biomarker profiles are:
- A−T−(N)−: Normal Alzheimer’s disease biomarkers
- A+T−(N)−: Alzheimer’s pathologic change; Alzheimer’s continuum
- A+T+(N)−: Alzheimer’s disease; Alzheimer’s continuum
- A+T+(N)+: Alzheimer’s disease; Alzheimer’s continuum
- A+T−(N)+: Alzheimer’s with suspected non-Alzheimer’s pathologic change; Alzheimer’s continuum
- A−T+(N)−: Non-Alzheimer’s disease pathologic change
- A−T−(N)+: Non-Alzheimer’s disease pathologic change
- A−T+(N)+: Non-Alzheimer’s disease pathologic change.
A normal amyloid biomarker with abnormal tau or neurodegeneration “implies evidence of one or more neuropathologic processes other than Alzheimer’s disease and has been labeled ‘suspected non-Alzheimer’s pathophysiology’ (or SNAP),” according to the paper.
Cognitive staging further refines each person’s status. There are two clinical staging schemes in the framework. One is the familiar syndromal staging system of cognitively unimpaired, MCI, and dementia, which can be subdivided into mild, moderate, and severe. This staging scheme can be applied to anyone with a biomarker profile.
Biomarker Grouping and Cognitive Status Interactions
“This three-category division serves as the basis for cognitive categorization in many large, ongoing studies,” Dr. Jack and his colleagues wrote. “Numerous researchers feel that it has been and continues to be effective for clinical research and that abandoning it would unnecessarily disrupt ongoing studies.”
The second staging scheme, a six-stage numeric clinical staging scheme, will apply only to those who are amyloid-positive and on the Alzheimer’s continuum. Stages run from 1 (unimpaired) to 6 (severe dementia). The numeric staging does not concentrate solely on cognition, but also takes into account neurobehavioral and functional symptoms. It includes a transitional stage during which measures may be within population norms, but have declined relative to the individual’s past performance.
The numeric staging scheme is intended to mesh with FDA guidance for clinical trials outcomes, the committee noted.
“A useful application envisioned for this numeric cognitive staging scheme is interventional trials. Indeed, the NIA-AA numeric staging scheme is intentionally similar to the categorical system for staging Alzheimer’s disease outlined in recent FDA guidance for industry pertaining to developing drugs for treatment of early Alzheimer’s disease…. It was our belief that harmonizing this aspect of the framework with FDA guidance would enhance cross-fertilization between observational and interventional studies, which in turn would facilitate conduct of interventional clinical trials early in the disease process.”
The entire system yields a shorthand biomarker profile for each subject. For example, an A+T−(N)+ MCI profile suggests that Alzheimer’s and non-Alzheimer’s pathologic change may be contributing to the cognitive impairment. A cognitive staging number could also be added.
This biomarker profile introduces the option of completely avoiding traditional Alzheimer’s disease nomenclature, the committee noted.
“Some investigators may prefer to not use the biomarker category terminology … but instead simply report biomarker profile (ie, A+T+(N)+ instead of Alzheimer’s disease),” the authors said. An alternative is to combine the biomarker profile with a descriptive term—for example, “A+T+(N)+ with dementia” instead of “Alzheimer’s disease with dementia.”
Dr. Jack cautioned that the paradigm is not currently intended for clinical use. It relies on biomarkers obtained by methods that are either invasive (lumbar puncture), unavailable outside research settings (tau scans), or expensive when privately obtained (amyloid scans). Until this situation changes, the biomarker profile paradigm has little clinical impact.
IDEAS on the Horizon
Change may be coming, however. The Alzheimer’s Association-sponsored Imaging Dementia–Evidence for Amyloid Scanning (IDEAS) study is assessing the clinical usefulness of amyloid PET scans and their impact on patient outcomes. The goal is to accumulate enough data to prove whether amyloid scans are a cost-effective addition to the management of dementia patients. If federal payers decide to cover amyloid scans, advocates hope that private insurers might follow suit.
An interim analysis of 4,000 scans presented at the 2017 Alzheimer’s Association International Conference found that scan results changed patient management in 68% of cases, including by refining dementia diagnoses; adding, stopping, or switching medications; and altering patient counseling.
IDEAS uses an FDA-approved amyloid imaging agent. Tau PET ligands are in development, but have not been approved. However, other less invasive and less costly options may soon be developed, the committee noted. The search continues for a validated blood-based biomarker, including neurofilament light protein, plasma amyloid beta, and plasma tau.
“In the future, … blood-based biomarker tests—along with genetics, clinical, and demographic information—will likely play an important screening role in selecting individuals for more expensive or more invasive biomarker testing. This has been the history in other biologically defined diseases such as cardiovascular disease,” Dr. Jack and his colleagues noted.
In any case, without an effective treatment, much of the information conveyed by the biomarker profile paradigm remains academic, Dr. Jack said.
“If [the biomarker profile] were easy to determine and inexpensive, I imagine a lot of people would ask for it,” Dr. Jack said. “Certainly, many people would want to know, especially if they have a cognitive problem. People who have a family history, who may have Alzheimer’s pathology without the symptoms, might want to know. But the reality is that until there is a treatment that alters the course of this disease, finding out that you actually have Alzheimer’s disease is not going to enable you to change anything.”
Alzheimer’s & Dementia is the official journal of the Alzheimer’s Association. Dr. Jack has served on scientific advisory boards for Elan/Janssen AI, Bristol-Meyers Squibb, Eli Lilly, GE Healthcare, Siemens, and Eisai; received research support from Baxter International and Allon Therapeutics; and holds stock in Johnson & Johnson.
—Michele G. Sullivan
Suggested Reading
Jack CR Jr., Bennett DA, Blennow K, et al. NIA-AA Research Framework: toward a biological definition of Alzheimer’s disease. Alzheimers Dement. 2018;14(4):535-562.
Khachaturian AS, Hayden KM, Mielke MM, et al. Future prospects and challenges for Alzheimer’s disease drug development in the era of the NIA-AA Research Framework. Alzheimers Dement. 2018;14(4):532-534.
Silverberg N, Elliott C, Ryan L, et al. NIA commentary on the NIA-AA Research Framework: towards a biological definition of Alzheimer’s disease. Alzheimers Dement. 2018;14(4):576-578.
A new definition of Alzheimer’s disease based solely on biomarkers has the potential to strengthen clinical trials and change the way physicians talk to patients.
The paradigm recasts Alzheimer’s disease from a symptomatic syndrome validated by biomarkers to a strictly biologic construct defined by the presence of amyloid beta, tau, and neuronal damage.
Amyloid beta is the key to this classification paradigm—any patient with it is on the Alzheimer’s continuum. But only those with both amyloid and tau in the brain are classified as having Alzheimer’s disease. A third biomarker, neurodegeneration, may be either present or absent for an Alzheimer’s disease profile. Cognitive staging adds important details, but remains secondary to the biomarker classification.
Jointly created by the National Institute on Aging (NIA) and the Alzheimer’s Association (AA), the system—dubbed the NIA-AA Research Framework—represents a common language that researchers around the world may now use to generate and test Alzheimer’s hypotheses and to optimize epidemiologic studies and interventional trials. It will be especially important as Alzheimer’s disease prevention trials seek to target patients who are cognitively normal, yet harbor the neuropathologic hallmarks of the disease.
This recasting adds Alzheimer’s disease to the list of biomarker-defined disorders such as hypertension, diabetes, and hyperlipidemia. It is a timely and necessary reframing, said Clifford R. Jack Jr, MD, chair of the 20-member committee that created the paradigm, which was published in the April issue of Alzheimer’s & Dementia.
Refining Research Cohorts
“This is a fundamental change in the definition of Alzheimer’s disease,” Dr. Jack said in an interview. “We are advocating that the disease be defined by its neuropathology [of plaques and tangles], which is specific to Alzheimer’s, and no longer by clinical symptoms which are not specific for any disease.”
One of the primary intents is to refine Alzheimer’s disease research cohorts, allowing pure stratification of patients who actually have the intended therapeutic targets of amyloid beta or tau. Without biomarker screening, as much as 30% of subjects who enroll in Alzheimer’s disease drug trials do not have the target pathologies—a situation that researchers say contributes to the long string of failed Alzheimer’s drug studies.
For now, the system is intended only for research settings, said Dr. Jack, an Alzheimer’s disease investigator at the Mayo Clinic in Rochester, Minnesota. But as biomarker testing comes of age and less expensive tests are discovered, the paradigm will likely be incorporated into clinical practice. The process can begin even now with a simple change in the way doctors talk to patients about Alzheimer’s disease, he said.
“We advocate that people stop using the terms ‘probable’ or ‘possible Alzheimer’s disease,’” Dr. Jack said. “A better term is ‘Alzheimer’s clinical syndrome.’ Without biomarkers, the clinical syndrome is the only thing you can know. What you can’t know is whether they do or do not have Alzheimer’s disease. When I am asked by physicians, ‘What do I tell my patients now?’ my very direct answer is ‘Tell them the truth.’ And the truth is that they have Alzheimer’s clinical syndrome and may or may not have Alzheimer’s disease.”
A Reflection of Evolving Science
The research framework reflects advances in Alzheimer’s disease science that have occurred since the NIA last updated its Alzheimer’s disease
Since the 2011 diagnostic criteria emergered, advances in understanding the biology and pathology of Alzheimer’s disease, as well as technical advances in biomarker measurements, have made it possible not only to measure amyloid beta and tau in CSF, but also to see these proteins in living brains with specialized PET ligands. It also became obvious that about a third of subjects in any given Alzheimer’s disease study did not have the disease-defining brain plaques and tangles—the therapeutic targets of all the largest drug studies to date. And while it is clear that none of the interventions in those studies have exerted a significant benefit yet, “treating people for a disease they don’t have can’t possibly help the results,” Dr. Jack said.
These research observations and biomarker advances have reshaped the way researchers think about Alzheimer’s disease. To maximize research potential and create a global classification standard to unify studies, the NIA and the Alzheimer’s Association convened several meetings to redefine Alzheimer’s disease biologically by pathologic brain changes, as measured by biomarkers. In this paradigm, cognitive dysfunction is a symptom of Alzheimer’s disease, not its primary classification driver.
“The way Alzheimer’s disease has historically been defined is by clinical symptoms. A progressive amnestic dementia was Alzheimer’s, and if there was no progressive amnestic dementia, it was not,” Dr. Jack said. “Well, it turns out that both of those statements are wrong. About 30% of people with progressive amnestic dementia have other things causing it.”
It makes much more sense, he said, to define the disease based on its unique neuropathologic signature: amyloid beta plaques and tau neurofibrillary tangles in the brain.
The Three-Part Key: AT(N)
The NIA-AA Research Framework yields eight biomarker profiles with different combinations of amyloid (A), tau (T), and neurodegeneration or neuronal injury (N).
“Different measures have different roles,” Dr. Jack and his colleagues said. “Amyloid beta biomarkers determine whether or not an individual is in the Alzheimer’s continuum. Pathologic tau biomarkers determine if someone who is in the Alzheimer’s continuum has Alzheimer’s disease, because both amyloid beta and tau are required for a neuropathologic diagnosis of the disease. Neurodegenerative/neuronal injury biomarkers and cognitive symptoms, neither of which is specific for Alzheimer’s disease, are used only to stage severity, not to define the presence of the Alzheimer’s continuum.”
The “N” category is not as cut and dried at the other biomarkers, the paper noted. “Biomarkers in the (N) group are indicators of neurodegeneration or neuronal injury resulting from many causes; they are not specific for neurodegeneration due to Alzheimer’s disease. In any individual, the proportion of observed neurodegeneration/injury that can be attributed to Alzheimer’s disease versus other possible comorbid conditions (most of which have no extant biomarker) is unknown.”
The biomarker profiles are:
- A−T−(N)−: Normal Alzheimer’s disease biomarkers
- A+T−(N)−: Alzheimer’s pathologic change; Alzheimer’s continuum
- A+T+(N)−: Alzheimer’s disease; Alzheimer’s continuum
- A+T+(N)+: Alzheimer’s disease; Alzheimer’s continuum
- A+T−(N)+: Alzheimer’s with suspected non-Alzheimer’s pathologic change; Alzheimer’s continuum
- A−T+(N)−: Non-Alzheimer’s disease pathologic change
- A−T−(N)+: Non-Alzheimer’s disease pathologic change
- A−T+(N)+: Non-Alzheimer’s disease pathologic change.
A normal amyloid biomarker with abnormal tau or neurodegeneration “implies evidence of one or more neuropathologic processes other than Alzheimer’s disease and has been labeled ‘suspected non-Alzheimer’s pathophysiology’ (or SNAP),” according to the paper.
Cognitive staging further refines each person’s status. There are two clinical staging schemes in the framework. One is the familiar syndromal staging system of cognitively unimpaired, MCI, and dementia, which can be subdivided into mild, moderate, and severe. This staging scheme can be applied to anyone with a biomarker profile.
Biomarker Grouping and Cognitive Status Interactions
“This three-category division serves as the basis for cognitive categorization in many large, ongoing studies,” Dr. Jack and his colleagues wrote. “Numerous researchers feel that it has been and continues to be effective for clinical research and that abandoning it would unnecessarily disrupt ongoing studies.”
The second staging scheme, a six-stage numeric clinical staging scheme, will apply only to those who are amyloid-positive and on the Alzheimer’s continuum. Stages run from 1 (unimpaired) to 6 (severe dementia). The numeric staging does not concentrate solely on cognition, but also takes into account neurobehavioral and functional symptoms. It includes a transitional stage during which measures may be within population norms, but have declined relative to the individual’s past performance.
The numeric staging scheme is intended to mesh with FDA guidance for clinical trials outcomes, the committee noted.
“A useful application envisioned for this numeric cognitive staging scheme is interventional trials. Indeed, the NIA-AA numeric staging scheme is intentionally similar to the categorical system for staging Alzheimer’s disease outlined in recent FDA guidance for industry pertaining to developing drugs for treatment of early Alzheimer’s disease…. It was our belief that harmonizing this aspect of the framework with FDA guidance would enhance cross-fertilization between observational and interventional studies, which in turn would facilitate conduct of interventional clinical trials early in the disease process.”
The entire system yields a shorthand biomarker profile for each subject. For example, an A+T−(N)+ MCI profile suggests that Alzheimer’s and non-Alzheimer’s pathologic change may be contributing to the cognitive impairment. A cognitive staging number could also be added.
This biomarker profile introduces the option of completely avoiding traditional Alzheimer’s disease nomenclature, the committee noted.
“Some investigators may prefer to not use the biomarker category terminology … but instead simply report biomarker profile (ie, A+T+(N)+ instead of Alzheimer’s disease),” the authors said. An alternative is to combine the biomarker profile with a descriptive term—for example, “A+T+(N)+ with dementia” instead of “Alzheimer’s disease with dementia.”
Dr. Jack cautioned that the paradigm is not currently intended for clinical use. It relies on biomarkers obtained by methods that are either invasive (lumbar puncture), unavailable outside research settings (tau scans), or expensive when privately obtained (amyloid scans). Until this situation changes, the biomarker profile paradigm has little clinical impact.
IDEAS on the Horizon
Change may be coming, however. The Alzheimer’s Association-sponsored Imaging Dementia–Evidence for Amyloid Scanning (IDEAS) study is assessing the clinical usefulness of amyloid PET scans and their impact on patient outcomes. The goal is to accumulate enough data to prove whether amyloid scans are a cost-effective addition to the management of dementia patients. If federal payers decide to cover amyloid scans, advocates hope that private insurers might follow suit.
An interim analysis of 4,000 scans presented at the 2017 Alzheimer’s Association International Conference found that scan results changed patient management in 68% of cases, including by refining dementia diagnoses; adding, stopping, or switching medications; and altering patient counseling.
IDEAS uses an FDA-approved amyloid imaging agent. Tau PET ligands are in development, but have not been approved. However, other less invasive and less costly options may soon be developed, the committee noted. The search continues for a validated blood-based biomarker, including neurofilament light protein, plasma amyloid beta, and plasma tau.
“In the future, … blood-based biomarker tests—along with genetics, clinical, and demographic information—will likely play an important screening role in selecting individuals for more expensive or more invasive biomarker testing. This has been the history in other biologically defined diseases such as cardiovascular disease,” Dr. Jack and his colleagues noted.
In any case, without an effective treatment, much of the information conveyed by the biomarker profile paradigm remains academic, Dr. Jack said.
“If [the biomarker profile] were easy to determine and inexpensive, I imagine a lot of people would ask for it,” Dr. Jack said. “Certainly, many people would want to know, especially if they have a cognitive problem. People who have a family history, who may have Alzheimer’s pathology without the symptoms, might want to know. But the reality is that until there is a treatment that alters the course of this disease, finding out that you actually have Alzheimer’s disease is not going to enable you to change anything.”
Alzheimer’s & Dementia is the official journal of the Alzheimer’s Association. Dr. Jack has served on scientific advisory boards for Elan/Janssen AI, Bristol-Meyers Squibb, Eli Lilly, GE Healthcare, Siemens, and Eisai; received research support from Baxter International and Allon Therapeutics; and holds stock in Johnson & Johnson.
—Michele G. Sullivan
Suggested Reading
Jack CR Jr., Bennett DA, Blennow K, et al. NIA-AA Research Framework: toward a biological definition of Alzheimer’s disease. Alzheimers Dement. 2018;14(4):535-562.
Khachaturian AS, Hayden KM, Mielke MM, et al. Future prospects and challenges for Alzheimer’s disease drug development in the era of the NIA-AA Research Framework. Alzheimers Dement. 2018;14(4):532-534.
Silverberg N, Elliott C, Ryan L, et al. NIA commentary on the NIA-AA Research Framework: towards a biological definition of Alzheimer’s disease. Alzheimers Dement. 2018;14(4):576-578.
A new definition of Alzheimer’s disease based solely on biomarkers has the potential to strengthen clinical trials and change the way physicians talk to patients.
The paradigm recasts Alzheimer’s disease from a symptomatic syndrome validated by biomarkers to a strictly biologic construct defined by the presence of amyloid beta, tau, and neuronal damage.
Amyloid beta is the key to this classification paradigm—any patient with it is on the Alzheimer’s continuum. But only those with both amyloid and tau in the brain are classified as having Alzheimer’s disease. A third biomarker, neurodegeneration, may be either present or absent for an Alzheimer’s disease profile. Cognitive staging adds important details, but remains secondary to the biomarker classification.
Jointly created by the National Institute on Aging (NIA) and the Alzheimer’s Association (AA), the system—dubbed the NIA-AA Research Framework—represents a common language that researchers around the world may now use to generate and test Alzheimer’s hypotheses and to optimize epidemiologic studies and interventional trials. It will be especially important as Alzheimer’s disease prevention trials seek to target patients who are cognitively normal, yet harbor the neuropathologic hallmarks of the disease.
This recasting adds Alzheimer’s disease to the list of biomarker-defined disorders such as hypertension, diabetes, and hyperlipidemia. It is a timely and necessary reframing, said Clifford R. Jack Jr, MD, chair of the 20-member committee that created the paradigm, which was published in the April issue of Alzheimer’s & Dementia.
Refining Research Cohorts
“This is a fundamental change in the definition of Alzheimer’s disease,” Dr. Jack said in an interview. “We are advocating that the disease be defined by its neuropathology [of plaques and tangles], which is specific to Alzheimer’s, and no longer by clinical symptoms which are not specific for any disease.”
One of the primary intents is to refine Alzheimer’s disease research cohorts, allowing pure stratification of patients who actually have the intended therapeutic targets of amyloid beta or tau. Without biomarker screening, as much as 30% of subjects who enroll in Alzheimer’s disease drug trials do not have the target pathologies—a situation that researchers say contributes to the long string of failed Alzheimer’s drug studies.
For now, the system is intended only for research settings, said Dr. Jack, an Alzheimer’s disease investigator at the Mayo Clinic in Rochester, Minnesota. But as biomarker testing comes of age and less expensive tests are discovered, the paradigm will likely be incorporated into clinical practice. The process can begin even now with a simple change in the way doctors talk to patients about Alzheimer’s disease, he said.
“We advocate that people stop using the terms ‘probable’ or ‘possible Alzheimer’s disease,’” Dr. Jack said. “A better term is ‘Alzheimer’s clinical syndrome.’ Without biomarkers, the clinical syndrome is the only thing you can know. What you can’t know is whether they do or do not have Alzheimer’s disease. When I am asked by physicians, ‘What do I tell my patients now?’ my very direct answer is ‘Tell them the truth.’ And the truth is that they have Alzheimer’s clinical syndrome and may or may not have Alzheimer’s disease.”
A Reflection of Evolving Science
The research framework reflects advances in Alzheimer’s disease science that have occurred since the NIA last updated its Alzheimer’s disease
Since the 2011 diagnostic criteria emergered, advances in understanding the biology and pathology of Alzheimer’s disease, as well as technical advances in biomarker measurements, have made it possible not only to measure amyloid beta and tau in CSF, but also to see these proteins in living brains with specialized PET ligands. It also became obvious that about a third of subjects in any given Alzheimer’s disease study did not have the disease-defining brain plaques and tangles—the therapeutic targets of all the largest drug studies to date. And while it is clear that none of the interventions in those studies have exerted a significant benefit yet, “treating people for a disease they don’t have can’t possibly help the results,” Dr. Jack said.
These research observations and biomarker advances have reshaped the way researchers think about Alzheimer’s disease. To maximize research potential and create a global classification standard to unify studies, the NIA and the Alzheimer’s Association convened several meetings to redefine Alzheimer’s disease biologically by pathologic brain changes, as measured by biomarkers. In this paradigm, cognitive dysfunction is a symptom of Alzheimer’s disease, not its primary classification driver.
“The way Alzheimer’s disease has historically been defined is by clinical symptoms. A progressive amnestic dementia was Alzheimer’s, and if there was no progressive amnestic dementia, it was not,” Dr. Jack said. “Well, it turns out that both of those statements are wrong. About 30% of people with progressive amnestic dementia have other things causing it.”
It makes much more sense, he said, to define the disease based on its unique neuropathologic signature: amyloid beta plaques and tau neurofibrillary tangles in the brain.
The Three-Part Key: AT(N)
The NIA-AA Research Framework yields eight biomarker profiles with different combinations of amyloid (A), tau (T), and neurodegeneration or neuronal injury (N).
“Different measures have different roles,” Dr. Jack and his colleagues said. “Amyloid beta biomarkers determine whether or not an individual is in the Alzheimer’s continuum. Pathologic tau biomarkers determine if someone who is in the Alzheimer’s continuum has Alzheimer’s disease, because both amyloid beta and tau are required for a neuropathologic diagnosis of the disease. Neurodegenerative/neuronal injury biomarkers and cognitive symptoms, neither of which is specific for Alzheimer’s disease, are used only to stage severity, not to define the presence of the Alzheimer’s continuum.”
The “N” category is not as cut and dried at the other biomarkers, the paper noted. “Biomarkers in the (N) group are indicators of neurodegeneration or neuronal injury resulting from many causes; they are not specific for neurodegeneration due to Alzheimer’s disease. In any individual, the proportion of observed neurodegeneration/injury that can be attributed to Alzheimer’s disease versus other possible comorbid conditions (most of which have no extant biomarker) is unknown.”
The biomarker profiles are:
- A−T−(N)−: Normal Alzheimer’s disease biomarkers
- A+T−(N)−: Alzheimer’s pathologic change; Alzheimer’s continuum
- A+T+(N)−: Alzheimer’s disease; Alzheimer’s continuum
- A+T+(N)+: Alzheimer’s disease; Alzheimer’s continuum
- A+T−(N)+: Alzheimer’s with suspected non-Alzheimer’s pathologic change; Alzheimer’s continuum
- A−T+(N)−: Non-Alzheimer’s disease pathologic change
- A−T−(N)+: Non-Alzheimer’s disease pathologic change
- A−T+(N)+: Non-Alzheimer’s disease pathologic change.
A normal amyloid biomarker with abnormal tau or neurodegeneration “implies evidence of one or more neuropathologic processes other than Alzheimer’s disease and has been labeled ‘suspected non-Alzheimer’s pathophysiology’ (or SNAP),” according to the paper.
Cognitive staging further refines each person’s status. There are two clinical staging schemes in the framework. One is the familiar syndromal staging system of cognitively unimpaired, MCI, and dementia, which can be subdivided into mild, moderate, and severe. This staging scheme can be applied to anyone with a biomarker profile.
Biomarker Grouping and Cognitive Status Interactions
“This three-category division serves as the basis for cognitive categorization in many large, ongoing studies,” Dr. Jack and his colleagues wrote. “Numerous researchers feel that it has been and continues to be effective for clinical research and that abandoning it would unnecessarily disrupt ongoing studies.”
The second staging scheme, a six-stage numeric clinical staging scheme, will apply only to those who are amyloid-positive and on the Alzheimer’s continuum. Stages run from 1 (unimpaired) to 6 (severe dementia). The numeric staging does not concentrate solely on cognition, but also takes into account neurobehavioral and functional symptoms. It includes a transitional stage during which measures may be within population norms, but have declined relative to the individual’s past performance.
The numeric staging scheme is intended to mesh with FDA guidance for clinical trials outcomes, the committee noted.
“A useful application envisioned for this numeric cognitive staging scheme is interventional trials. Indeed, the NIA-AA numeric staging scheme is intentionally similar to the categorical system for staging Alzheimer’s disease outlined in recent FDA guidance for industry pertaining to developing drugs for treatment of early Alzheimer’s disease…. It was our belief that harmonizing this aspect of the framework with FDA guidance would enhance cross-fertilization between observational and interventional studies, which in turn would facilitate conduct of interventional clinical trials early in the disease process.”
The entire system yields a shorthand biomarker profile for each subject. For example, an A+T−(N)+ MCI profile suggests that Alzheimer’s and non-Alzheimer’s pathologic change may be contributing to the cognitive impairment. A cognitive staging number could also be added.
This biomarker profile introduces the option of completely avoiding traditional Alzheimer’s disease nomenclature, the committee noted.
“Some investigators may prefer to not use the biomarker category terminology … but instead simply report biomarker profile (ie, A+T+(N)+ instead of Alzheimer’s disease),” the authors said. An alternative is to combine the biomarker profile with a descriptive term—for example, “A+T+(N)+ with dementia” instead of “Alzheimer’s disease with dementia.”
Dr. Jack cautioned that the paradigm is not currently intended for clinical use. It relies on biomarkers obtained by methods that are either invasive (lumbar puncture), unavailable outside research settings (tau scans), or expensive when privately obtained (amyloid scans). Until this situation changes, the biomarker profile paradigm has little clinical impact.
IDEAS on the Horizon
Change may be coming, however. The Alzheimer’s Association-sponsored Imaging Dementia–Evidence for Amyloid Scanning (IDEAS) study is assessing the clinical usefulness of amyloid PET scans and their impact on patient outcomes. The goal is to accumulate enough data to prove whether amyloid scans are a cost-effective addition to the management of dementia patients. If federal payers decide to cover amyloid scans, advocates hope that private insurers might follow suit.
An interim analysis of 4,000 scans presented at the 2017 Alzheimer’s Association International Conference found that scan results changed patient management in 68% of cases, including by refining dementia diagnoses; adding, stopping, or switching medications; and altering patient counseling.
IDEAS uses an FDA-approved amyloid imaging agent. Tau PET ligands are in development, but have not been approved. However, other less invasive and less costly options may soon be developed, the committee noted. The search continues for a validated blood-based biomarker, including neurofilament light protein, plasma amyloid beta, and plasma tau.
“In the future, … blood-based biomarker tests—along with genetics, clinical, and demographic information—will likely play an important screening role in selecting individuals for more expensive or more invasive biomarker testing. This has been the history in other biologically defined diseases such as cardiovascular disease,” Dr. Jack and his colleagues noted.
In any case, without an effective treatment, much of the information conveyed by the biomarker profile paradigm remains academic, Dr. Jack said.
“If [the biomarker profile] were easy to determine and inexpensive, I imagine a lot of people would ask for it,” Dr. Jack said. “Certainly, many people would want to know, especially if they have a cognitive problem. People who have a family history, who may have Alzheimer’s pathology without the symptoms, might want to know. But the reality is that until there is a treatment that alters the course of this disease, finding out that you actually have Alzheimer’s disease is not going to enable you to change anything.”
Alzheimer’s & Dementia is the official journal of the Alzheimer’s Association. Dr. Jack has served on scientific advisory boards for Elan/Janssen AI, Bristol-Meyers Squibb, Eli Lilly, GE Healthcare, Siemens, and Eisai; received research support from Baxter International and Allon Therapeutics; and holds stock in Johnson & Johnson.
—Michele G. Sullivan
Suggested Reading
Jack CR Jr., Bennett DA, Blennow K, et al. NIA-AA Research Framework: toward a biological definition of Alzheimer’s disease. Alzheimers Dement. 2018;14(4):535-562.
Khachaturian AS, Hayden KM, Mielke MM, et al. Future prospects and challenges for Alzheimer’s disease drug development in the era of the NIA-AA Research Framework. Alzheimers Dement. 2018;14(4):532-534.
Silverberg N, Elliott C, Ryan L, et al. NIA commentary on the NIA-AA Research Framework: towards a biological definition of Alzheimer’s disease. Alzheimers Dement. 2018;14(4):576-578.