Literature Review

Alzheimer’s Disease Biomarkers, Not Cognition, Will Now Define Disorder

The NIA-AA Research Framework establishes eight biomarker profiles with different combinations of amyloid, tau, and neuropathologic damage.


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.

Clifford R. Jack Jr, MD

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.


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