Alzheimer’s: Biomarkers, not cognition, will now define disorder

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 from a symptomatic syndrome validated by biomarkers to a strictly biological construct defined by the presence of amyloid beta (AB), tau, and neuronal damage.

AB is the key to this classification paradigm – any patient with it (A+) is on the Alzheimer’s continuum. But only those with both amyloid and tau in the brain (A+T+) receive the “Alzheimer’s disease” classification. A third biomarker, neurodegeneration, may be either present or absent for an Alzheimer’s disease profile (N+ or N-). Cognitive staging adds important details, but remains secondary to the biomarker classification.

^{Courtesy Mayo Clinic}

Dr. Clifford Jack

Jointly created by National Institute on Aging and the Alzheimer’s Association, the system – dubbed the NIA-AA Research Framework – represents a new, common language that researchers around the world may now use to generate and test Alzheimer’s hypotheses, and to optimize both epidemiologic studies and interventional trials. It will be especially important as Alzheimer’s prevention trials seek to target patients who are cognitively normal, yet harbor the neuropathological hallmarks of the disease.

This recasting adds Alzheimer’s to the list of biomarker-defined disorders, including hypertension, diabetes, and hyperlipidemia. It is a timely and necessary reframing, said Clifford Jack, MD, chair of the 20-member committee that created the paradigm. It appears in the April 10 issue of Alzheimer’s & Dementia.

“This is a fundamental change in the definition of Alzheimer’s disease,” Dr. Jack said in an interview. “We are advocating 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 AD research cohorts, allowing pure stratification of patients who actually have the intended therapeutic targets of amyloid beta or tau. Without biomarker screening, up to 30% of subjects who enroll in AD drug trials don’t have the target pathologies – a situation researchers say contributes to the long string of failed Alzheimer’s drug studies.