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

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 diagnostic criteria in 2011. Those criteria divided the disease continuum into three phases—preclinical Alzheimer’s disease, mild cognitive impairment (MCI), and Alzheimer’s dementia—largely based on cognitive symptoms, but were the first to recognize a presymptomatic Alzheimer’s disease phase marked by brain changes, including amyloid buildup, without evidence of significant clinical symptoms. In the MCI stage, which may or may not progress to Alzheimer’s dementia, memory or other thinking problems are greater than normal for a patient’s age and education, but do not interfere with his or her independence. Alzheimer’s dementia is the final stage of the disease in which the symptoms of Alzheimer’s disease, such as memory loss, word-finding difficulties, and visual or spatial problems, are significant enough to impair a person’s ability to function independently.

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.