From the Journals

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

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A logical and modern approach

The biologically defined amyloid beta–tau–neuronal damage (ATN) framework is a logical and modern approach to Alzheimer’s disease (AD) diagnosis. It is hard to argue that more data are bad. Having such data on every patient would certainly be a luxury, but, with a few notable exceptions, the context in which this will most frequently occur is within the context of clinical trials.

While having this information does provide a biological basis for diagnosis, it does not account for non-AD contributions to the patient’s symptoms, which are found in more than half of all AD patients at autopsy; these non-AD pathologies also can influence clinical trial outcomes.

Dr. Richard J. Caselli, professor of neurology at the Mayo Clinic in Scottsdale, Ariz., and associate director and clinical core director of Mayo’s Alzheimer’s Disease Center.

Dr. Richard J. Caselli

This expensive framework might unintentionally lock out research that does not employ all these biomarkers either because of cost or because of clinical series–based studies. These biomarkers generally can be obtained only if paid for by a third party – typically a drug company. Some investigators may feel coerced into participating in studies they might not otherwise be inclined to do.

It also seems a bit ironic that the only meaningful manifestation of AD is now essentially left out of the diagnostic framework or relegated to nothing more than an adjective. Yet having a head full of amyloid means little if a person does not express symptoms (and vice versa), and we know that all people do not progress in the same way.

In the future, genomic and exposomic profiles may provide an even-more-nuanced picture, but further work is needed before that becomes a clinical reality. For now, the ATN biomarker framework represents the state of the art, though not an end.

Richard J. Caselli, MD, is professor of neurology at the Mayo Clinic Arizona in Scottsdale. He is also associate director and clinical core director of the Arizona Alzheimer’s Disease Center. He has no relevant disclosures.



The next 6 years brought striking advances in understanding the biology and pathology of AD, as well as technical advances in biomarker measurements. It became possible not only to measure AB and tau in cerebrospinal fluid 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 AD study didn’t have the disease-defining brain plaques and tangles – the therapeutic targets of all the largest drug studies to date. And while it’s clear that none of the interventions that have been through trials 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 revolutionary biomarker advances have reshaped the way researchers think about AD. To maximize research potential and to create a global classification standard that would unify studies as well, 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 steps aside as the primary classification driver, becoming a symptom of AD rather than its definition.

“The way AD has historically been defined is by clinical symptoms: a progressive amnestic dementia was Alzheimer’s, and if there was no progressive amnestic dementia, it wasn’t,” 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.


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