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.



For now, the system is intended only for research settings said Dr. Jack, an Alzheimer’s investigator at the Mayo Clinic, Rochester, Minn. But as biomarker testing comes of age and new less-expensive markers 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, he said in an interview.

“We advocate people stop using the terms ‘probable or possible AD.’ 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 don’t have Alzheimer’s disease. When I’m 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 science that have occurred since the NIA last updated it AD diagnostic criteria in 2011. Those criteria divided the disease continuum into three phases largely based on cognitive symptoms, but were the first to recognize a presymptomatic AD phase.

  • Preclinical: Brain changes, including amyloid buildup and other nerve cell changes already may be in progress but significant clinical symptoms are not yet evident.
  • Mild cognitive impairment (MCI): A stage marked by symptoms of memory and/or other thinking problems that are greater than normal for a person’s age and education but that do not interfere with his or her independence. MCI may or may not progress to Alzheimer’s dementia.
  • Alzheimer’s dementia: The final stage of the disease in which the symptoms of Alzheimer’s, such as memory loss, word-finding difficulties, and visual/spatial problems, are significant enough to impair a person’s ability to function independently.


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