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.



“If [the biomarker profile] were easy to determine and inexpensive, I imagine a lot of people would ask for it. Certainly many people would want to know, especially if they have a cognitive problem. People who have a family history, who may have Alzheimer’s pathology without the symptoms, might want to know. But the reality is that, until there’s a treatment that alters the course of this disease, finding out that you actually have Alzheimer’s is not going to enable you to change anything.”

The editors of Alzheimer’s & Dementia are seeking comment on the research framework. Letters and commentary can be submitted through June and will be considered for publication in an e-book, to be published sometime this summer, according to an accompanying editorial (

Alzheimer’s & Dementia is the official journal of the Alzheimer’s Association. Dr. Jack has served on scientific advisory boards for Elan/Janssen AI, Bristol-Meyers Squibb, Eli Lilly, GE Healthcare, Siemens, and Eisai; received research support from Baxter International, Allon Therapeutics; and holds stock in Johnson & Johnson. Disclosures for other committee members can be found here.

SOURCE: Jack CR et al. Alzheimer’s Dement. 2018;14:535-62. doi: 10.1016/j.jalz.2018.02.018.


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