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.



An interim analysis of 4,000 scans, presented at the 2017 Alzheimer’s Association International Conference, was quite positive. Scan results changed patient management in 68% of cases, including refining dementia diagnoses, adding, stopping, or switching medications, and altering patient counseling.

IDEAS uses an FDA-approved amyloid imaging agent. But although several are under investigation, there are no approved tau PET ligands. However, other less-invasive and less-costly options may soon be developed, the committee noted. The search continues for a validated blood-based biomarker, including neurofilament light protein, plasma amyloid beta, and plasma tau.

“In the future, less-invasive/less-expensive blood-based biomarker tests - along with genetics, clinical, and demographic information - will likely play an important screening role in selecting individuals for more-expensive/more-invasive biomarker testing. This has been the history in other biologically defined diseases such as cardiovascular disease,” Dr. Jack and his colleagues noted in the paper.

In any case, however, without an effective treatment, much of the information conveyed by the biomarker profile paradigm remains, literally, academic, Dr. Jack said.


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