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.



This biomarker profile introduces the option of completely avoiding traditional AD nomenclature, the committee noted.

“Some investigators may prefer to not use the biomarker category terminology but instead simply report biomarker profile, i.e., A+T+(N)+ instead of ‘Alzheimer’s disease.’ An alternative is to combine the biomarker profile with a descriptive term – for example, ‘A+T+(N)+ with dementia’ instead of ‘Alzheimer’s disease with dementia’.”

Again, Dr. Jack cautioned, the paradigm is not intended for clinical use – at least not now. It relies entirely on biomarkers obtained by methods that are either invasive (lumbar puncture), unavailable outside research settings (tau scans), or very expensive when privately obtained (amyloid scans). Until this situation changes, the biomarker profile paradigm has little clinical impact.

IDEAS on the horizon

Change may be coming, however. The Alzheimer’s Association-sponsored Imaging Dementia–Evidence for Amyloid Scanning (IDEAS) study is assessing the clinical usefulness of amyloid PET scans and their impact on patient outcomes. The goal is to accumulate enough data to prove that amyloid scans are a cost-effective addition to the management of dementia patients. If federal payers agree and decide to cover amyloid scans, advocates hope that private insurers might follow suit.


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