Commentary—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 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-Alzheimer’s disease contributions to the patient’s symptoms, which are found in more than half of all patients with Alzheimer’s disease at autopsy; these non-Alzheimer’s disease pathologies also can influence clinical trial outcomes.

Richard J. Caselli, MD

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 Alzheimer’s disease 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
Professor of Neurology
Mayo Clinic Arizona
Scottsdale