Clinical Edge

Summaries of Must-Read Clinical Literature, Guidelines, and FDA Actions

A/T/N System Predicts Cognitive Decline

Key clinical point: The A/T/N research framework can predict cognitive decline within its classification groups.

Major finding: About 50% of progressive cognitive decline among cognitively normal elderly can be assigned to Alzheimer’s disease pathology.

Study details: A longitudinal cohort study of 480 participants in Olmsted County, Minn.

Disclosures: Dr. Jack reported receiving grants from the National Institutes of Health and the Alexander Family Professorship of Alzheimer’s Disease.


Jack CR et al. JAMA. 2019;321(23):2316-25


The findings reported by Jack et al. most immediately affect research cohorts, but they raise an interesting suggestion: Only in the presence of concomitant tau, neuropathology, or both does amyloidosis appear related to an increased rate of cognitive decline when compared with non-Alzheimer’s groups.

Prevention studies lasting only a few years may be more likely to find treatment effects on disease progression in actively treated groups of those patients.

An interesting finding in the study is that A+/T–/N+ subjects showed faster rates of cognitive decline than did the A–/T–/N+ groups even though, in both cases, neurodegeneration is thought to be driven by non-Alzheimer’s pathology. What is causing disease in the A–/T–/N+ group will be unclear until the framework is enriched with other important contributors to age-related cognitive decline.

Currently, A/T/N classification – based on neuroimaging – is costly and impractical on a large scale, and so far lacks data on the added value of each specific A/T/N measure and generalizability to more diverse patient populations.

Despite these concerns, the study by Jack et al. represents an important contribution in conceptualizing Alzheimer’s disease and testing the research framework in a relatively large sample of participants.

David Wolk, MD, of the University of Pennsylvania Memory Center, Philadelphia, and colleagues’ comments here are paraphrased from an accompanying editorial (JAMA. 2019;321[23]:2289-91). Dr. Wolk reported receiving grants and personal fees from Avid/Eli Lilly and Merck; personal fees from Janssen, GE Healthcare, and Neuronix; and grants from Biogen and Functional Neuromodulation.