Clinical heterogeneity in Alzheimer's disease

Clinical heterogeneity in Alzheimer's disease
We aim to understand the biological substrate for the vast clinical heterogeneity in Alzheimer's disease using a multi-disciplinary and comprehensive approach.


Alzheimer's disease has been widely considered to be rather homogeneous clinically, however this concept has been challenged by studies showing atypical clinical presentations differing from the classical amnestic deficits. Non-AD neurodegenerative changes have been shown to contribute to atypical AD presentations, either by driving the expression of non-amnestic symptoms early in the disease course or by modifying the rate of disease progression. However, these changes have never been addressed together in a single study using prospectively collected data including comprehensive pathologic and genetic information.

The MAC is a national reference center for complex dementias and our postmortem sample is enriched for atypical AD presentations; about half of our confirmed AD cases expressed a non-amnestic clinical phenotype. We aim to take advantage of our well-characterized clinicopathological cohorts to investigate the factors influencing the clinical expression of Alzheimer’s pathology which may lead to better diagnostic tools, the identification of risk factors for accelerated decline, and theraputic targets that minimize clinical decline in AD.

We are specifically investigating the impact of three particular atypical neurodegenerative changes in AD: argyrophilic grain disease (AGD), argyrophilic thorny astrocyte clusters (ATACs), and limbic-type TDP43 proteinopathy. Our research aims to decipher the clinical phenotypes as well as specific genomic variants that are associated with the these neurodegenerative changes when overlapping with a primary AD pathology.

Funding Sources

NIH Grant #K24 AG053435
NIH Grant #P01 AG019724
NIH Grant #P50 AG02350