Characterizing the spatiotemporal variability of Alzheimer’s disease pathology

Alzheimer’s disease (AD) is characterized by the progressive spread of tau pathology throughout the cerebral cortex. The pattern of spread is thought to be fairly consistent across individuals, though more recent work has demonstrated substantial variability in the AD population that is often associated with distinct clinical phenotypes. Still, a systematic, unbiased, wholebrain characterization of spatiotemporal variation in tau deposition in AD is lacking. We analyzed 1612 tau-PET scans and applied to this sample a disease progression modeling framework designed to identify spatiotemporal trajectories of pathological progression. We identified four distinct trajectories of tau progression, ranging in prevalence from 18–33%, with no one progession predominating. We replicated previously described limbic-predominant and medial temporal lobe-sparing variants, while also discovering posterior and lateral temporal subtypes resembling atypical clinical variants of AD. These “subtypes” were stable during longitudinal follow-up, and could be replicated in a separate sample using a different radiotracer. The subtypes presented with distinct demographic and cognitive profiles and differing longitudinal outcomes, however, no “typical” variant predominated. Across all subtypes, younger age was related to worse cognition and more rapid tau accumulation. Additionally, network diffusion models implicated that pathology originates and spreads through distinct corticolimbic in the different subtypes. Together, our results suggest variation in tau pathology is common and systematic, perhaps warranting a re-examination of the notion of “typical AD”, and a revisiting of tau pathological staging.