Spatiotemporal imaging phenotypes of tau pathology in Alzheimer’s disease

Abstract Background The Braak staging scheme describes a stereotypical spread of tau pathology in Alzheimer’s disease (AD). However, apparent subtypes described at autopsy and clinical variants of AD both suggest variability in the pattern of tau spreading across the population. To address this discrepancy, we applied a validated spatiotemporal clustering algorithm to a large, multisite dataset of tau‐PET images. We verified these findings both longitudinally and on a separate tau‐PET dataset using a different radiotracer, and we characterized the phenotype and potential biological determinants of each subtype. Method Subtype and Stage Inference (SuStaIn, Young et al., 2018 ) is a data‐driven, probabilistic algorithm that combines disease progression modeling with clustering to extract distinct spatiotemporal patterns (subtypes) from large cross‐sectional datasets. We applied SuStaIn to a multisite dataset (n=1143) of [18F]‐flortaucipir tau‐PET baseline scans to identify spatiotemporal subtypes of tau spreading. We investigated differences in demographic, cognitive and genetic measures. In a subsample of individuals with multiple tau‐PET scans over time (n=536), we tested longitudinal subtype stability and change in disease stage over time. We verified these subtypes in a second single‐site dataset (n=509) of [18F]‐RO948 tau‐PET scans. Finally we used the Epidemic Spreading Model (ESM, Iturria‐Medina et al., 2014) and imaging or transcriptomic analysis to determine if anatomical brain networks or specific cell‐types, respectively, could explain the differing spatial patterns across subtypes. Result In those subjects with significant tau‐PET signal in the brain, SuStaIn identified four spatiotemporal subtypes of tau‐PET spreading: Typical (worse memory, more APOE4 carriers), limbic‐sparing (younger, less APOE4 carriers), posterior (worse visuospatial cognition), and lateral‐temporal (worse language and executive function scores; Fig 1A, Fig 2). These same four subtypes were observed in a separate cohort using a different radiotracer (similarity 0.7–0.9; Fig 1B). 86% of subjects exhibited the same subtype at multiple visits (Fig 1C), and of that group, 83% advanced in disease stage or remained stable within model uncertainty. The ESM suggested different epicenters for each subtype, and each subtype pattern exhibited a different profile of cell‐type enrichment (Fig 3). Conclusion Four stable tau‐spreading phenotypes were observed with distinct cognitive profiles, which may be characterized by vulnerability of different corticolimbic networks involving distinct cell classes.

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