Abstract
Alzheimers Dement. 2025 Dec;21 Suppl 2:e104871. doi: 10.1002/alz70856_104871.
ABSTRACT
BACKGROUND: The link between regional tau load and clinical manifestation of Alzheimer's disease (AD) highlights the importance of characterizing spatial tau distribution. In typical (memory-predominant) AD, the spatial progression of tau pathology mirrors the functional connections from temporal lobe epicenters. However, atypical (non-amnestic-predominant) AD variants with heterogeneous tau patterns provide a key opportunity to assess the universality of connectivity as a scaffold for tau progression.
METHOD: We included tau-PET data from 320 subjects with atypical AD, characterized by highly heterogeneous tau patterns (n = 139 posterior cortical atrophy/PCA-AD; n = 103 logopenic variant primary progressive aphasia/lvPPA-AD; n = 35 behavioural variant AD/bvAD; n = 43 corticobasal syndrome/CBS-AD) from 14 sites, with a subset of patients (n = 78) having longitudinal tau-PET data. As an independent sample, we further included regional post-mortem tau stainings from 93 atypical AD patients from two sites (n = 19 PCA-AD, n = 32 lvPPA-AD, n = 23 bvAD, n = 19 CBS-AD). Gaussian mixture modeling was used to harmonize different tau-PET tracers by transforming tau-PET standardized uptake value ratios to tau positivity probabilities (a uniform scale ranging from 0% to 100%). Using linear regression, we assessed whether 1) brain regions with stronger functional connectivity showed greater covariance in cross-sectional and longitudinal tau-PET and post-mortem tau pathology, and 2) functional connectivity of tau-PET epicenters and tau-PET accumulation epicenters was associated with cross-sectional and longitudinal tau patterns.
RESULT: Tau-PET epicenters-defined as the 5% brain regions with the highest tau load-aligned with clinical variants, e.g. a posterior pattern in PCA-AD ("visual AD") and left-hemispheric temporal predominance in lvPPA-AD ("language AD") (Figure 1). More strongly functionally connected regions showed correlated concurrent tau-PET levels, which was confirmed with post-mortem data (Figure 2). Moreover, the connectivity profile of tau-PET epicenters and accumulation epicenters corresponded to tau-PET progression patterns (Figure 3).
CONCLUSION: Our data are consistent with the hypothesis that tau propagation occurs along functional connections originating from local epicenters, across all AD clinical variants. Since tau proteinopathy is a key driver of neurodegeneration and cognitive decline, this finding may advance personalized medicine and participant-specific endpoints in clinical trials.
PMID:41499762 | DOI:10.1002/alz70856_104871
UK DRI Authors
