Background: There is a strong link between tau and progression of Alzheimer's disease (AD), necessitating an understanding of tau spreading mechanisms. Prior research, predominantly in typical AD, suggested that tau propagates from epicenters (regions with earliest tau) to functionally connected regions. However, given the constrained spatial heterogeneity of tau in typical AD, validating this connectivity-based tau spreading model in AD variants with distinct tau deposition patterns is crucial.
Method: We included 269 amyloid-β-positive (PET/CSF) individuals with clinically diagnosed atypical AD (113 posterior cortical atrophy, PCA-AD; 83 logopenic variant primary progressive aphasia, lvPPA-AD; 33 behavioural variant AD, bvAD; 40 corticobasal syndrome, CBS-AD) and 68 with typical AD from 12 international cohorts, who underwent tau-PET (54% [18F]AV1451/[18F]flortaucipir/Tauvid, 27% [18F]MK6240, 19% [18F]PI2620). Using Gaussian mixture modeling including amyloid-β-negative controls, cross-sectional tau-PET standardized uptake value ratios within Schaefer-200 atlas regions were transformed to tau positivity probabilities. Tau epicenters were defined as the 5% regions with highest tau positivity probabilities. For each variant, the association between functional connectivity-based distance (using the 30% strongest positive region-to-region connections of a group-average connectivity matrix from ADNI elderly controls) and tau-PET covariance (group-average correlation per region pair) was assessed through linear regression, adjusting for age, sex, site, and Euclidean distance. Regions were categorized based on functional proximity to the epicenter (quartiles 1-4) and tau positivity probabilities were assessed accordingly.
Result: Tau positivity probabilities matched clinical variants, with a posterior pattern in PCA-AD, left-hemispheric dominant pattern in lvPPA-AD, widespread pattern in bvAD, sensorimotor cortex involvement in CBS-AD, and temporo-parietal predominance in typical AD (Figure 1). In line with this, tau epicenters were highly heterogeneous across variants (Figure 1). In all variants, greater tau-PET covariance was associated with shorter functional connectivity-based distance (Figure 2). We observed that regions in closer functional proximity to the epicenter exhibited higher tau positivity probabilities than regions functionally further away (p<0.05, Figure 3).
Conclusion: This multi-center study shows that the brain's functional architecture serves as a universal predictor of tau spreading in AD. Since tau is a key driver of neurodegeneration and cognitive decline in AD, this finding holds potential for personalized medicine and defining participant-specific endpoints in clinical trials.
© 2024 The Alzheimer's Association. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.