# Heterogeneous tau patterns in atypical AD are explained by connectivity‐associated tau progression

## TL;DR

This study shows that tau protein spreads through brain connections in different types of Alzheimer's disease, supporting the idea that brain connectivity guides tau progression.

## Contribution

The study demonstrates that connectivity-based tau progression applies to atypical Alzheimer's disease variants with heterogeneous tau patterns.

## Key findings

- Tau-PET epicenters align with clinical AD variants, such as posterior patterns in PCA-AD and left-hemispheric patterns in lvPPA-AD.
- Stronger functional connectivity correlates with synchronized tau levels, confirmed by post-mortem data.
- Connectivity profiles of tau-PET epicenters match tau progression patterns across AD variants.

## Abstract

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.

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.

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).

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.