Patient-specific functional brain architecture explains cortical patterns of tau PET in Alzheimer's disease

Abstract

The spatial distribution of tau pathology, a key correlate of neurodegeneration and cognitive decline in Alzheimer's disease (AD), varies markedly across individuals. While tau is thought to spread along brain networks, the role of inter-individual variability in accounting for these patterns remains underexplored. Using resting-state fMRI and tau-PET from 805 BioFINDER participants across the AD continuum, with replication in ADNI (n=361) and A4 (n=336), we studied whether subject-specific functional connectivity (FC) profiles enhance the characterization of tau deposition patterns. A hybrid approach integrating individual and group-average FC explained individual tau-PET topographies better than either FC representation alone, particularly in symptomatic individuals and at finer spatial resolutions. Hybrid FC also better captured individual tau topographies than canonical tau-PET maps derived from cohort-level data. These effects were specific to tau and not similarly observed for {beta}-amyloid, and the explanatory advantage of FC-based models increased with spatial granularity. Furthermore, baseline hybrid FC explained follow-up tau-PET topography better than template FC, suggesting that individualized baseline connectivity contains information about future tau-PET progression. The main FC model-comparison findings replicated in ADNI and A4. Collectively, these findings show that individual functional brain architecture is associated with heterogeneity in tau-PET topography. While not establishing a causal propagation mechanism, our findings are consistent with network-spread models. This work advances the methodological characterization of tau-PET heterogeneity in AD and highlights functional connectivity as a potentially informative marker of individual tau-PET trajectories.