Understanding Mechanistic Role of Structural and Functional Connectivity in Tau Propagation Through Multi-Layer Modeling

TL;DR

This study uses multi-layer graph diffusion modeling on longitudinal neuroimaging data to elucidate how structural and functional brain connectivity interact and influence tau protein spread in Alzheimer's disease, revealing region-specific and disease-stage-dependent mechanisms.

Contribution

It introduces a multi-layer graph diffusion model that uncovers the asymmetric and dynamic roles of structural and functional connectivity in tau propagation across different brain regions and disease stages.

Findings

FC dominates tau spread in early AD regions

SC becomes more influential in later disease stages

Gene expression patterns align with connectivity-driven tau propagation

Abstract

Emerging neuroimaging evidence shows that pathological tau proteins build up along specific brain networks, suggesting that large-scale network architecture plays a key role in the progression of Alzheimer's disease (AD). However, how structural connectivity (SC) and functional connectivity (FC) interact to influence tau propagation remains unclear. Leveraging an unprecedented volume of longitudinal neuroimaging data, we examine SC-FC interactions through a multi-layer graph diffusion model. Beyond showing that connectome architecture constrains tau spread, our model reveals a regionally asymmetric contribution of SC and FC. Specifically, FC predominantly drives tau spread in subcortical areas, the insula, frontal and temporal cortices, whereas SC plays a larger role in occipital, parietal, and limbic regions. The relative dominance of SC versus FC shifts over the course of disease, with FC generally prevailing in early AD and SC becoming primary in later stages. Spatial patterns of SC- and FC-dominant regions strongly align with the regional expression of AD-associated genes involved in inflammation, apoptosis, and lysosomal function, including CHUK (IKK-alpha), TMEM106B, MCL1, NOTCH1, and TH. In parallel, other non-modifiable risk factors (e.g., APOE genotype, sex) and biological mechanisms (e.g., amyloid deposition) selectively reshape tau propagation by shifting dominant routes between anatomical and functional pathways in a region-specific manner. Findings are validated in an independent AD cohort.