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

2025-10-22

AI Summary

The dynamic interplay between structural connectivity (SC) and functional connectivity (FC) in the spatiotemporal propagation of tau pathology in Alzheimer’s disease (AD) remains poorly understood. Method: We developed a multilayer graph diffusion model integrating longitudinal multimodal neuroimaging (structural/functional MRI, tau-PET, amyloid-PET), genetic data (APOE genotype), and spatial transcriptomics to quantify region-specific contributions of SC and FC to tau spread. Contribution/Results: We identified a disease-stage-dependent shift in dominance: FC primarily drives early tau propagation in high-metabolism regions (e.g., frontal/temporal cortex), whereas SC governs later spread in structural hub regions (e.g., parietal/occipital cortex). This SC–FC dominance transition correlates significantly with spatial expression patterns of AD-risk genes (e.g., MAPT, BIN1). Findings were replicated in an independent cohort. This study is the first to characterize the stage- and region-specific network constraints governing tau propagation, providing a mechanistic foundation for network-informed, stage-targeted AD interventions.

Technology Category

• Planning, Routing, and Scheduling: Optimization of Spatio-temporal Systems
• Data Mining & Knowledge Management: Graph Mining, Social Network Analysis & Community
• Machine Learning: Graph-based Machine Learning

Application Category

• Social Networks and Social Media: Influence propagation, information diffusion, and the prediction on networks
• Graph Algorithms and Modeling for the Web: Algorithms and analysis for heterogeneous, signed, attributed, multi-relational, temporal, higher-order, and annotated Web-related graphs
• Web Mining and Content Analysis: Content-based information diffusion

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.

Problem

• Investigating how structural and functional connectivity interact in tau propagation
• Modeling regionally asymmetric roles of connectivity in Alzheimer's disease progression
• Identifying how risk factors shift dominant pathways for tau spread

Innovation

• Multi-layer graph diffusion model analyzes SC-FC interactions
• Model reveals regionally asymmetric roles of SC and FC
• Identifies shifting SC-FC dominance across disease stages