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<p>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 the interaction between structural (SC) and functional connectivity (FC) is associated with tau propagation remains largely unexplored. Using longitudinal neuroimaging data, we develop a multi-layer graph diffusion model to investigate this interplay. We identify a regionally asymmetric pattern, FC dominates tau accumulation in subcortical, insular, and frontotemporal regions, whereas SC prevails in occipital, parietal, and limbic areas. The principal conduit of tau propagation shifts from FC-mediated spread in early stages to SC-constrained diffusion as the disease advances. Furthermore, these propagation patterns correlate with regional expression of AD-associated genes (e.g., <i>CHUK, TMEM106B, MCL1, NOTCH1, TH</i>) and are selectively modulated by risk factors like <i>APOE</i> genotype and biological sex. By disentangling these dynamic pathways, our framework enables personalized trajectory prediction and refined patient stratification. These findings offer mechanistic insights into selective regional vulnerability, providing a quantitative basis for stage-specific therapeutic targeting and the optimization of clinical trial designs through network-based biomarkers. Our results are validated in an independent cohort, yielding consistent findings.</p>

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Understanding mechanistic role of structural and functional connectivity in tau propagation through multilayer modeling

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月29日

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  • Tingting Dan,
  • Xinwei Huang,
  • Jiaqi Ding,
  • Yinggang Zheng,
  • Guorong Wu

摘要

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 the interaction between structural (SC) and functional connectivity (FC) is associated with tau propagation remains largely unexplored. Using longitudinal neuroimaging data, we develop a multi-layer graph diffusion model to investigate this interplay. We identify a regionally asymmetric pattern, FC dominates tau accumulation in subcortical, insular, and frontotemporal regions, whereas SC prevails in occipital, parietal, and limbic areas. The principal conduit of tau propagation shifts from FC-mediated spread in early stages to SC-constrained diffusion as the disease advances. Furthermore, these propagation patterns correlate with regional expression of AD-associated genes (e.g., CHUK, TMEM106B, MCL1, NOTCH1, TH) and are selectively modulated by risk factors like APOE genotype and biological sex. By disentangling these dynamic pathways, our framework enables personalized trajectory prediction and refined patient stratification. These findings offer mechanistic insights into selective regional vulnerability, providing a quantitative basis for stage-specific therapeutic targeting and the optimization of clinical trial designs through network-based biomarkers. Our results are validated in an independent cohort, yielding consistent findings.