标题： 通过多层建模理解结构和功能连接在tau传播中的机制作用 显示英文标题

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

摘要： 新兴的神经影像学证据表明，病理性tau蛋白沿着特定的脑网络积累，这表明大规模网络结构在阿尔茨海默病（AD）进展中起着关键作用。 然而，结构连接（SC）和功能连接（FC）如何相互作用以影响tau传播仍不清楚。 利用前所未有的纵向神经影像数据，我们通过多层图扩散模型来研究SC-FC相互作用。 除了显示连接组架构限制了tau的传播外，我们的模型揭示了SC和FC在区域上的不对称贡献。 具体而言，FC主要驱动皮层下区域、岛叶、额叶和颞叶皮层的tau传播，而SC在枕叶、顶叶和边缘区域起更大作用。 在疾病过程中，SC与FC的相对主导地位发生了变化，早期AD中FC通常占主导地位，而在后期阶段SC成为主要因素。 SC和FC主导区域的空间模式与涉及炎症、细胞凋亡和溶酶体功能的AD相关基因的区域表达高度一致，包括CHUK（IKK-alpha）、TMEM106B、MCL1、NOTCH1和TH。 同时，其他不可改变的风险因素（例如APOE基因型、性别）和生物机制（例如淀粉样蛋白沉积）通过在特定区域内在解剖和功能通路之间改变主导路径，选择性地重塑tau传播。 研究结果在独立的AD队列中得到验证。 显示英文摘要

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 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.