Abstract
Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by the disconnection of white matter fibers and disrupted functional connectivity of gray matter; however, the pathological mechanisms linking structural and functional changes remain unclear. This study aimed to explore the interaction between the structural and functional brain network in AD using advanced structural-functional coupling (S-F coupling) models to assess whether these changes correlate with cognitive function, Aβ deposition levels, and gene expression. In this study, we utilized multimodal magnetic resonance imaging data from 41 individuals with AD, 112 individuals with mild cognitive impairment, and 102 healthy controls to explore these mechanisms. We applied different computational models to examine the changes in the S-F coupling associated with AD. Our results showed that the communication and graph harmonic models demonstrated greater heterogeneity and were more sensitive than the statistical models in detecting AD-related pathological changes. In addition, S-F coupling increases with AD progression at the global, subnetwork, and regional node levels, especially in the medial prefrontal and anterior cingulate cortices. The S-F coupling of these regions also partially mediated cognitive decline and Aβ deposition. Furthermore, gene enrichment analysis revealed that changes in S-F coupling were strongly associated with the regulation of cellular catabolic processes. This study advances our understanding of the interaction between structural and functional connectivity and highlights the importance of S-F coupling in elucidating the neural mechanisms underlying cognitive decline in AD.