Purpose <p>Brain structure-function coupling (SFC), which reflects the degree to which anatomical structure supports neural function, is an emerging imaging marker in neurodegenerative diseases. However, its pathological underpinnings in Alzheimer’s disease (AD) remain poorly understood. This study aimed to examine the association among amyloid pathology, SFC disruption and cognitive decline.</p> Methods <p>We included 173 participants from the SILCODE cohort, comprising cognitively unimpaired (CU) and cognitively impaired (CI) individuals. Amyloid pathology was quantified using [¹⁸F]-florbetapir PET standardized uptake value ratios (SUVR). Structural connectivity (SC) was derived from diffusion-weighted MRI with probabilistic tractography, while functional connectivity (FC) was calculated from resting-state functional MRI. SFC was defined as the coefficient of determination from linear models predicting FC based on SC at regional level. Linear regression and mediation analyses were conducted to assess relationships between amyloid pathology, SFC, and multiple cognitive performances.</p> Results <p>Compared to CU individuals, CI participants exhibited increased regional SFC primarily within the default mode network regions (<i>p</i> &lt; 0.05). In CI participants, amyloid pathology correlated with SFC across occipital lobe, precuneus and temporoparietal regions, which was specific by APOE ε4 status (<i>p</i> &lt; 0.05). Mediation analyses revealed that SFC partially mediated the relationship between amyloid pathology and cognitive impairment (<i>ab</i>_{<i>MoCA−B</i>} = -0.14, 95% CI [-0.27, -0.02]). Similar findings were replicated with plasma markers.</p> Conclusion <p>Amyloid pathology may underlie SFC disruptions, contributing to cognitive decline in AD. These findings suggest that SFC may serve as a potential biomarker for amyloid-related neurodegeneration and cognitive impairment.</p> Trial registration <p>The SILCODE is listed on the ClinicalTrials.gov registry (SILCODE: NCT03370744).</p>