Disrupted dynamics of brain structure function coupling link genetic risk of Alzheimer's Disease and aging to cognitive decline in 34,067 adults

Abstract

AbstractUnderstanding how a stable structural connectome supports flexible cognition, especially in aging, is a fundamental question in neuroscience. While static structure-function coupling (SFC) is well-studied, the dynamic decoupling of functional activity from structural constraints--dynamic SFC (DSFC)--remains poorly understood. Leveraging MRI data from 34,067 UK Biobank participants (ages 45-82), we characterized the distinct roles of SFC and DSFC in aging, cognition, and health. We found that SFC and DSFC followed spatially divergent aging trajectories: SFC declined primarily in sensorimotor systems, whereas DSFC decreased most prominently in higher-order networks. Both SFC and DSFC in higher-order networks were positively correlated with cognitive performance (e.g., fluid intelligence). However, the associations with mental and physical health diverged between the two measures: reduced DSFC was predominantly linked to health burdens in high-order default/limbic networks, whereas weakened SFC was primarily associated with health burdens in low-order sensory-motor networks. Genetic analyses revealed that Alzheimers risk, specifically APOE {varepsilon}4 dosage, significantly reduced DSFC in higher-order cognitive networks and SFC in visual cortex. Mediation analyses further demonstrated that aging and APOE {varepsilon}4-linked cognitive decline were mediated via visual SFC and ventral attention DSFC. These findings position static and dynamic coupling as complementary mechanisms: static SFC preserves network robustness, while dynamic SFC enables transient reconfiguration for complex integration. Together, our results highlight these dual mechanisms as crucial for maintaining cognitive flexibility, providing potential biomarkers for age-related neurodegeneration.