Stable brain architecture but flexible dynamics: distinct structure - function coupling signatures link aging and genetic Alzheimer's risk to cognitive decline in 34,067 adults

Understanding 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 temporal variability of structure-function coupling, referred to as dynamic SFC (DSFC), remains poorly characterized, particularly in relation to aging and cognitive outcomes. 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 spatially between the two measures: reduced DSFC was predominantly linked to health burden in high-order default/limbic networks, whereas weakened SFC was primarily associated with health burden in low-order sensory-motor networks. Genetic analyses revealed that Alzheimer's risk, specifically APOE ε4 dosage, significantly reduced DSFC in higher-order cognitive networks and SFC in low-order visual cortex. Mediation analyses further suggested that SFC and DSFC partially mediated the associations of aging and APOE ε4 dosage with cognitive performance. These findings suggest that static and dynamic coupling capture complementary aspects of brain organization: static SFC reflects the degree of functional alignment with structural architecture, whereas DSFC captures temporal variability in this alignment. Together, our results highlight these dual mechanisms as crucial for maintaining cognitive flexibility, providing potential biomarkers for age-related neurodegeneration.