White matter microstructure in mid- to late adulthood is influenced by pathway-stratified polygenic risk for Alzheimer's disease.

Introduction: Alzheimer's disease involves progressive white matter microstructural degeneration that may precede clinical symptoms by decades. While polygenic risk scores (PRS) quantify cumulative genetic liability for AD, genome-wide PRS lack mechanistic specificity. We tested whether pathway-specific PRS, targeting areas of biology including tau binding, lipid metabolism, and immune response, are differentially associated with diffusion MRI measures across the lifespan. Methods: We analyzed two population-based cohorts: the Avon Longitudinal Study of Parents and Children (ALSPAC; mean age = 19.8 years, Results: In UK Biobank, higher PRS for protein-lipid complex assembly and tau protein binding were robustly associated with lower fractional anisotropy and higher mean diffusivity in both dorsal and parahippocampal cingulum segments (False discovery rate-corrected Conclusion: Pathway-specific polygenic risk for Alzheimer's disease manifests in white matter microstructure by mid- to late adulthood but not in early adulthood, suggesting an age-dependent emergence of genetic effects. dMRI phenotypes may thus serve as intermediate biomarkers for dissecting mechanistic pathways of preclinical Alzheimer's disease vulnerability.