| Description: |
Copyright © 2025 Harrison, Foley, Simmonds, Bracher-Smith, Holmans, Stergiakouli, Caseras, Escott-Price and Jones.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, n = 517) and UK Biobank (mean age = 64.2 years, n = 18,172). Genome-wide and nine pathway-specific PRS for Alzheimer’s disease were constructed using GWAS summary statistics and a clumping threshold of r2 < 0.2 at p < 0.001. Diffusion MRI data were processed separately within each cohort: in ALSPAC, tract-based fractional anisotropy (FA) and mean diffusivity (MD) were extracted using probabilistic tractography from native-space regions of interest; in UK Biobank, diffusion metrics were derived from TBSS-aligned skeletons and standard atlas-based ROIs. Analyses focused on three tracts vulnerable to early AD pathology: the dorsal cingulum, parahippocampal cingulum, and fornix. Multiple linear regression models were used to assess PRS associations with FA and MD, adjusting for demographic, scanner, and genetic ancestry covariates. False discovery rate correction addressed multiple comparisons, and sensitivity analyses were performed excluding the APOE region. 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 p < 0.05), explaining more variance than APOE alone; no significant effects ... |