Hemispheric Asymmetry Defines Brain Aging: Five Reproducible NMF Modes Linked to Sex, Lifestyle, Transdiagnostic Genetic Risk, and Molecular Pathways

Population aging heightens the burden of cognitive decline and brain disorders, yet trajectories of brain aging vary widely across individuals. Because the human brain is intrinsically lateralized, age-related shifts in hemispheric asymmetry may reveal latent aging subtypes that are masked by bilateral averages. Here, we derived reproducible and interpretable asymmetry-based brain-aging modes and validated their behavioral, genetic, and molecular signatures. Using UK Biobank MRI, we computed cortical-thickness asymmetry across 68 Desikan-Killiany regions, transformed signed asymmetry into non-negative channels, and assembled a region-by-participant matrix. We then applied non-negative matrix factorization (NMF) to estimate spatial mode maps and participant-specific loadings, selecting the factorization rank by reconstruction-error elbow criterion (k = 13). Age associations were assessed with covariate-adjusted partial correlations controlling sex and handedness and corrected for multiple testing using false discovery rate (FDR). Generalizability was evaluated by projecting an independent cohort (Cam-CAN; n = 608) onto UK Biobank-derived spatial maps. We additionally tested sex differences, lifestyle/behavioral correlates, transdiagnostic polygenic risk score (PRS) coupling across 12 neuropsychiatric/neurodegenerative disorders, and imaging-transcriptomic pathway enrichment using Allen Human Brain Atlas expression and Metascape. We identified five age-linked asymmetry modes that replicated directionally in Cam-CAN. Modes differed systematically by sex and displayed distinct lifestyle signatures spanning sleep, physical activity, alcohol intake, diet, device use, and smoking. Genetic coupling was mode-specific, with different modes aligning with distinct constellations of transdiagnostic PRS. Imaging-transcriptomic analyses further indicated mechanistic dissociability, implicating mitochondrial bioenergetics, antigen presentation, innate immune/inflammatory pathways, and synaptic/neurodevelopmental programs. Hemispheric asymmetry decomposes into reproducible, mechanistically diverse aging modes that connect to modifiable behaviors and transdiagnostic genetic liability. This asymmetry-informed, mode-based framework advances subtype-oriented phenotyping of brain aging and provides a foundation for individualized risk stratification and mechanistic hypothesis generation.