Latent Multidimensional Organization of White Matter Microstructural Aging: A Generative Adversarial Network...

Background: White matter (WM) aging is commonly characterized as a largely unitary process of progressive microstructural decline, yet substantial interindividual variation suggests that this view may obscure distinct biological dimensions. Whether WM aging retains a multidimensional organization after minimizing variation attributable to overt clinical pathology remains unknown. Methods: We constructed a clinically defined aging reference cohort (CDAR; n = 17,310) from the UK Biobank (UKB) by excluding overt clinical pathology and analyzed 144 skeleton-based WM microstructural metrics. An additional 10,272 participants with overt clinical diagnoses were included for downstream association analyses, yielding a total analytic sample of 27,582. Surreal-GAN was applied to disentangle latent dimensions of WM aging, with reproducibility-based model selection and cross-sample and cross-sex validation. The biological relevance of the identified dimensions was evaluated through associations with cognitive, lifestyle, peripheral, and disease-related outcomes. Results: Three reproducible and coexisting dimensions of WM aging emerged, comprising distinct spatial configurations rather than a single diffuse aging axis. R₁ displayed an anterior-vulnerable/posterior-preserved gradient, R₂ reflected a widespread diffuse aging load, and R₃ showed a dissociation between the limbic-frontal system and sensorimotor pathways. The three patterns exhibited good cross-sample (r = 0.887-0.935) and cross-sex (r = 0.891-0.937) reproducibility, with strong bilateral hemispheric correspondence (r > 0.86). All three patterns were associated with age but exhibited partially shared and partially independent associations with cognition, lifestyle factors, peripheral phenotypes, and disease risk. Conclusions: WM aging is not adequately captured by a single neuroanatomical process. Even after minimizing overt clinical pathology, it retains a reproducible multidimensional organization, with partially shared and partially independent phenotypic profiles across aging dimensions. These findings suggest that individual differences in WM aging reflect partially separable biological processes rather than variation along a single aging axis.