Tissue- and compartment-resolved brain age reveals vascular-metabolic and neurodegenerative aging

Brain aging reflects heterogeneous vascular-metabolic and neurodegenerative processes, yet brain age is often reduced to a gray matter (GM)-dominant estimate. Emerging evidence suggests that subtle “dirty-appearing” T2-FLAIR abnormalities may mark diffuse white matter (WM) vulnerability that precedes or extends beyond overt WM hyperintensities (WMH). Here we developed a compartment-resolved framework integrating T1-weighted GM features with unthresholded T2-FLAIR WM signal across depth- and lobe-specific surfaces. In 26,446 UK Biobank and 992 ADNI participants, WM brain age captured variation beyond WMH burden and was preferentially associated with cardiometabolic risk before age 65; periventricular WM age statistically linked cardiometabolic burden to cognition. Across the Alzheimer’s disease continuum, GM and WM brain age increased with diagnostic severity but showed distinct molecular associations: GM aging aligned more closely with amyloid burden, whereas WM aging showed prominent tau associations. These findings reveal complementary vascular-metabolic and neurodegenerative dimensions of brain aging obscured by global brain age estimates.