White matter impairment as an early signature of incident dementia

Background: Alzheimer’s disease (AD), the leading cause of dementia worldwide, is characterized by pathological changes that begin decades before clinical symptoms emerge. White matter disruption has long been recognized as an early pathological feature of dementia, yet its dynamic longitudinal trajectory, utility for dementia risk forecasting, and upstream molecular regulatory pathways remain poorly delineated. Methods: In this study, we leveraged the prospective UK Biobank cohort to systematically identify white matter diffusion metrics associated with incident dementia, delineate their temporal trajectories prior to dementia diagnosis, evaluate their capacity for early prediction, and explore the peripheral molecular mechanisms via plasma proteomics. Results: Impaired cerebral white matter microstructure, characterized by reduced fractional anisotropy and increased mean diffusivity, exhibited robust significant associations with elevated incident risk of both all-cause dementia (ACD) and sporadic AD. Notably, these microstructural white matter aberrations were reliably detectable up to 7–8 years in advance of formal clinical dementia diagnosis. A composite signature derived from five specific white matter tracts demonstrated exceptional predictive accuracy for 5-year incident ACD (area under the curve [AUC] = 0.86) and AD (AUC = 0.92). Plasma proteomic profiling identified 257 proteins associated with the integrity of dementia-related white matter tracts. Functional pathway enrichment further revealed that these proteins were predominantly enriched in biological cascades governing cell death signaling, enzyme activity modulation, innate and adaptive immune response cascades, as well as cellular redox balance and oxidative stress homeostasis. Conclusions: Our findings suggest that tract-specific white matter microstructural deterioration as a robust neuroimaging signature capable of identifying individuals at elevated risk of ACD and AD. Beyond translational screening implications, this work also yields novel mechanistic evidence linking circulating peripheral molecular perturbations to cerebral white matter breakdown, illuminating the systemic biological cascades driving white matter degeneration in AD and related dementias.