Age-inappropriate white matter injury reveals hidden cerebral small vessel disease burden and mortality risk.

Objective: White matter hyperintensities (WMH) are a core marker of cerebral small vessel disease (CSVD), but their interpretation is limited by strong age-dependence. We hypothesized that WMH burden disproportionate to age- and sex-expected norms had clinical significance by reflecting disease burden and outcomes. Methods: We developed an age- and sex-referenced normative model of WMH using hierarchical Bayesian regression in 2544 neurologically healthy community-dwelling adults from Taiwan and Japan (50.0-92.1 years, 1319 women). Individualized WMH deviation scores were applied to 1237 community-dwelling participants. Participants were classified into four normative model-defined WMH deviation categories: low, mild, moderate, and high. We tested associations of WMH deviation with vascular risk profiles, cognitive performance, gray matter volumes, and all-cause mortality. Results: Higher WMH deviation identified individuals who were not older but had more adverse vascular profiles. Each one-level increase in WMH deviation was associated with lower global cognition (MMSE β = -0.179, FDR-p = 0.034), poorer verbal memory (β = -0.121, FDR-p = 0.034), and worse visuospatial function (β = -0.330, FDR-p = 0.049), as well as reduced global gray matter (β = -4.180, FDR-p < 0.001) and lower hippocampal and thalamic volumes (all FDR-p ≤ 0.002). During a mean follow-up of 9.4 years, high WMH deviation was associated with increased all-cause mortality after adjustment for age, sex, hypertension, and diabetes (hazard ratio 1.72, 95% CI 1.05-2.82), despite younger age. Interpretation: WMH deviation from age- and sex-expected norms provides clinically-relevant information identifying individuals at increased risk of neurodegeneration and mortality.