Region-specific vulnerability to vascular risk factors and modifiable protective influences on white matter hyperintensities.

BACKGROUND: Region-specific vulnerabilities to single and combined vascular risk factors and the role of modifiable behaviors in white matter hyperintensity (WMH) progression remain unclear. We aimed to characterize neuroanatomical patterns of WMH vulnerability and to identify subgroup-specific factors associated with lower burden and slower progression.
METHODS: We included 1146 participants (60.9% female; age 45-86 years) from the Beijing Aging Brain Rejuvenation Initiative (2008-2023), all of whom underwent standardized magnetic resonance imaging together with clinical and behavioral assessments. We used age- and sex-specific centile curves of WMH burden to examine associations with vascular risk factors, their combinations, and behavioral profiles.
RESULTS: Here we show that vascular risk factors have region-specific associations with WMH burden: hypertension is linked mainly to periventricular frontal regions, whereas smoking is linked to deep subcortical regions. Combined risk factors show broader involvement, especially in periventricular frontal regions and the corpus callosum. Better control of some vascular risk factors is associated with lower burden (e.g., diabetes: approximately 2.0 mL lower; hyperlipidemia: approximately 2.3 mL lower) and slower progression (e.g., controlled total cholesterol: 0.176 vs. 0.939 mL/year, p = 0.007), and behavioral associations differ across risk profiles. More frequent leisure activity is associated with lower burden mainly in obesity, whereas lower depressive symptoms are associated with lower burden or slower progression in some vascular-risk subgroups.
CONCLUSIONS: Vascular risk factors and behavioral factors show subgroup- and region-specific associations with WMH burden and progression. These findings may help refine risk stratification, improve understanding of vulnerability patterns, and inform future intervention studies.