Obesity and Subclinical Cerebral Small Vessel Disease Burden in Asymptomatic Japanese Adults: Mediation by Hypertension.

BACKGROUND: Although obesity is associated with cerebral small vessel disease (CSVD), the extent to which hypertension (HTN) and diabetes mellitus (DM) statistically account for this association in Asian populations remains unclear. METHODS: We analyzed asymptomatic Japanese adults enrolled in a Japanese Brain Dock registry between 2018 and 2024. The primary outcome was high CSVD burden, defined as a composite score ≥2 on a 0-4 scale based on the STandards for ReportIng Vascular changes on nEuroimaging criteria and incorporating moderate-to-severe white matter hyperintensities, lacunes, cerebral microbleeds, and pathologic basal ganglia perivascular spaces. Obesity was defined as a body mass index ≥25 kg/m² according to Asian-specific criteria. We performed multivariable logistic regression, parametric mediation-decomposition analyses with bootstrap-derived 95% confidence intervals (CIs), and Karlson-Holm-Breen (KHB) decomposition. RESULTS: Among 84,204 participants (45.7% women; median age, 50 years), obesity was associated with high CSVD burden (adjusted odds ratio [OR] 1.51 [95% CI 1.32-1.71]); this association attenuated to 1.24 (1.09-1.41) after adjustment for HTN and 1.21 (1.07-1.38) after additional adjustment for DM. In KHB decomposition, HTN and DM jointly accounted for 49.4% of the association (HTN, 91.9%; DM, 8.1%). The natural indirect effect was significant for HTN (1.27 [1.20-1.36]) but not for DM (1.00 [0.99-1.01]). A significant obesity × DM interaction was observed (p <0.05). CONCLUSION: In this large Japanese brain-screening cohort, approximately half of the association between obesity and high subclinical CSVD burden was statistically apportioned to HTN and DM, predominantly through HTN. These cross-sectional decomposition findings should be interpreted as statistical, not mechanistic, mediation and support prioritizing blood-pressure assessment in obese adults undergoing brain screening.