White matter hyperintensities partly mediate genetically predicted blood pressure effects on vascular dementia

Abstract Background White matter hyperintensities (WMH) mark cerebral small vessel disease and sit on the path from hypertension to vascular dementia (VaD). Prior Mendelian randomization in European ancestry has linked blood pressure (BP) to WMH. We tested whether that association replicates in Japanese ancestry and whether WMH captures part of the genetically predicted BP effect on VaD after a priori APOE exclusion. Methods Two-sample Mendelian randomization used European genome-wide association studies of BP, WMH, and VaD, with Japanese replication of BP residual to WMH residual. The primary estimator was random-effects inverse-variance weighted analysis. Two-step Mendelian randomization multiplied each APOE -excluded BP to WMH estimate by the APOE -excluded WMH to VaD log-odds ratio. Results Genetically predicted diastolic and systolic BP associated with higher WMH in Europeans (β = 0.176 and 0.091 WMH SD per 10 mm Hg). The same direction replicated in Japanese ancestry on a residual-SD scale. Pulse pressure did not. Diastolic and systolic BP associated with VaD (odds ratios 1.36 and 1.12). Both had an indirect path through WMH (indirect odds ratios 1.10 and 1.05). The descriptive mediated proportion was 0.31 for diastolic BP. The systolic proportion interval included 0. Conclusions Genetically predicted BP raises WMH in European and Japanese ancestry. Diastolic and systolic BP have an indirect path through WMH to VaD. A descriptive mediated proportion whose interval excludes 0 is limited to diastolic BP.