Elevated blood pressure accelerates white matter brain aging among late middle-aged women: a Mendelian Randomization study in the UK Biobank

Background Elevated blood pressure (BP) is a modifiable risk factor associated with cognitive impairment and cerebrovascular diseases. However, the causal effect of BP on white matter (WM) brain aging remains unclear. Methods In this study, we focused on N=219,968 non-pregnant, family-unrelated individuals of European ancestry who had genotype data and two non-null clinical BP measurements available (99,532 male and 120,436 female, mean age=56.55, including 16,901 participants with neuroimaging data available) collected from UK Biobank (UKB). We adopted a chronological age-adjusted brain age metric, Brain Age Gap (BAG), as the outcome variable to measure the brain aging status. As a first step, we established a machine learning model to compute BAG based on white matter microstructure integrity measured by fractional anisotropy (FA) derived from diffusion tensor imaging data in a training set of subjects without hypertension (N=7,728). We then performed a two-sample Mendelian Randomization (MR) analysis to estimate the causal effect of BP on WM BAG in the whole population and subgroups stratified by gender and age brackets using two non-overlapping data sets (N=20,3067 for the set with genotype and BP data but no FA data; and N=8,822 for the set with genotype, BP and FA data). The main MR method used was generalized inverse variance weighted (gen-IVW) with other MR methods also included as sensitivity analysis. Results The hypertension group is on average 0.3098 years (95%CI=0.1313,0.4884; p <0.0001) older in WM brain age than the non-hypertension group of the same chronological age. Females are on average 0.8143 years (95% CI=0.6797 to 0.949; p <0.0001) younger in WM brain age than males of the same chronological age. The MR analyses showed an overall significant positive causal effect of diastolic blood pressure (DBP) on WM BAG, where every 10 mm Hg increase in DBP can lead to 0.371 years increase in brain age (CI: 0.034-0.709, p=0.0311). The stratified analysis by age and gender group found such significant causal effect of DBP on BAG to be most prominent among female women aged 50-59 (0.686 years/10mm Hg, CI: 0.054-1.318, p=0.0335) and aged 60-69 (0.962 years/10mm Hg, CI: 0.209-1.714, p=0.0122). Conclusion Hypertension and genetic predisposition to higher BP can accelerate WM brain aging specifically targeting at late middle-aged women, providing insights on planning effective control of BP for women in this age group.