Abstract P307: Elevated Blood Pressure Accelerates White Matter Brain Aging in Late Middle-Aged Women: A Mendelian Randomization Study in UK Biobank

Abstract

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. In this study, we hypothesize that increasing BP will accelerate WM brain aging. Methods: In our 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, age range: 40-69, 16,901 have neuroimaging data available) collected from UK Biobank (UKBB). In the current study, 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 applied machine learning method to establish the model to compute BAG based on fractional anisotropy (FA) measurements derived from structural neuroimaging data among a group of subjects without hypertension (N=7,728). The established model will be applied to calculate WM BAG in other subjects with or without hypertension. We then performed association analysis as well as 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 . In the first sample with genotype and BP data but no WM FA data (N=20,3067), we tested the genetic-exposure association and identified relevant genetic variants as instrumental variables. In the second non-overlapping sample with genotype, BP, and WM FA data, we tested the genetic-outcome association (N=8,822). The causal effect of BP on WM BAG is estimated by using a generalized version of the inverse-variance weighted (IVW) approach. Results: The non-hypertension group and females had younger brains (WM BAG) across all the year cycles than the hypertension group by 0.3098 year and males by 1.2666 years, respectively, both p <0.0001. The association analysis revealed that both Diastolic Blood Pressure (DBP) and Systolic Blood Pressure (SBP) had a stronger significant relationship with WM BAG among females (βSBP=0.0149; βDBP=0.0233), 50-59 aged group (βSBP=0.0163; βDBP=0.0259), and 60-69 aged group (βSBP=0.0086; βDBP=0.0147), all p < 0.0001. The MR analyses showed that DBP had a significant causal effect on WM BAG among females aged 50-59 (β=0.0720, p=0.0243) and females aged 60-69 (β=0.1000, p=0.0085). We only observed SBP had a marginal causal effect (0.05<p<0.1) among males aged 50-59 (β= -0.0458), females aged 40-49 (β= -0.0446) and aged 50-59 (β=0.0326). 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.