High blood pressure and risk of dementia : a two-sample Mendelian randomization study in the UK biobank

Abstract

Background: Findings from randomized controlled trials have yielded conflicting results on the association between blood pressure (BP) and dementia traits. We tested the hypothesis that a causal relationship exists between systolic BP (SBP) and/or diastolic BP (DBP) and risk of Alzheimer's disease (AD). Methods: We performed a generalized summary Mendelian randomization (GSMR) analysis using summary statistics of a genome-wide association study meta-analysis of 299,024 individuals of SBP or DBP as exposure variables against three different outcomes: 1) AD diagnosis (International Genomics of Alzheimer's Project), 2) maternal family history of AD (UK Biobank), and 3) paternal family history of AD (UK Biobank). Finally, a combined meta-analysis of 368,440 individuals that included these three summary statistics was used as final outcome. Results: GSMR applied to the International Genomics of Alzheimer's Project dataset revealed a significant effect of high SBP lowering the risk of AD (βGSMR = −0.19, p =.04). GSMR applied to the maternal family history of AD UK Biobank dataset (SBP [βGSMR = −0.12, p =.02], DBP [βGSMR = −0.10, p =.05]) and to the paternal family history of AD UK Biobank dataset (SBP [βGSMR = −0.16, p =.02], DBP [βGSMR = −0.24, p = 7.4 × 10−4]) showed the same effect. A subsequent combined meta-analysis confirmed the overall significant effect for the other SBP analyses (βGSMR = −0.14, p =.03). The DBP analysis in the combined meta-analysis also confirmed a DBP effect on AD (βGSMR = −0.14, p =.03). Conclusions: A causal effect exists between high BP and a reduced late-life risk of AD. The results were obtained through careful consideration of confounding factors and the application of complementary MR methods on independent cohorts.