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 (β_GSMR = -0.19, p = .04). GSMR applied to the maternal family history of AD UK Biobank dataset (SBP [β_GSMR = -0.12, p = .02], DBP [β_GSMR = -0.10, p = .05]) and to the paternal family history of AD UK Biobank dataset (SBP [β_GSMR = -0.16, p = .02], DBP [β_GSMR = -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 (β_GSMR = -0.14, p = .03). The DBP analysis in the combined meta-analysis also confirmed a DBP effect on AD (β_GSMR = -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.

Keywords: Alzheimer's disease; Blood pressure; Family history of Alzheimer's disease; Genetic variants; Mendelian randomization.