High Blood Pressure and Risk of Dementia: A Two-Sample Mendelian Randomization Study in the UK Biobank

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).

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.

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).

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.