Repurposing antihypertensive drugs for the prevention of Alzheimer’s disease: a Mendelian Randomization study

Background:
Evidence concerning the potential repurposing of antihypertensives for Alzheimer’s disease (AD) prevention is inconclusive. We used Mendelian randomization (MR), which can be more robust to confounding by indication and patient characteristics, to investigate the effects of lowering systolic blood pressure (SBP), via the protein targets of different antihypertensive drug classes, on AD.

Methods:
We used summary statistics from genome-wide association studies of SBP and AD in a two-sample MR analysis. We identified single nucleotide polymorphisms (SNPs) that mimic the action of antihypertensive protein targets and estimated the effect of lowering SBP on AD in three ways: (1) combining the protein targets of antihypertensive drug classes; (2) combining all protein targets; and (3) without consideration of the protein targets.

Results:
There was limited evidence that lowering SBP, via the protein targets of antihypertensive drug classes, affected AD risk. For example, the protein targets of calcium channel blockers had an odds ratio (OR) per 10mmHg lower SBP of 1.53 (95% confidence interval (CI): 0.94 to 2.49; p=0.09; SNPs=17). We also found limited evidence for an effect when combining all protein targets (OR per 10mmHg lower SBP: 1.14; 95%CI: 0.83 to 1.56; p=0.41; SNPs=59) and without consideration of the protein targets (OR per 10mmHg lower SBP: 1.04; 95%CI: 0.95 to 1.13; p=0.45; SNPs=153).

Conclusions:
MR suggests that lowering SBP via the protein targets of antihypertensive drugs is unlikely to affect risk of developing AD. Consequently, if specific antihypertensive drug classes do affect risk of AD, they may not do so via SBP.