Abstract
BackgroundEvidence concerning the potential repurposing of antihypertensives for Alzheimer’s disease prevention is inconclusive. We used Mendelian randomization, which can be more robust to confounding by indication and patient characteristics, to investigate the effects of lowering systolic blood pressure, via the protein targets of different antihypertensive drug classes, on Alzheimer’s disease.MethodsWe used summary statistics from genome-wide association studies of systolic blood pressure and Alzheimer’s disease in a two-sample Mendelian randomization analysis. We identified single-nucleotide polymorphisms (SNPs) that mimic the action of antihypertensive protein targets and estimated the effect of lowering systolic blood pressure on Alzheimer’s disease in three ways: (i) combining the protein targets of antihypertensive drug classes, (ii) combining all protein targets and (iii) without consideration of the protein targets.ResultsThere was limited evidence that lowering systolic blood pressure, via the protein targets of antihypertensive drug classes, affected Alzheimer’s disease risk. For example, the protein targets of calcium channel blockers had an odds ratio (OR) per 10 mmHg lower systolic blood pressure 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 10 mmHg lower systolic blood pressure: 1.14; 95% CI: 0.83 to 1.56; p = 0.41; SNPs = 59) and without consideration of the protein targets (OR per 10 mmHg lower systolic blood pressure: 1.04; 95% CI: 0.95 to 1.13; p = 0.45; SNPs = 153).ConclusionsMendelian randomization suggests that lowering systolic blood pressure via the protein targets of antihypertensive drugs is unlikely to affect the risk of developing Alzheimer’s disease. Consequently, if specific antihypertensive drug classes do affect the risk of Alzheimer’s disease, they may not do so via systolic blood pressure.
Highlights
Drug repurposing applies existing drugs to novel indications to identify potential treatments in a more rapid and cost-effective manner than traditional drug development
We identified a total of 73 unique protein targets of antihypertensive drugs (Supplementary Table 1, available as Supplementary data at IJE online)
A further six targets were excluded prior to the main analysis because neither the genetic instrument nor a suitable proxy was available in the outcome genome-wide association studies (GWASs)
Summary
Drug repurposing applies existing drugs to novel indications to identify potential treatments in a more rapid and cost-effective manner than traditional drug development. This approach is of interest for Alzheimer’s disease, as there are currently no preventative or disease-modifying therapies, despite investment in 1120 unique drug targets between 1995 and 2014.1–3 Antihypertensive drugs have previously been highlighted as priority repurposing candidates for Alzheimer’s disease prevention and several observational studies and a handful of trials have investigated this hypothesis.[2,4] the evidence to date is inconclusive.[4]. Results: There was limited evidence that lowering systolic blood pressure, via the protein targets of antihypertensive drug classes, affected Alzheimer’s disease risk.
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