Plasma Angiotensin‐Converting Enzyme as a Prioritized Candidate Target for Alzheimer's Disease: Evidence From Proteome‐Wide Mendelian Randomization and a Large Prospective Cohort Study

Background We aimed to provide hypothesis‐generating evidence on druggable targets for Alzheimer's disease (AD) by integrating proteome‐wide Mendelian randomization (MR) with evidence from a conventional observational analysis of drug use in a large prospective cohort. Methods Proteome‐wide MR analysis was conducted to identify plasma proteins causally related to AD risk using the largest summary‐level data to date, followed by colocalization and multiomic validation analyses (on the gene expression, alternative splicing, and DNA methylation levels in blood and brain, respectively) to prioritize potential druggable targets. We also replicated our MR findings using additional genetic data and performed multivariable MR for the prioritized findings. Conventional observational analysis in UK Biobank, a large prospective cohort, was performed to provide further clinical implications, using active comparator to minimize confounding by indication. Results MR analysis identified 15 plasma proteins with putative causal effects on AD risk. Of them, inhibition of angiotensin‐converting enzyme was found to increase the risk of AD (odds ratio, 1.10 [95% CI, 1.08–1.14]), which was likely independent of blood pressure as suggested by multivariable MR. Observational analysis in UK Biobank showed a higher incidence (hazard ratio, 1.23 [95% CI, 1.00–1.50]) of AD among regular users of angiotensin‐converting enzyme inhibitors, compared with the active comparator angiotensin receptor blocker users. Conclusions Our genetic analyses prioritized angiotensin‐converting enzyme as a candidate target, and a conventional observational analysis in a large prospective cohort provided supportive evidence that regular angiotensin‐converting enzyme inhibitor use was associated with a higher AD risk, which needs further investigation with high‐quality real‐world evidence and clinical trials before being translated into practice changes.