Angiotensin-converting enzyme inhibition and Alzheimer's disease: Findings from proteome-wide Mendelian randomization and a large prospective cohort study

BackgroundWe aimed to provide clinically translatable insights for drug discovery, repurposing, and vigilance for preventing Alzheimers disease (AD) by integrating genetic and "real-world" drug use data. MethodsProteome-wide Mendelian randomization (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 multi-omic 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, where appropriate, performed multivariable MR for the prioritized findings. Conventional observational analysis using the data from UK Biobank, a large prospective cohort, was performed to provide further clinical implications for our genetic findings. ResultsMR analysis identified 15 plasma proteins with putative causal effects on AD risk. Of them, inhibition of angiotensin-converting enzyme (ACE) was found to increase the risk of AD (OR 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 (HR 1.24, 95% CI 1.01-1.52) of AD among regular users of ACE inhibitors (ACEI), compared with the counterpart angiotensin receptor blocker users. ConclusionsIn addition to expanding the understanding of druggable targets for AD prevention, our findings highlighted the potential risk of AD associated with the use of ACEIs, a widely prescribed antihypertensive medication, suggesting the need for caution in clinical practice and further research on the effect of antihypertensives on neurodegenerative diseases.