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
Year: 2026
Type: article
Study design: Observational Study
Abstract: 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.
Institutions: Shanghai Jiao Tong University, Ruijin Hospital, University of Bristol, MRC Integrative Epidemiology Unit, State Key Laboratory of Medical Genomics, National Health Commission of the People's Republic of China, Central South University, Third Xiangya Hospital, National Institute for Health and Care Research, NIHR Bristol Biomedical Research Centre, King's College London
Language: English
Subfield: Cellular and Molecular Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $3,810
Funders: Innovative Research Team of High-level Local University in Shanghai, Wellcome Trust, University of Bristol, National Natural Science Foundation of China, Central South University, National Science and Technology Major Project, Medical Research Council, National Key Research and Development Program of China
OpenAlex ID: W7223261789