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
7 affiliations
- 1Bristol Medical School, University of Bristol
- 2Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine
- 3Ruijin Hospital, Shanghai Jiao Tong University School of Medicine
- 4The Third Xiangya Hospital, Central South University
- 5Clinical Trial Institution Office, Liuzhou Hospital of Guangzhou Women and Children's Medical Center
- 6National Institute for Health and Care Research Bristol Biomedical Research Centre
- 7School of Life Course Sciences, King's College London, Guy's Campus
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.
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BibTeX
@article{huang2026plasma,
title = {{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}},
author = {Peiyuan Huang and Haibo Tang and Zeying Feng and Evie Stergiakouli and Tom R. Gaunt and Jie Zheng and Yao Lu},
journal = {Journal of the American Heart Association},
year = {2026},
month = oct,
doi = {10.1161/jaha.124.038766},
url = {https://www.ahajournals.org/doi/10.1161/JAHA.124.038766},
note = {CC BY},
}
RIS
TY - JOUR
TI - 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
AU - Peiyuan Huang
AU - Haibo Tang
AU - Zeying Feng
AU - Evie Stergiakouli
AU - Tom R. Gaunt
AU - Jie Zheng
AU - Yao Lu
PY - 2026
DA - 2026/10/23
JO - Journal of the American Heart Association
DO - 10.1161/jaha.124.038766
UR - https://www.ahajournals.org/doi/10.1161/JAHA.124.038766
AB - 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.
SN - 2047-9980
ER -