Background: We aimed to provide clinically translatable insights for drug discovery, repurposing, and vigilance for preventing Alzheimer's disease (AD) by integrating genetic and "real-world" drug use data. Methods: Proteome-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. Results: MR 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. Conclusions: In 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.

Tom R Gaunt declares that he receives funding from Biogen for other research not represented in this manuscript, while other authors declare no conflict of interest.

This study is not a clinical trial.

This work was supported by grants from the National Key Research and Development Program of China (2022YFC2505203, 2022YFC3602400, 2022YFC3602401), National Natural Science Foundation of China (82170437), Central South University Innovation-Driven Research Program (2023CXQD007). JZ is a member of the Innovative Research Team of High-level Local Universities in Shanghai. TRG and ES work at a unit that receives funding from the University of Bristol and the UK Medical Research Council (MC_UU_00011/1, MC_UU_00032/01, MC_UU_00032/03 and MC_UU_00011/4). T.R.G. also holds a Turing Fellowship from the Alan Turing Institute. PH is funded by Wellcome Trust PhD Studentship in Molecular, Genetic and Lifecourse Epidemiology (224979/Z/22/Z). The funding sources were not involved in the study design, the interpretation of data, the writing of the report, and the decision to submit the article for publication.

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

Conventional observational analysis corresponds to UK Biobank Project ID 75283. Data from the UK Biobank are available at https://biobank.ndph.ox.ac.uk/ by application. The included GWASes had obtained the necessary ethical approvals from the relevant committees and written informed consent was obtained from all individuals involved in these studies. The UK Biobank study protocol was approved by the North West Multi-centre Research Ethics Committee (11/NW/0382).

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

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I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

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Mendelian randomization and other relevant analyses were based on publicly available data, for example, from publications by Zheng et al. (https://doi.org/10.1038/s41588-020-0682-6), Bellenguez et al. (https://doi.org/10.1038/s41588-022-01024-z), Schwartzentruber et al. (https://doi.org/10.1038/s41588-020-00776-w), Wightman et al. (https://doi.org/10.1038/s41588-021-00921-z), Kunkle et al. (https://doi.org/10.1038/s41588-019-0358-2), and Gudjonsson et al. (https://doi.org/10.1038/s41467-021-27850-z), as well as data resources such as eQTLGen (https://www.eqtlgen.org/), BrainMeta (https://yanglab.westlake.edu.cn/data/SMR/BrainMeta_v1.tar.gz; https://yanglab.westlake.edu.cn/data/SMR/BrainMeta_cis_sqtl_summary.tar.gz), GTEx (https://www.gtexportal.org/), GoDMC (http://mqtldb.godmc.org.uk/), Brain-mMeta (https://yanglab.westlake.edu.cn/data/SMR/Brain-mMeta.tar.gz), and IEU OpenGWAS Project (http://gwas.mrcieu.ac.uk/). Conventional observational analysis corresponds to UK Biobank Project ID 75283. Data from the UK Biobank are available at https://biobank.ndph.ox.ac.uk/ by application. The included GWASes had obtained the necessary ethical approvals from the relevant committees and written informed consent was obtained from all individuals involved in these studies. The UK Biobank study protocol was approved by the North West Multi-centre Research Ethics Committee (11/NW/0382).