Objective To examine the causal relationship between alcohol use and dementia risk across multiple ancestry groups. Design We triangulated evidence from observational and univariable and multivariable Mendelian randomization. Setting and participants Cross-ancestry observational analyses were conducted in two large prospective studies: the US Million Veteran Program and UK Biobank. One- and two-sample univariable and multivariable Mendelian randomization used de novo data from a genome-wide association study in Million Veteran Program plus publicly available data. Main outcome measure All-cause dementia. Results Among 559,559 participants (aged 56-72 years old at baseline) included in observational analyses, 14,540 received developed dementia and 48,034 died during follow-up. Observational associations between alcohol and dementia were U-shaped. Non-, heavy (>40 drinks per week - hazard ratio (HR)1.41; 95% confidence interval [CI], 1.15 to 1.74]) and dependent (1.51[1.42-1.60]) drinkers were at higher dementia risk than light drinkers. In contrast, genetic analyses revealed a monotonically increasing association between alcohol dose and dementia, with no evidence supporting a protective effect of any level of drinking. A two-fold increase in genetically-predicted alcohol use disorder prevalence was associated with a 16% increase in dementia cases (IVW OR=1.16[1.03-1.30]), and a one standard deviation increase in log-transformed drinks per week was associated with a 15% increase (IVW OR=1.15[1.03-1.27]). Conclusions Alcohol consumption has a causal role for dementia. These findings challenge a purported protective effect of moderate drinking. Reducing alcohol use could be an effective dementia prevention strategy.

The authors have declared no competing interest.

This research used data from the Million Veteran Program and was supported by funding from the Department of Veterans Affairs Office of Research and Development, Million Veteran Program Grant #I01CX001849, and the VA Cooperative Studies Program (CSP) study #575B, and MVP025. This publication does not represent the views of the Department of Veterans Affairs or the United States Government. AT is supported by the Wellcome Trust (216462/Z/19/Z). SBu is supported by the Wellcome Trust (225790/Z/22/Z) and the United Kingdom Research and Innovation Medical Research Council (MC_UU_00002/7). This research was supported by the National Institute for Health Research Cambridge Biomedical Research Centre (NIHR203312).

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

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

This research was conducted according to the guidelines of the Declaration of Helsinki and approved by the Department of Veteran Affairs Central IRB (protocol code MVP001, approved in 2010). Written informed consent has been obtained from the participants in accordance with all VA policies and under the authority of the VA Central IRB.UKB received ethical approval from the Research Ethics Committee (reference 11/NW/0382), and all participants provided written informed consent.

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.

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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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Access to UK Biobank data is available following a successful application. Access to Million Veteran Program summary statistics is available through via dbGAP.