Anya Topiwala, Daniel F. Levey, Hang Zhou, Joseph D. Deak, Keyrun Adhikari, Klaus P. Ebmeier, Steven Bell, Stephen Burgess, Thomas E. Nichols, VA Million Veteran Program, J. Michael Gaziano, Murray B Stein, Joel Gelernter

To investigate the relationship between alcohol consumption and dementia. Prospective cohort and case-control analyses combined with linear and non-linear Mendelian randomisation. Two large-scale population-based cohorts: the US Million Veteran Programme and the UK Biobank. Genetic analyses used summary statistics from genome-wide association studies (GWAS). 559 559 adults aged 56-72 years at baseline were included in observational analyses (mean follow-up: 4 years in the US cohort; 12 years in the UK cohort). Genetic analyses used summary data from multiple large GWAS consortia (2.4 million participants). Incident all-cause dementia, determined through health record linkage, and genetic proxies. During follow-up, 14 540 participants developed dementia and 48 034 died. Observational phenotype-only analyses revealed U-shaped associations between alcohol and dementia risk: higher risk was observed among non-drinkers, heavy drinkers (>40 drinks per week; HR 1.41, 95% CI 1.15 to 1.74), and those with alcohol use disorder (AUD) (HR 1.51, 95% CI 1.42 to 1.60) compared with light drinkers. In contrast, Mendelian randomisation genetic analysis identified a monotonic increase in dementia risk with greater alcohol consumption. A 1 SD increase in log-transformed drinks per week was associated with a 15% dementia increase (inverse-variance weighted (IVW) OR 1.15, 95% CI 1.03 to 1.27). A twofold increase in AUD prevalence was associated with a 16% increase in dementia risk (IVW OR 1.16, 95% CI 1.03 to 1.30). Alcohol intake increased dementia, but individuals who developed dementia also experienced a decline in alcohol intake over time, suggesting reverse causation-where early cognitive decline leads to reduced alcohol consumption-underlies the supposed protective alcohol effects in observational studies. These findings provide evidence for a relationship between all types of alcohol use and increased dementia risk. While correlational observational data suggested a protective effect of light drinking, this could be in part attributable to reduced drinking seen in early dementia; genetic analyses did not support any protective effect, suggesting that any level of alcohol consumption may contribute to dementia risk. Public health strategies that reduce the prevalence of alcohol use disorder could potentially lower the incidence of dementia by up to 16%.