¹University of Oxford, Nuffield Department of Population Health, Oxford, United Kingdom

Background: The impact of alcohol use on brain health including dementia remains contentious. Methodological limitations of previous studies have made distinguishing causation from confounding difficult. Genetic analyses has the potential to improve causal inference.

Aims & Objectives: To examine the role of alcohol on brain structure, cognitive decline and dementia.

Method: Relationships between alcohol and brain health were examined using advanced neuroimaging techniques and genetics in large population cohorts in the UK (Whitehall II, UK Biobank) and USA (Million Veteran Program). Observational and genetic analyses were triangulated to improve causal inference.

Results: Even small amounts of alcohol intake associate with neuroimaging markers of adverse brain health, including hippocampal volume (a biomarker of Alzheimer's disease) and elevated brain iron markers, as well as accelerated cognitive decline. Observational associations between alcohol and dementia were U-shaped, with 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 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]).

Discussion & Conclusions: Alcohol consumption, even at moderate levels, appears to have a causal role for dementia. Halving the population prevalence of alcohol use disorder would lead to a 16% reduction in dementia cases.