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Objective: Heavy alcohol consumption is associated with poorer cognitive function in older adults. Although understudied in middle-aged adults, the relationship between alcohol and cognition may also be influenced by genetics such as the apolipoprotein (ApoE) ε4 allele, a risk factor for Alzheimer's disease. We examined the relationship between alcohol consumption, ApoE genotype, and cognition in middle-aged adults and hypothesized that light and/or moderate drinkers (≤2 drinks per day) would show better cognitive performance than heavy drinkers or non-drinkers. Additionally, we hypothesized that the association between alcohol use and cognitive function would differ by ApoE genotype (ε4+ vs. ε4−). Method: Participants were 1266 men from the Vietnam Era Twin Study of Aging (VETSA; M age = 56; range 51–60) who completed a neuropsychological battery assessing seven cognitive abilities: general cognitive ability (GCA), episodic memory, processing speed, executive function, abstract reasoning, verbal fluency, and visuospatial ability. Alcohol consumption was categorized into five groups: never, former, light, moderate, and heavy. Results: In fully adjusted models, there was no significant main effect of alcohol consumption on cognitive functions. However, there was a significant interaction between alcohol consumption and ApoE ε4 status for GCA and episodic memory, such that the relationship of alcohol consumption and cognition was stronger in ε4 carriers. The ε4+ heavy drinking subgroup had the poorest GCA and episodic memory. Conclusions: Presence of the ε4 allele may increase vulnerability to the deleterious effects of heavy alcohol consumption. Beneficial effects of light or moderate alcohol consumption were not observed. [ABSTRACT FROM AUTHOR]