Abstract The purpose of this study is to examine alcohol consumption as a modifiable risk factor for Alzheimer's disease and related dementias (ADRD). Approximately 40% of risk for dementia has been attributed to modifiable risk factors, with heavy alcohol use in midlife (12+ standard US drinks weekly) added to the list of risk factors by the Lancet Commission in 2020. It is well established that more women have ADRD and men have higher rates of heavy drinking, yet alcohol-related problems occur at lower levels of consumption for women than for men. Moreover, the APOE gene, one of the strongest genetic risk factors for ADRD, begins to increase risk for women who have only one e4 allele but for men increased risk is only seen in those who have two e4 alleles. Prior research has also been mixed as to whether APOE interacts with alcohol consumption to increase risk for ADRD. This exploratory/developmental project will examine the relationships of midlife alcohol use and APOE in over 32,000 male and female twins from the Swedish Twin Registry who have lifetime alcohol consumption data and clinical or registry-based diagnoses of ADRD, plus APOE genotypes in over 8,000 twins, thus making it possible to detect phenotypic relationships as well as additive (i.e. G+E) and interactive (i.e. GxE) genetic and environmental relationships. Specifically, in Aim 1 we will delineate the relationship of mid-life alcohol consumption with late-life ADRD diagnosis and age of onset, paying particular attention to whether these relationships are similar in men and women. We will also explore whether incorporating alcohol consumption levels from earlier and later adulthood adds to our understanding of alcohol consumption as a lifecourse risk factor for ADRD. In Aim 2, we will test the alcohol consumption-APOE risk relationship with ADRD diagnosis and age of onset, again focusing on sex differences in elucidating these relationships. Finally, in Aim 3 we will leverage the genetically informative design of the Swedish Twin Registry to characterize differences in alcohol involvement within ADRD discordant and concordant monozygotic and dizygotic twin pairs of both sexes, thereby better understanding genetic contributions to alcohol-ADRD associations. This exploratory/ developmental research study will have the power to model alcohol risk for ADRD in nuanced ways and broaden our understanding of how and why alcohol may affect ADRD risk. If successful, it will set the stage for us to incorporate alcohol consumption as a risk factor for ADRD in more sophisticated models in future work.

Narrative This project leverages 50 years of data from a longitudinal twin study to explore how alcohol use in midlife relates to risk for Alzheimer’s disease and related dementias (ADRD). We seek to understand differences in these relationships between men and women and in conjunction with the APOE gene, the strongest genetic risk factor for ADRD. Results of this study will contribute to our understanding of the confluence of genetic and environmental factors that increase risk for ADRD and will point to potential mechanisms underlying ADRD risk and protection, which is necessary for designing effective interventions toward reducing the burden of ADRD.