Linking alcohol use to Alzheimer's disease: Interactions with aging and APOE along immune pathways

Although it is known that APOE genotype is the strongest genetic risk factor for late-onset Alzheimer's disease, development is a multifactorial process. Alcohol use is a contributor to the epidemic of Alzheimer's disease and related dementias in the US and globally, yet mechanisms are not fully understood. Carriers of the APOE ε4 allele show elevated risk of dementia in relation to several lifestyle factors, including alcohol use. In this review, we describe how alcohol interacts with APOE genotype and aging with potential implications for Alzheimer's disease promotion. Age-related immune senescence and "inflammaging" (i.e., low-grade inflammation associated with aging) are increasingly recognized as contributors to age-related disease. We focus on three immune pathways that are likely contributors to Alzheimer's disease development, centering on alcohol and APOE genotype interactions, specifically: 1) microbial translocation and immune activation, 2) the senescence associated secretory phenotype, and 3) neuroinflammation. First, microbial translocation, the unphysiological movement of gut products into systemic circulation, elicits a proinflammatory response and increases with aging, with proposed links to Alzheimer's disease. Second, the senescence associated secretory phenotype is a set of intercellular signaling factors, e.g., proinflammatory cytokines and chemokines, growth regulators, and proteases, that drives cellular aging when senescent cells remain metabolically active. The senescence associated secretory phenotype can drive development of aging-diseases such as Alzheimer's disease. Third, neuroinflammation occurs via numerous mechanisms such as microglial activation and is gaining recognition as an etiological factor in the development of Alzheimer's disease. This review focuses on interactions of alcohol with APOE genotype and aging along these three pathways that may promote Alzheimer's disease. Further research on these processes may inform development of strategies to prevent onset and progression of Alzheimer's disease and to delay associated cognitive decline.