Project Summary/Abstract Cognitive decline and neurodegenerative diseases including Alzheimer’s dementia greatly impact the health and quality of life of older adults, as well as their families and support systems. Prior research has identified environmental and genetic risk factors for pathological cognitive decline and described pathophysiologic processes. The Apolipoprotein (ApoE) ε4 allele is well established as the strongest genetic risk factor for Alzheimer’s disease and has also been shown to be associated with dementia, cognitive decline and progressive memory loss. Risk estimates vary widely, suggesting that other factors, potentially including both other genes and environmental exposures, could modify the effect of ApoE on cognitive outcomes. Indeed, there is evidence that genetic penetrance of ApoE variants do vary by engagement in cognitively stimulating activities in adulthood and older ages, physical activity in adulthood and older ages, and education achieved. Most studies that have considered whether socio-environmental conditions modify the effect of genetic polymorphisms on late-life cognitive outcomes have examined individual educational attainment or social and environmental measurements taken later in life as potential effect modifiers. There is less evidence as to whether early-life circumstance might modify genetic effects. This is a striking gap, as there is a substantial body of research exploring the relationship between early life circumstances and late-life health outcomes, including cognition. Further, the primary mechanism by which the ApoE ε4 allele is thought to negatively impact cognitive outcomes is via increased neuropathological burden. There is some evidence that early life cognitive ability is associated with neuropathological burden. However, other environmental measures, such as level of education, have not shown any associations with neuropathology, and instead appear to influence cognitive capacity despite accumulation of AD related neuropathologies, i.e. by creating cognitive reserve. In this study, I plan to explore whether the penetrance of genetic risk for cognitive decline varies by early life environment, operationalized as birth cohort, childhood socioeconomic status, and childhood adversity. Further, I plan to examine whether individual early life factors modify genetic effects on neuropathological damage or on cognitive function given the level of neuropathological damage (i.e. via cognitive reserve).