1 PROJECT SUMMARY 2 Alzheimer's disease (AD) is the most common form of dementia worldwide, incurring a projected healthcare 3 burden of $1 trillion in the United States alone by 2060. It is the 7th leading cause of mortality in the United States 4 and it disproportionately impacts minoritized racial and ethnic groups. Although many pharmacologic 5 therapeutics have been tested to slow or remove the hallmark amyloid and tau aggregates, none have proved 6 effective at reversing AD cognitive decline. Thus, there remains urgency to identify factors that contribute to 7 dementia risk and novel approaches to intervene. With known correlations to conditions that include gut microbial 8 dysbiosis and exposure to sociocontextual factors that increase dementia risk, such as neighborhood 9 disadvantage, AD may be preventable or treatable at several points of individual- and community-level 10 intervention. However, the exact mechanisms by which these factors can contribute to AD are unknown. Our 11 group was first to identify gut microbiome alterations in AD, and subsequent studies in humans and mouse 12 models have correlated AD pathology with microbial components and associated increases in peripheral and 13 central inflammation. Exposure to neighborhood disadvantage is similarly related to both AD pathology/cognitive 14 decline and to inflammatory profiles. In fact, examining health outcomes linked to the gut microbiome and 15 neighborhood disadvantage more broadly reveals shared alterations in inflammation, methylation profiles, and 16 risk for cardiovascular disease. These are all comorbid risk factors for AD, begging the question as to the role of 17 neighborhood environment in altering gut microbiota composition and subsequently exacerbating AD pathology. 18 Studies of geography and household social relationships show an effect on macro- and micro-environment on 19 microbial composition, however it remains unclear whether this impact extends to mid-level neighborhood 20 environment. Thus, the proposed research rests on the central hypothesis that exposure to neighborhood 21 disadvantage is linked to a proinflammatory microbiota, thereby disrupting the intestinal barrier and aggravating 22 AD pathology. Work leading to this F99 proposal (Aims 1A, 1B) addressed metabolic and gut barrier mechanisms 23 of microbiota impact on AD. To test neighborhood effects, the proposed project features human cohort studies 24 to address the following F99 aim: 1C. Test the extent to which gut microbiome composition mediates the 25 relationship between exposure to neighborhood level disadvantage and AD pathology. In proceeding to a 26 postdoctoral fellowship, the proposed K00 research program will feature training to studying timing, exposure 27 and mechanistic effects of neighborhood disadvantage on AD pathology. The completed research is expected 28 to elucidate combined mechanistic effects of neighborhood disadvantage on AD, informing therapeutic and policy 29 interventions and developing the applicant’s training toward career goals of conducting translational 30 neuroscience research at a major academic medical center.