Project Summary: Alzheimer’s disease (AD) is a growing public health threat that places an immense burden on patients, caregivers, and the economy. Despite a century of research and over 2,000 clinical trials, AD has limited treatment options and no cure. The failure to develop effective therapeutics likely stems from an incomplete understanding of AD etiology—highlighting the crucial need to identify and better understand modifiable disease risk factors. Recent evidence suggests that, in addition to brain pathology, AD patients also display alterations in the gut microbiome that may contribute to disease. Manipulation of the gut microbiome is sufficient to improve or exacerbate AD-like symptoms and pathology in mouse models, suggesting that the microbiome may directly contribute to disease development and progression. The mechanism by which the microbiome impacts disease etiology is currently unknown, however, one possibility is through modulation of inflammatory responses. The gut microbiome has been shown to influence the development and activation states of both peripheral and brain- resident immune cells that are critical for amyloid clearance and neuronal health. However, the contribution of individual AD-associated microbial species to neuroinflammatory and disease outcomes is unknown, and the mechanisms of this gut-to-brain communication have yet to be explored. The present NRSA will address this gap, determining the consequences of, and mechanisms by which, specific AD-associated gut microbes shape neuroinflammatory and disease outcomes. Aim 1 will establish the effects of individual AD-associated gut microbes on microglia functional state and response to stimulation (1.1). Furthermore, it will determine whether these gut-to-brain signals are mediated by specific peripheral immune signals triggered by discrete bacterial molecules (1.2). Aim 2 will concurrently determine the pathophysiological impacts of specific AD-associated bacteria on disease outcomes (2.1) and evaluate whether microglia and specific bacterial inflammogens are necessary for these effects. This innovative, interdisciplinary approach will provide key mechanistic links between gut dysbiosis and AD outcomes. In addition, by identifying both microbe and host-derived cellular pathways that impact disease state, it will identify novel and specific treatment targets for AD.