ABSTRACT The concept of the “microbiota-gut-brain axis”, which originated from behavioral studies in microbiome- reconstituted mice, has advanced to current research that supports the microbiome may be responsible for some of the most devastating neurodegenerative disorders, including Alzheimer's Disease (AD). Recent studies have interrogated this connection among the intestinal microbiome and identified significant changes in the abundance of certain taxa in AD patients. Thus, one current theory is that AD pathogenesis is closely related to the imbalance of the gut microbiome and may originate in the gut. Our group has recently published findings among a cohort of nursing home elders demonstrating a dysbiotic pattern in AD elders that is hallmarked by a reduction in the prevalence of bacteria with anti-inflammatory properties, as well as an acquisition of taxa that are known to cause pro-inflammatory states. In this proposal we will: 1) leverage our current nursing home experience to enroll elders assessing cognitive decline; 2) advance our work within the local Senior Centers' elder groups to enroll a comparative community-dwelling cohort; 3) determine both microbiota taxonomy and gene function among these elders; 4) utilize stool samples to determine how the microbiome can induced intestinal inflammation and how this correlates back to observed systemic inflammation; and 5) study the microbiome metabolic product differences and explain how these products can influence microglia functioning. We hypothesize that there is a characteristic dysbiotic microbiome among AD elders, regardless of living environment, and that the level of inflammation-type dysbiosis positively correlates with both local and systemic inflammation and eventually cognitive decline. We further hypothesize that the AD microbiome metabolites negatively impact microglial functioning. Specifically, in Aim 1 we will assess characteristics of the AD elder's microbiome from different environments in comparison to elders without dementia and longitudinally assess the microbiome composition and correlate it to changes in cognition. In Aim 2 we will determine the extent of microbiome dysbiosis among AD elders, correlate this with the level of induce (in vivo/vitro) epithelial dysfunction, and then back to elder cytokine markers of inflammation and T cell population markers of immunosenescence. Finally, in Aim 3 we will perform metabolomics to identify metabolite profile differences between AD elders and those without dementia and use the identified metabolites in our in vivo/vitro assays to describe its effects on microglial functioning. This work takes a critical step forward to bridge microbiome associations with AD to causality by showing how the AD elder's microbiome dysbiosis observed can adversely affect intestinal epithelial homeostasis leading to systemic inflammation, inflammation-causing immunosenescence, and ultimately cognitive dysfunction. It will also describe the microbial metabolic product differences and how these metabolites influence microglial functioning. Understanding how this crucial “microbiota-gut-brain axis” impacts AD development and progression will provide novel therapeutic targets and enable future trials aimed at intervening upon these pathways.

PROJECT NARRATIVE Alzheimer's disease (AD) is the most frequent causes of dementia of which there is no cure and treatment options are limited. Recently the human gut microbiome, the community of microorganisms that live within our intestines, has been connected to several neurodegenerative disorders, however this research among AD elders has been limited. Accordingly, our goal is to compare the microbiome of elders with AD to those without dementia, living in different settings, to determine the role the microbiome plays in cognitive decline while studying local and systemic immune function and brain cellular activity. Understanding how the intestinal microbiome impacts AD development and progression will provide novel therapeutic targets and enable future trials aimed at improving the memory of patients with AD.