PROJECT SUMMARY/ABSTRACT Despite decades of research, the etiology underlying the development of Alzheimer’s disease (AD) remains unknown, and there are currently no preventative or disease-modifying treatments available. Accumulating evidence suggests microbes, including those derived from the gut, may play a role in development or progression of AD pathology. Humans harbor complex communities of microbes, with the vast majority of the microbial population residing in the distal gut. Gut microbes perform essential functions for human health, and recent studies point toward the importance of gut microbiota in brain development, function, and disease. Alterations in the gut microbiome have been associated with several neurological conditions including autism spectrum disorder, multiple sclerosis, and Parkinson’s disease. With respect to AD, the applicant’s preliminary studies have revealed broad scale gut microbiome alterations in human subjects with AD and demonstrated associations between differentially abundant bacterial taxa and cerebrospinal fluid (CSF) biomarkers of AD pathology. This project seeks to further determine the extent to which gut microbes influence the development or progression of AD pathology in humans. Specifically, the project will use bacterial 16S rRNA gene sequencing of DNA isolated from fecal samples to characterize the gut microbiome of human subjects in order to determine the cross- sectional relationship between gut microbiota composition and neuroimaging markers, including regional AD pathology as measured by in vivo amyloid and tau positron emission tomography (PET) imaging, regional brain volume as measured by T1-weighted magnetic resonance imaging (MRI), and neural microstructure as measured by neurite orientation dispersion and density imaging (NODDI). Furthermore, this project will assess the longitudinal relationship between gut microbiota composition and development and progression of AD pathology as indexed by longitudinal CSF AD biomarkers (Aβ42 and phosphorylated tau), amyloid PET imaging, and neuroinflammatory CSF biomarkers. This project will study both cognitively-healthy participants as well as participants with dementia due to AD, which will allow determination of how the gut microbiota impact the entire continuum of AD pathology, from the earliest biomarker changes in non-demented middle-aged adults to the extensive neurodegeneration and amyloid deposition in overt AD dementia. Establishing a role for gut microbiota in the pathogenesis of AD, especially early in the disease process, may lead to novel interventions aimed at restoring or augmenting gut microbiota in order to help prevent or slow this devastating disease.