Alzheimer’s disease affects 5.5 million Americans and leads to progressive memory loss. Currently, there are few treatments to help prevent or slow this disease. Recently, the gut microbiota—essential for maintaining health—has emerged as a potential therapeutic target for AD. As we age, the gut microbiota becomes less stable and can drive disease. We think slowing the aging process in the microbiome could be used to help prevent or treat AD. While it has been shown that the human gut microbiota contributes to other neurologic diseases, no study has proven contribution of the microbiota to AD. In this proposal, we will colonize mice with microbiota from AD patients to determine whether the AD microbiota results in worse disease. We will identify key bacteria and metabolites associated with protection from healthy control patients that may be developed into new therapies for AD. The immune system plays an important role in AD, and specialized cells in the brain called microglia help clear up amyloid beta plaques in early disease but can lead to toxicity in late-stage disease. It recently has been shown that the microbiota can alter microglia immune function. In this proposal, we also will test whether the human AD microbiota alters microglia in an animal model of AD. Altering the microbiota and microglia function could serve as a novel therapeutic modality, in addition to providing unique characterization of an “AD phenotype” in the gut.