Alzheimer’s disease (AD) remains the most common form of dementia, affecting 50 million people worldwide. Recent studies from our laboratory established a clear role for the gut microbiome in the pathology of AD. These studies also suggested rampant neuroinflammation in the AD brain, triggered by imbalances in gut-microbiome diversity. However, the exact mechanism through which the gut microbiome exerts its effect on the AD brain remains unknown. Our lack of knowledge in this area can be attributed partly to the absence of quantifiable brain imaging data from microbiome-perturbed animal models of AD. In this proposal, we intend to image brains of normal and AD mice treated with antibiotics using noninvasive Positron Emission Tomography (PET) to study the effects of the gut microbiome on neuroinflammation in AD. We will perform serial PET imaging using brain permeable radiotracers to monitor the amount and location of neuroinflammation and amyloid beta deposition in age- and sex-matched mouse models. Using this imaging strategy, we also will quantify the direct effects of gut-microbial metabolites (e.g., short-chain fatty acids (SCFA)) and fecal microbiome transplantation (FMT) on the progression of AD. The proposed PET imaging study is anticipated to provide new insights into the molecular mechanisms of gut-brain communication that may lead to the development of new therapeutic approaches for treating AD.