PROJECT SUMMARY/ABSTRACT Alzheimer’s disease is a progressive and invariably fatal neurodegenerative disease resulting in loss of cognitive and bodily function, and no cure or effective treatment currently exists. While several pathological processes have been implicated in Alzheimer’s disease, including protein aggregation, inflammation, decreased blood flow, and metabolic defects, the exact mechanism of neuronal death and how the disease spreads from one region of the brain to another is unknown. The goal of this research project is to test whether molecular and cellular dysfunction can be transmitted from cell to cell along their pathways of communication in the brain. To achieve this goal, we will first map the functional connectivity between regions of brain in a mouse model of Alzheimer’s disease using resting-state functional magnetic resonance imaging, observe how these connections change over the progression of the disease, and link these functional changes to behavioral phenotypes in animals. We will then profile levels of inflammatory cytokines and metabolites in tissue from several brain regions in these same mice, and observe whether changes in immunometabolic state coincide in time and space with the functional connections measured by MRI. Successful completion of this work will test a potential mechanism of Alzheimer’s disease spreading through the brain, and provide a map of coupling between immune, metabolic, and functional pathology that could open new directions for future development of early disease diagnostics and therapeutic strategies.