PROJECT SUMMARY / ABSTRACT Alzheimer's disease (AD) is a progressive neurodegenerative disease. While pathogenetic mechanisms are unresolved, neuroinflammation appears to play a contributory or possibly even a causative role. A recently published study has described an expansion of terminally differentiated effector T cells in the peripheral blood of Alzheimer's patients, reminiscent of findings in individuals with chronic infection or autoimmune disease. Moreover, oligoclonal T cell population were found in the brain of AD patients, including T cells specific for EBV antigens. Based on our current studies of ex vivo tetramer-sorted cells specific for a variety of viral antigens, we propose here that chromatin accessibility mapping of such antigen-specific T cells is an excellent tool to determine whether they have a distinct activation or differentiation history compared to non-AD amyloid-negative individuals. Specifically, we will compare chromatin accessible sites in T cells specific for EBV latent and lytic antigens with varicella zoster virus and influenza antigens as controls. Detection of a unique pattern of chromatin accessibility would strongly support the notion that these T cells are actively involved in the disease process. Moreover, identification of such sites would allow us to infer transcription factor networks that regulate the differentiation of these T cells. In a second step, we plan to compare AD patients to non-AD amyloid-positive individuals to determine whether the T cell response is already present in the early stages of the disease. Conversely, a negative result would strongly imply that the reported expansion of and brain infiltration with oligoclonal T cell populations specific to EBV in Alzheimer's patients is non-specific.