PROJECT SUMMARY/ABSTRACT Alzheimer disease (AD) is the most common form of age-related cognitive failure in humans. Progressive accumulation of b-amyloid (Ab) and neuroinflammation of certain parts of the brain are dominant pathological features of AD 1. Aging represents the greatest risk for development of AD. As like in the brain, aging in humans is associated with many changes in the peripheral adaptive immunity. Most of the genetic association in AD points to genes involved in innate inflammation and microglial cell activation, adaptive immunity and its role in cognitive decline and AD is almost ignored. However, the presence of Ab specific T cells has been noted in AD patients and shown to increase with age. Recently, by employing unbiased approaches we explored the role of T cells in multiple cohorts of AD patients as well as age and sex matched healthy controls. Our study showed that there is increased frequency of effector memory CD8 T cells in the peripheral blood and cerebrospinal fluid of AD patients with enhanced proinflammatory potential. In addition, we found that these CD8 effector T cells were negatively correlated with cognition. Further, T cell receptor (TCR) sequencing in the peripheral blood and cerebrospinal fluid showed increased clonal expansion. Our study also associated a T cell immune signature with higher clonal expansion in AD. However, whether these T cells are beneficial or detrimental in AD, whether these clonal T cells respond specifically to Ab, and what their actual TCR repertoire and phenotypes are in AD remain unknown. Therefore, additional studies are required to gain insight into the role of CD4 and CD8 T cell reactivity to Ab in AD. With increasing evidence for T cell effects in AD, our central hypothesis is that the dysregulated amyloid specific T cell responses contribute to AD pathogenesis. We will address this hypothesis by determining 1) the Ab specific T cell responses in healthy controls and AD patients and 2) the Ab specific T cell receptor (TCR) repertoire in healthy controls and AD patients. The proposed studies will lay the groundwork to enhance our understanding of Ab mediated T cell response and unique cellular and molecular programming pathways. Further, testing intrinsic CD4 and CD8 T cell activity in AD patients to Ab before offering Ab-based immunotherapy based in AD will help stratify patients and have major implications for future Ab-directed therapies.