PROJECT SUMMARY/ABSTRACT Aging is the greatest known risk factor for neurodegenerative disease development, such as Alzheimer’s disease (AD). However, we lack an understanding of how aging predisposes the brain to these consequences. Neuroinflammation is believed to play a prominent role in the early pathogenesis of AD. Microglia, the resident macrophages of the central nervous system, are suspected to be key components of these changes as the brain’s primary immune defense and principal players in neuroinflammation. The further development of non- human primate models for AD and related dementias offers the opportunity to bridge the gap between knowledge gained from rodent models and clinical testing in the elderly human population and to focus on key mechanistic drivers such as microglia. While the common marmoset has proven to be a valuable resource and model for translational aging studies, it is imperative we identify and evaluate early biomarkers of AD-like pathology in this model. In this pilot project we will investigate whether neuroinflammation (microglial activation) and blood analytes of inflammation are associated with age-related cognitive change in the common marmoset. This application will build upon our previous research which has indicated that approximately 15-20% of aged animals display marked cognitive decline, to test two hypotheses: (a) cognitive decline is associated with elevated microglial activation in the hippocampus and prefrontal cortex, and (b) cognitive decline is associated with elevated biomarkers associated with neuroinflammation and AD. In Aim 1, we will test the hypothesis that cognitive decline is associated with elevated microglial activation in the prefrontal cortex and hippocampus. PET imaging with 18F-DPA-714 (a second-generation radiotracer of the translocator protein 18kDA, TSPO) will be used to image microglial activation. In Aim 2, we will test the hypothesis that cognitive decline is associated with elevated peripheral biomarkers associated with inflammation and aging, including glial fibrillary acidic protein (GFAP), soluble urokinase plasminogen activator receptor (suPAR), and inflammatory cytokines. The development of these resources will further the marmoset as a model of early AD and associated dementias.