Project Summary This supplemental application seeks funding to explore the potential shared neurodegenerative mechanisms between Alzheimer's Disease (AD) and radiation-induced brain injury (RIBI) in aging nonhuman primates (NHP; here rhesus macaques, Macaca mulatta) through a multi-investigator, multidisciplinary collaborative effort involving functional Positron Emission Tomography (PET) neuroimaging, neuropathology, and molecular biomarkers of neuropathology in brain and cerebrospinal fluid. This project will leverage the substantial existing investment of NIH in the NIAID-sponsored Wake Forest Non-Human Primate Radiation Survivor Cohort. This work is within the scope of the original application's goal of "to identify and study relevant patterns of post- irradiation morbidity and mortality in a unique, controlled, well-defined NHP population, by collaborating and sharing data with NIH-funded and other federally-funded investigators". This supplemental application is focused on Alzheimer's Disease and related dementias. The proposed work requires additional funding for (1) PET imaging of NHP brains to quantitatively assess amyloid and tubulin in vivo; (2) gold-standard neuropathology assessments including immunohistochemistry for amyloid beta and phospho-tau proteins; and (3) molecular studies of key biomarkers of neurodegenerative processes in brain tissue and cerebrospinal fluid. For Aim 1 animals will be assessed by neuroimaging in vivo, including age matched subsets with and without prior exposure to total body irradiation. For Aims 2 and 3, we will assess archived brain and CSF samples from control and TBI subjects which have already gone to necropsy and from subjects in Aim 1 which come to necropsy. We hypothesize that there will be both common and divergent mechanisms underlying age- associated AD-like pathology and the neuropathologic injury of RIBI. The proposed work will contribute to our basic understanding of vascular, inflammatory, and degenerative processes in chronic age and radiation- related pathologies of the primate brain. The studies will lead to publications and future grant applications to understand accelerated neurodegeneration in irradiated nonhuman primates and potential relationships within the amyloid/tau/neurodegeneration + vascular (ATN+V) framework of AD.