Project Summary Alzheimer's disease (AD) is the most common neurodegenerative disease causing dementia in the elderly. Vervets/African green monkeys are an excellent nonhuman primate model to study the various pathological changes associated with progression of AD. Like humans, AD-related brain changes in vervets occurs on a systemic background of aging that includes insulin resistance, physical inactivity and dysfunction, and type 2 diabetes. It is the ineffectual modeling of this systemic aging in humans that is a primary obstacle to the development of effective AD therapies, yielding poor translation of therapeutic efficacy from preclinical models of AD to human disease. Vervets provide the unique opportunity to address this limitation in AD drug discovery. The purpose of this new supplement is to develop vervets as a NHP AD model for preclinical testing of therapeutic compounds. To achieve this goal, we will conduct pilot testing of a novel anti-aging compound, SPL-850. SPL-850 targets the S-nitrosylation pathway. Like phosphorylation, nitrosylation is a critical determinant of protein biology. Unlike phosphorylation, 90% of S-nitrosylation is regulated by a single enzyme – S-nitrosoglutathione reductase (GSNOR). SPL-850 is an inhibitor of GSNOR (GSNORi) that serves to increase systemic, circulating levels of S-nitrosoglutathione (GSNO). Our published and preliminary studies indicate that restoration of GSNO homeostasis via GSNORi reverses dysfunction of numerous systems, including those associated with aging and AD. Here, we will test the central hypothesis that GSNORi will provide reliable and measurable improvement in systemic and CNS risk factors for AD in aging vervets. To test this hypothesis, we will identify 8 middle- to late-age female vervets with and without age-related diabetes and treat both groups with SPL-850 (16 mg/day) for 90 days via vascular access. In a repeated measures paradigm, we will test the working hypotheses that GSNORi will: 1) improve age-related risk factors for AD pathology (Aim 1) and 2) reduce age-related oxidative stress and inflammatory signaling (Aim 2). In Aim 1, we will perform PET imaging with amyloid-β-[11C]PiB radiotracer and co-register with structural MRI and additional MRI measures of AD-related brain pathology. We will collect CSF, blood and plasma samples for measurement of AD-related biomarkers, as well as overall cardiovascular and metabolic health. In Aim 2, we will measure indicators of both oxidative stress and inflammatory signaling, using multi-plex ELISA in both plasma and CSF samples. To evaluate potential interdependence, oxidative stress and inflammatory signaling signatures will be co-registered with outcomes from Aim 1, using regression analysis. Successful completion of the proposed aims will validate vervets as a preclinical testing model for AD therapeutics, while also providing pilot data on the efficacy of GSNORi as an anti-aging therapeutic.