Project Summary Alzheimer’s disease (AD) is a major health concern defined by pathologic changes in the brain that produce altered behavior and cognitive function. There is a need for primate models of AD because they naturally recapitulate some neuropathological features of AD with advanced age whereas other model organisms (i.e., rodents) do not. For instance, while amyloid-beta (Aβ) deposition occurs in a few mammals, tau-positive neurofibrillary tangles have only been identified in a very limited nonhuman species studied to date. Additionally, elderly nonhuman primates, develop cerebral amyloid angiopathy (CAA), a neurovascular condition found in almost 100% of AD patients and associated with cognitive decline. Here, we are proposing to further develop squirrel monkeys as a model species for current and future studies on the biology of aging and AD research. In the R21 component, we propose to train a cohort of group living squirrel monkeys on the use of an automated cognitive testing system (ACTS) that is designed to assess a variety of cognitive functions including learning, memory and executive control. Creating large cohorts of squirrel monkeys trained on the ACTS system will provide animals with established cognitive phenotypes for use in preclinical studies and allow for examining of their association with potential age-related differences in neuroanatomical, neuropathological and biomarker data. In the R33 component of the proposed studies, we will test for associations between age-related changes in cognition and measures of blood/CSF biomarkers, neural organization and integrity and neuropathology. Additionally, we will test for the effect of ACTS training on aged related changes in neuroanatomy, neuropathology and AD-related biomarkers. Specifically, during Years 3 to 5, we will obtain magnetic resonance images (MRI) and biological samples from 40 elderly and geriatric monkeys trained on the ACTS system. With this cohort, 20 monkeys will receive continued cognitive training (ACTS+) during year 3 to 5 while the remaining 20 individuals will not receive training on any new cognition asks (ACTS-). In a subset of ACTS+ and ACTS- monkeys, we will obtain postmortem measures of neuropathology. In one set of analyses within the ACTS cohort, we will test for longitudinal changes in cognition and their association with variation in (1) neural organization and integrity quantified form MRI scans and (2) several key biomarkers of AD-related neuropathology. Additionally, to examine whether cognitive stimulation slows down the normal brain aging process, we will compare age-related changes in cognition and the brain between the ACTS+ and ACTS- monkeys. The proposed studies, in their entirety, will fill an important gap in our knowledge about the comparative biology of aging and disease in squirrel monkeys and provide critical translational insight into how those processes contribute to the progression of CAA and AD in humans. This information wil...