Given the significant gap between preclinical success and clinical failure and the stagnant development of effective novel therapies for age-related cognitive decline and dementias, it is essential to develop more relevant preclinical models. Our overarching goal is to establish the baboon as a relevant model of age- related cognitive impairment by validating behavioral, cognitive, and neuroanatomical features affected in aged baboons and identifying the appropriate miRNA biomarkers that may be causal of the age-related structural and functional changes. The Southwest National Primate Research Center (SNPRC) has a pedigreed colony of 1,400 well-phenotyped, genetically characterized baboons at all ages for the study of cognitive and behavioral traits and this project will further enhance these resources. With the data we already generated, we propose to complete this project in 1 year. Nonhuman primates (NHP) are phylogenetically close to humans and share many similarities including age-related decline in neural and immune functions; thus, complex human-like behavioral endpoints may be measured in NHPs. Baboons have larger brains, high degree of gyrification and the primary cortical structures found in humans making them well suited for aging translational and neuroimaging studies. The goal of this proposal is to expand on our findings in using baboons as a preclinical model for age-related cognitive decline. Our preliminary data using Cambridge Neuropsychological Test Automated Battery (CANTAB) demonstrated significant age- related impairment in movement planning, learning novel tasks, simple discrimination tasks and level of motivation in aged baboons compared to adults. These results suggest that baboons may offer a model of age-related cognitive decline and dementias. We have submitted a manuscript describing these data. In this supplement to P51 we propose to expand on these data to provide evidence for the utility of baboons as a preclinical model for age-related cognitive impairment. To achieve this, the following Specific Aims will be addressed: 1) Segregation of baboons based on cognitive impairment using CANTAB neuropsychological test on adult baboons 13±3 year old versus aged baboons 20±3 year old; 2) Identify variation in brain structure between adult baboons and aged baboons using structural magnetic resonance imaging (MRI); 3) Identify relevant biomarker signature of miRNA expression in peripheral blood cells and in exosomes derived from plasma and cerebrospinal fluid (CSF). By linking peripheral miRNA biomarkers to cognitive behavioral deficits and structural brain variations, a more complete understanding of the biology of aging can be achieved providing a strong rationale to use baboons as a preclinical model for age-related cognitive decline. This model may expedite translational research and enhance animal resources while supporting the mission of the Regenerative Medicine and Aging Scientific Unit within the SNPRC P51 grant.