Alzheimer’s Disease (AD) represents a major public health concern, affecting more than 5.7 million Americans and being the fifth leading cause of death among individuals aged 65 and over. Despite recent progress made through the advent of amyloid-beta (AB)-targeting immunotherapies, AD remains incurable, highlighting the urgent need for improved animal models and biomarkers that recapitulate the key processes underlying AD pathogenesis. Non- human primates (NHPs) are prime candidates to fulfill this role, thanks to their phylogenetic proximity, long lifespan, highly differentiated prefrontal cortex, and sophisticated behavioral repertoire, which has greatly contributed to our understanding of cognitive aging. However, the use of this vital animal model is still limited by the lack of tools to investigate synaptic health, neuroinflammation, and AD-like pathology in vivo. Fluid biomarkers are powerful tools in clinical settings, yet the effectiveness of fluid biomarkers in monitoring age-related brain changes in NHPs is almost entirely unknown. We have recently demonstrated the utility of CSF biomarkers in monitoring pathology progression in middle-aged animals that received experimental interventions to induce aspects of AD pathology (Beckman et al., 2019; Beckman et al., 2021), but the dynamics of CSF biomolecules in both healthy and pathological brain aging remain entirely unknown. With support from the parent award, a large biobank of geriatric NHP samples has been established at the CNPRC. We propose, therefore, to biochemically and neuropathologically characterize AD-like pathology and neuroinflammation in this cohort of geriatric macaques and correlate those findings to the levels of CSF and plasma biomarkers. Upon successful completion of this project, we will have new tools to identify candidate NHP subjects for aging- and dementia-focused studies and a method to monitor the occurrence and progression of brain aging and pathology in rhesus macaques across all National Primate Research Centers. We will test the following hypotheses through 3 Specific Aims. Hypothesis 1: We hypothesize that, by employing a large cohort of aged Rhesus macaques of both sexes, we will be able to observe multiple trajectories of AD-like pathology, including distinct patterns of amyloid plaque burden and tau hyperphosphorylation, which may have been too subtle to be detected in previous NHP studies. Hypothesis 2: We hypothesize that AD-like pathology in aged Rhesus macaques will be associated with a unique pattern of neuroinflammatory markers compared to healthy aged subjects. Hypothesis 3: We hypothesize that multiple human core AD and neuroinflammation biomarkers will be altered in the plasma and CSF of aged Rhesus macaques, and these alterations will be correlated with the degree of AD-like pathology in the brain of these animals in an age- and sex-dependent manner.

Aging is the single most important risk factor for Alzheimer’s Disease AD, yet the transition from synaptic and cellular alterations that occur with aging and lead to cognitive decline to the pathology of AD is not well understood. We have now developed rhesus macaque models of AD, but it has become very clear that in order to fully exploit these models we need to have a comprehensive understanding of the nature and extent of AD- like pathology in normal aging with no experimental manipulation to create an AD model. We will employ the NIA-supported geriatric colony at the California national Priumate Research Center to begin to characterize this interface and potential basis for a transition to AD.