Development of an Innovative Vervet (Chlorocebus aethiops sabaeus) Model of Early Alzheimer's-like Neuropathology and Symptomatology

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This application is in response to RFA-AG-21-003: New/Unconventional Animal Models of Alzheimer’s Disease (AD). Currently available animal models of AD mostly model the less common early-onset familial AD and have poor predictive value in clinical trials. However, nonhuman primates are useful for studying characteristics of the more clinically relevant late-onset sporadic AD because of their phylogenetic similarity to humans in brain structure and function; complex endocrine, social, and cognitive characteristics; large size favorable for imaging studies and cerebrospinal fluid collection; and sequence homology with humans for both tau and Aβ beta-amyloid (Aβ). Vervets show age-related brain changes similar to humans, including increased Aβ plaque burden, cognitive and motor deficits, increased AD biomarkers in cerebrospinal fluid, paired helical filament tau (PHF-tau) formation, decreased brain volumes, decreased cerebral glucose utilization, and altered cortical transcription profiles. NHPs require further study to understand their apparent resistance to developing extensive neurofibrillary tangles which may provide insight into mechanisms underlying resilience, to characterize central nervous system tau species, and to develop PET tracers for Aβ and other targets associated with AD and dementia .Modifiable risk factors that are potential targets for early intervention in humans include obesity, hypertension, physical activity, impaired glucose tolerance, psychosocial stress, and poor sleep. Vervets respond to stress like humans and may become obese. Age increases their rates of hypertension and impaired glucose tolerance accompanied by decreased Aβ42/Aβ40 in cerebrospinal fluid. Thus, vervets may provide opportunities for translational and mechanistic research highly relevant to late-onset sporadic AD. The premise of the proposed research is that vervets are a promising model of late-onset sporadic AD in which AD-related disease progression could be characterized and altered by early intervention on modifiable risk factors. The overarching goal is to further develop, characterize, and validate the vervet model of neuropathology and cognitive decline, while identifying novel targets for early intervention for AD characteristics. Our Specific Aims are to determine age-related changes in cognitive and physical function, cerebrospinal fluid and imaging biomarkers; identify targets for early intervention by characterizing modifiable risk factors for late-onset sporadic AD; and assess the predictive validity of these risk factors for neuropathology in 30 vervets from our Vervet Research Colony (from 10 to 30 years old) which comprise the Aging Vervet Cohort. Unique resources at Wake Forest that will assure rapid progress toward our goal include our Alzheimer’s Disease Research Center; Aging Vervet Cohort, extensive Biospecimen, Data and Image Repository, unique nonhuman primate imaging capabilities, expertise in nonhuman primate research, and close collaboration with our Claude D. Pepper Older Americans Independence Center.