Project Summary Alzheimer's disease (AD) is a major health concern defined by pathologic changes in the brain that coincide with altered behavior and cognitive function. Animal models have advanced our understanding of AD, but these models artificially induce neuropathy to simulate the human disease. For instance, while amyloid- beta (Aβ) deposition occurs in most mammals, tau-positive neurofibrillary tangles (NFT) have only been identified in a few nonhuman species studied to date. Our research team recently discovered that chimpanzees, one of our closest genetic relatives, naturally develop both Aβ plaques and NFT, the pathological hallmarks of AD. In addition to AD pathology, elderly chimpanzees also develop cerebral amyloid angiopathy (CAA), a neurovascular condition found in 80% of AD patients associated with cognitive decline. Therefore, additional studies in chimpanzees could shed new light on the etiology of AD and CAA, leading to potentially new directions for therapeutic interventions. The overall goals of the proposed studies are to further examine the pathologic, epigenetic, and cognitive characteristics of aging, CAA, and AD in chimpanzees. In Aim 1, we will perform comprehensive pathologic analyses aimed at quantifying biomarkers of CAA and AD, including Aβ40 and Aβ42 plaque and vessel volumes, NFT density, pericyte and smooth muscle cell vessel volumes, neuron and synapse densities, and mitochondrial dysfunction. The collective neuropathologic measures will be examined in a sample of chimpanzees for which antemortem cognitive data is available, and the main focus will be determining which pathologic markers best predict individual variation in cognition. Moreover, we will test the correlation of AD and CAA pathologies with inflammatory processes, such as microglial activation and astrogliosis. In Aim 2, we will quantify epigenetic age in the chimpanzee population and evaluate whether chimpanzees with CAA or AD lesions demonstrate accelerated epigenetic aging in the brain relative to apes without pathology. We also will determine if epigenetic age is a better predictor than chronological age of changes in cognition, region-specific gray matter volume, and white matter integrity and connectivity. Finally, though previous studies have found cross-sectional age differences in cognition in chimpanzees, we will determine whether chimpanzees show longitudinal changes in cognition and whether any age-related loss in performance predicts the subsequent expression of AD pathology in this proposal. All biomaterials and cognitive data obtained in the proposed studies will be added to the National Chimpanzee Brain Resource and made publicly available to the scientific community through a web portal. The proposed studies, in their entirety, will fill an important gap in our knowledge about the comparative biology of aging and disease in chimpanzees and may provide critical translational insight into how those processes contribute to the progression of CAA and AD in humans. This information will provide crucial direction for future translational studies using rodent and nonhuman primate models.

Projective Narrative Alzheimer's disease (AD) and related forms of dementia are a major public health concern. The goal of the proposed studies is to examine the mechanism and consequences of AD pathology in chimpanzees, the only other living species that naturally develops this disease. Identifying similarities and differences between human and chimpanzee AD may provide important information on the factors that contribute to the profound loss in cognitive functions in human AD.