Project Summary The vast majority of Alzheimer's disease (AD) cases are late-onset and it ss now widely believed that development of late-onset AD is the consequence of accumulated brain damage over many years. This process begins with the generation of abnormal oligomeric proteins (amyloid beta oligomers, A?Os) from misprocessed amyloid precursor protein. A?Os are toxic to synapses, and over time A?O buildup and synaptic damage lead to deposition of amyloid plaques and hyperphosphorylated tau protein causing neurofibrillary tangles and neuronal loss, the hallmarks of AD neuropathology. Despite tremendous resource investment, the translation of this mechanistic understanding of AD pathogenesis into new therapies for AD remains elusive. We propose the development of a nonhuman primate model of early AD pathogenesis based on exogenous administration of A?Os to middle-aged rhesus monkeys. Our extensive preliminary data show that a month of twice-weekly A?O administration causes synapse loss targeted to highly plastic thin dendritic spines, and neuroinflammation, changes that mirror what is thought to occur in the earliest prodromal phase of human AD. This model therefore addresses a key limitation of existing animal models of AD: it is based on the pathogenetic process thought to lead to the vast majority of human late-onset AD cases. Based on the acute effects of A?O administration on synaptic and glial markers in rhesus monkeys, we hypothesize that deficits in cognition and affect mirroring symptoms of AD in humans will develop over time in rhesus monkeys chronically treated with A?Os and relate to synaptic disease observed in postmortem histology. To test our hypothesis, rhesus monkeys treated with A?Os or a scrambled peptide control will complete cognitive and affective tasks sensitive to cortical and subcortical function. Our design provides detailed assessment of the time course of behavioral changes, and we will determine synaptic, neuronal, and glial markers in the brains of these monkeys concurrently with the emergence of behavioral deficits. Behavior will be tested in repeated cycles so that changes over time with increasing cumulative dose of A?Os can be determined. These experiments will provide a multi-faceted behavioral characterization of how synaptic dysfunction caused by A?O treatment impacts cognitive and affective behaviors dependent on multiple cortical and subcortical structures, and will let us develop A?O administration in rhesus monkeys as a model for testing interventions that may derail the progression of pathological cascades before full-blown AD develops, providing a new setting for developing treatments for an urgent public health problem.