Project Summary Although cognitive detriments are the hallmark of Alzheimer’s disease (AD), increasing evidence demonstrates that people with AD experience significant changes to their affective lives as well. Neurobiological investigations of AD have focused heavily on understanding pathology in the cognitive hubs of the brain, although some evidence exists points to similar structural, cellular, and synaptic pathology in hubs of the interoceptive-allostatic network that generates and regulates affect. The proposed work will investigate neuropathogenesis in the interoceptive-allostatic network in our highly translatable nonhuman primate model of early AD pathogenesis. AD pathology is thought to begin with the generation of abnormal oligomeric proteins (amyloid beta oligomers, AβOs) from misprocessed amyloid precursor protein. AβOs are toxic to synapses, and over time AβO buildup and synaptic damage are thought to lead to deposition of amyloid plaques and formation of hyperphosphorylated tau protein causing neurofibrillary tangles and neuronal loss, the hallmarks of AD neuropathology. We have demonstrated that exogenous administration of AβOs to middle-aged rhesus monkeys causes synapse loss targeted to highly plastic thin dendritic spines and neuroinflammation in cognitive neural hubs, changes that mirror what is thought to occur in the earliest prodromal phase of human AD. We are currently carrying out a large-scale study which tracks cognitive and affective behavior as AβOs are administered to monkeys over time. The proposed research will build on that existing resource by carrying out detailed neuroimaging and histological analyses of the interoceptive-allostatic network in order to understand how AβOs damage neural hubs that generate and regulate affect. The proposed experiments are innovative because they evaluate early AD-related pathology in the network that generates affect. These experiments will allow us to develop AβO 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.