PROJECT SUMMARY Alzheimer’s disease is a progressive neurodegenerative disorder characterized by the accumulation of beta- amyloid (Aβ) plaques and neurofibrillary tau tangles. While Aβ is an important Alzheimer’s disease risk factor, tau is more closely tied to cognitive outcomes. Tau pathology accumulates locally and spreads through specific brain circuits, initially aggregating within the hippocampal (HC)-entorhinal cortex (EC) circuit and impairing episodic memory. New data, including our own, indicate that the basal forebrain (BF) and amygdala (AMY), regions supporting emotional memory processing, are also early sites of tau deposition. Whether tau deposition within these circuits contributes to distinct impairments in emotional and non-emotional memory function is unknown. HC-EC and BF-AMY circuits exhibit different brain network dynamics, express discrete facets of non- rapid eye movement (NREM) and REM sleep oscillatory activity, and support distinct aspects of sleep-dependent memory consolidation (SDMC). It is possible that tau deposition within these circuits results in deficits in sleep expression as well as dynamic network architecture important for SDMC. To address these critical knowledge gaps, we will use an innovative multimodal neuroimaging design combining high-resolution positron emission tomography with a novel [18F]MK-6240 tau tracer, polysomnography with high-density electroencephalography, and high-resolution resting-state functional magnetic resonance imaging combined with a memory task taxing HC-AMY function. Using these methods, we will test the novel hypothesis that local tau deposition within these circuits is associated with distinct deficits in sleep expression, dynamic resting state network architecture, and SDMC in cognitively unimpaired Aβ+ older adults. In Aim 1, we will test two hypotheses: (1) HC-EC tau will be associated with deficits in NREM slow wave-spindle coupling, which will be associated with impaired overnight memory retention across valence. (2) BF-AMY tau will be associated with reduced REM theta, which will be associated with impaired overnight retention of emotional memories. In Aim 2, will test three hypotheses. (1) HC- EC and BF-AMY tau will be associated with decreased network modularity, which will be associated with impaired SDMC. (2) HC-EC tau will be associated with reduced HC-EC flexibility, which will be associated with diminished sleep-dependent consolidation of non-emotional memories. (3) BF-AMY tau will be associated with lower BF-AMY flexibility, which will be associated with diminished emotional memory consolidation. We will also use mediation models to test if regional tau pathology impacts memory consolidation through these hypothesized mechanisms. Findings from the proposed study will provide novel insight into the mechanisms contributing to distinct deficits in SDMC in older adults at risk for Alzheimer’s disease, potentially guiding prospective intervention studies to minimize co...