Alzheimer’s disease (AD) is a leading public health problem. One of the many physiologic processes affected by AD is the circadian system, with disruption reflected in abnormalities of the sleep-wake cycle. While sleep and circadian rhythm defects are distressing symptoms of AD and other tauopathies, sleep disturbance may be a major risk factor for AD and is also thought to accelerate its pathology. Early in AD, disruption of circadian cycles, including sleep, is thought to contribute to the accumulation of amyloid, and subsequent cognitive decline. Current sleep-promoting treatments for insomnia in AD may have different efficacy and adverse effect profiles. We propose the following Specific Aims: 1) To test if use of sleep medication associates with improved sleep patterns and altered cognitive and cardiac outcomes in patients with high genetic risk of AD. We will leverage the UK Biobank to examine the links between sleep medications, sleep, cognitive function and heart health in people at high genetic risk for AD using prospective associations and novel mendelian randomization techniques designed to test the effects of perturbing drug targets. 2) To test sleep-promoting agents used to combat insomnia in AD patients in Drosophila models of AD for adverse effects on cognitive and cardiac health. We will also test novel therapeutics for potential use in individuals with AD with sundowning syndrome for their ability to ameliorate circadian phenotypes in Drosophila tauopathy models. 3) To test prevention of Tau aggregation using a novel proximity-directed O-GlcNAcylation strategy. Hyperphosphorylation of Tau is a major driver of self- assembled protein aggregation, which can be competed by O-GlcNAcylation. We will use nanobodies fused to OGT to direct O-GlcNAcylation to Tau and test amelioration of the effects of Tau-dependent neurodegeneration in vivo using Drosophila tauopathy models. Together these studies will help improve our understanding of sleep medications for treatment of AD, as well as help devise and test new therapeutic approaches.