Project Summary The goal of our funded proposal is to identify FDA approved compounds that will rescue synaptic dysfunction in Alzheimer's Disease (AD). This goal is motivated by the observation that one of the earliest events in AD is synaptic dysfunction. In microscopic post-mortem studies, synaptic loss correlates strongly with pre-mortem cognitive status, and serves as a better predictor of pre-mortem cognitive status than either plaque or tangle pathology. Faced with this evidence, multiple groups have proposed that synaptic dysfunction is central to the pathophysiology of AD. Our laboratory has previously utilized novel datamining techniques on RNA expression data to identify master regulators of synaptic and neurophysiologic dysfunction in AD. This computational effort has identified transcriptional regulators whose dysfunction in AD is predicted to cause impairment in expression of synaptic genes (we refer to these transcriptional regulators as “synaptic master regulators,” or synaptic MRs). Using similar techniques, we propose to screen a library of FDA-approved compounds for their ability to support synaptic function in AD by appropriately modifying disease-relevant synaptic MRs. At the end of our funded proposal, we will have a list of FDA-approved compounds that rescue synaptic MR dysfunction. The goal of this supplement is to expand our drug screen to include compounds from a library of bioactive compounds, which will screen for a wider range of therapeutic targets than is typically found in an FDA- approved compound library. In addition, we will incorporate a fluorescent screening method to better image neurite morphology in our neurons, which will be additive information that will help us eliminate compounds that that negatively affect neurite integrity, complexity, and length. In summary, this supplement will allow us to screen a wider range of compounds and will support gathering additional morphological information during our screen, both of which will enhance the impact of our drug screen.