PROJECT SUMMARY Alzheimer’s disease (AD) is a heterogeneous neurodegenerative disorder which is highly prevalent in the global population, affecting around 46 million individuals. Due to increased longevity, the prevalence is rising. AD is characterized pathophysiologically by extracellular β- amyloid deposition and intracellular hyperphosphorylated tau. Current medications for AD provide some relief from disease symptoms but are not effective in all patients while severe side effects are observed. The disease is highly heritable and has a complex molecular basis, with a substantial polygenic component. There is an urgent need for developing approaches to target discovery and drug repurposing. The combination of methodological analytic advances, functional genomics data, and phenotype-rich datasets can be the foundation for identifying new therapies. Our central hypothesis is that an integrative approach spanning human phenomics and genomics will offer new AD therapeutic possibilities, including drug repositioning, and provide a powerful approach to drug target discovery. We will develop cutting-edge genetics-anchored computational methodologies for AD drug repurposing, generate a community resource to advance research in AD therapeutics development, leverage a collaboration (infrastructure and machine learning) with Google, and conduct target validation in a zebrafish model of AD. We have engaged an interdisciplinary team to ensure the success and broad impact of our proposal and lay the groundwork for future innovative research.