Alzheimer's disease (AD) is a progressive neurodegenerative disease and the leading cause of dementia in the United States. Unfortunately, there is no cure for AD. Drug discovery for AD has suffered significant failures, many at late stage clinical trials, partly due to our poor understanding of AD pathology and the lack of disease-relevant and human-relevant discovery and development models. This calls for team efforts with diverse and complementary expertise to tackle the challenges together, by developing innovative approaches from multiple angles to achieve the goal of identifying AD drugs. In this application, we propose three complementary Specific Aims that together aim to identify FDA approved drugs with repurpose potential for AD, from distinct but complementary angles that act synergistically to boost the likelihood of success. AD is a highly heritable disease, with an estimated heritability of 70%, highlighting the critical role of genetics in understanding the disease etiology. Recent genetic studies have identified over 30 loci, enabling us to dissect the genetic architecture of AD, including the biological processes and cell types involved in disease etiology. In particular, we aim to dissect the highly polygenic AD etiology into distinct pathophysiological components to guide drug repurposing, which is only feasible in recent years thanks to large scale GWAS and massive genomics data available publicly (Aim 1). In parallel, we will mine millions of electronic health records (EHRs) to identify drugs that reduce AD risk and cognitive decline, by developing phenotyping algorithms from EHR for AD related phenotypes (Aim 2). In addition, we will develop a high throughput screening (HTS) gene expression profiling assay and use human induced pluripotent stem cell (iPSC) models to identify candidate compounds, and will further test the efficacy of the candidates in both patient-derived iPSC lines and AD mouse models (Aim 3). The three aims are complementary and synergistic, in the sense that they independently tackle the same problem from drastically distinct angles, while findings from one can be served as validation for others. Altogether, leveraging distinct and complementary expertise, we expect to yield bona fide repurposable drugs for AD with orthogonal support.