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Recent observations and advances in network medicine further indicate that AD likely shares common underlying mechanisms and intermediate pathophenotypes, or endophenotypes, with other diseases. In this review, we consider AD pathobiology, disease comorbidity, pleiotropy, and therapeutic development, and construct relevant endophenotype networks to guide future therapeutic development. Specifically, we discuss six main endophenotype hypotheses in AD: amyloidosis, tauopathy, neuroinflammation, mitochondrial dysfunction, vascular dysfunction, and lysosomal dysfunction. We further consider how this endophenotype network framework can provide advances in computational and experimental strategies for drug\u2010repurposing and identification of new candidate therapeutic strategies for patients suffering from or at risk for AD. We highlight new opportunities for endophenotype\u2010informed, drug discovery in AD, by exploiting multi\u2010omics data. Integration of genomics, transcriptomics, radiomics, pharmacogenomics, and interactomics (protein\u2013protein interactions) are essential for successful drug discovery. We describe experimental technologies for AD drug discovery including human induced pluripotent stem cells, transgenic mouse\/rat models, and population\u2010based retrospective case\u2013control studies that may be integrated with multi\u2010omics in a network medicine methodology. In summary, endophenotype\u2010based network medicine methodologies will promote AD therapeutic development that will optimize the usefulness of available data and support deep phenotyping of the patient heterogeneity for personalized medicine in AD.<\/jats:p>","DOI":"10.1002\/med.21709","type":"journal-article","created":{"date-parts":[[2020,7,13]],"date-time":"2020-07-13T08:33:04Z","timestamp":1594629184000},"page":"2386-2426","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":84,"title":["Harnessing endophenotypes and network medicine for Alzheimer's drug repurposing"],"prefix":"10.1002","volume":"40","author":[{"given":"Jiansong","family":"Fang","sequence":"first","affiliation":[{"name":"Science and Technology Innovation Center Guangzhou University of Chinese Medicine  Guangzhou Guangdong China"},{"name":"Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic  Cleveland Ohio 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