Harnessing endophenotypes and network medicine for Alzheimer's drug repurposing

Jiansong Fang, Andrew A. Pieper, Ruth Nussinov, Garam Lee, Lynn Bekris, James B. Leverenz, Jeffrey Cummings, Feixiong Cheng*

*Corresponding author for this work

Research output: Contribution to journalReview articlepeer-review


Following two decades of more than 400 clinical trials centered on the “one drug, one target, one disease” paradigm, there is still no effective disease-modifying therapy for Alzheimer's disease (AD). The inherent complexity of AD may challenge this reductionist strategy. 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-repurposing and identification of new candidate therapeutic strategies for patients suffering from or at risk for AD. We highlight new opportunities for endophenotype-informed, drug discovery in AD, by exploiting multi-omics data. Integration of genomics, transcriptomics, radiomics, pharmacogenomics, and interactomics (protein–protein 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-based retrospective case–control studies that may be integrated with multi-omics in a network medicine methodology. In summary, endophenotype-based 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.

Original languageEnglish
Pages (from-to)2386-2426
Number of pages41
JournalMedicinal Research Reviews
Issue number6
StatePublished - 1 Nov 2020


  • Alzheimer's disease
  • amyloidosis
  • drug repurposing
  • endophenotype
  • network medicine
  • omics
  • pathobiology
  • systems biology
  • tauopathy


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