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ApoE-Genotype-Specific Drug Repositioning Identifies Bumetanide as an Effective Compound in a Mouse Model of Alzheimer's Disease

  • Author(s): Taubes, Alice Lorraine
  • Advisor(s): Huang, Yadong
  • Sirota, Marina
  • et al.
Abstract

Alzheimer’s disease (AD) is the leading cause of dementia worldwide, and no effective therapies are available. The multifactorial etiology and pathophysiological complexity of AD cause patient heterogeneity and pose challenges for drug development, with almost all efforts to target AD-related pathways having failed in human trials. Although apolipoprotein (apo) E4 is the major genetic risk factor for AD—60–80% of patients have at least one APOE4 allele and ~70% of homozygotes develop AD by age 85—it has not been actively considered in drug target stratification and development for AD. Here, we used an apoE-genotype-specific drug repositioning approach to screen for drugs to treat apoE4-related AD. From a meta-analysis of 610 human temporal lobar samples from public databases, we established apoE-genotype-specific transcriptomic signatures of AD and applied them to a validated Connectivity Map (CMap) database containing transcriptomic perturbation signatures of 1300 existing drugs to identify those capable of perturbing an entire gene-expression network away from the apoE-genotype-driven disease state towards a normal state. The loop-diuretic bumetanide was the top predicted drug candidate for apoE4/4 AD. Treating aged apoE4 knock-in (apoE4-KI) mice with bumetanide rescued cognitive and neuronal plasticity deficits, warranting further efficacy tests in AD clinical trials. This study highlights the power of combining precision medicine, computational drug repositioning, and targeting network alterations in developing new therapies for AD and other neurodegenerative disorders.

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