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Drug Development.

Zhendong Sha1, Yadi Zhou1, Yuan Hou1

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Summary
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This study introduces a network medicine approach to design Alzheimer's disease (AD) drug combinations. By targeting multiple AD endophenotypes, these combinations show promise for more effective treatment strategies.

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Area of Science:

  • Network medicine
  • Computational biology
  • Pharmacogenomics

Background:

  • Alzheimer's disease (AD) is a complex, multifactorial disorder challenging traditional single-drug treatments.
  • Multi-targeted therapies and drug combinations offer enhanced therapeutic potential for AD.
  • Endophenotypes serve as multifactorial disease modules for designing targeted drug combinations.

Purpose of the Study:

  • To develop a network medicine framework for designing rational drug combinations for Alzheimer's disease.
  • To leverage AD endophenotypes and protein-protein interaction networks to identify synergistic drug pairs.
  • To prioritize drug combinations based on network proximity and therapeutic targeting of AD pathobiology.

Main Methods:

  • Curated AD endophenotype genes from Gene Ontology, KEGG, and literature.
  • Integrated genome-wide association study (GWAS) and brain tissue quantitative trait locus (xQTL) data for gene specialization.
  • Mapped genes to protein-protein interaction (PPI) networks to calculate network proximity for therapeutic potential estimation.
  • Prioritized drug combinations using a scoring framework evaluating common targeting and complementary exposure.

Main Results:

  • Meclofenamic Acid and Amlodipine identified as a promising combination targeting seven AD endophenotypes.
  • Memantine and Amlodipine combination suggested to address Memantine's limited coverage of Tau pathology.
  • Memantine and Tofacitinib combination proposed to enhance Tau targeting and broaden endophenotype coverage.
  • Identified drug combinations validated using electronic health record (EHR) data for real-world effectiveness.

Conclusions:

  • A network medicine framework enables rational design of effective drug combinations for Alzheimer's disease.
  • Integrating endophenotype-based network medicine with real-world data analysis provides a systematic platform for drug discovery.
  • This approach can advance drug combination design for AD and potentially other neurodegenerative dementias.