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<p>Drug repurposing (DR) offers a promising alternative to the high cost and low success rate of traditional drug development, especially for complex diseases like Alzheimer’s disease (AD). This study addressed DR for AD from three key angles: (1) demonstrating how disease-specific knowledge graphs can improve DR performance, (2) evaluating the role of large language models (LLMs) in enhancing the usability and efficiency of these graphs, and (3) assessing whether Graph-of-Thoughts (GoT)-enhanced LLMs, when integrated with AD knowledge graphs, can outperform traditional machine learning and LLM-based approaches. We tested five distinct DR strategies (DR1–DR5) for AD: DR1, a machine learning method using TxGNN; DR2, a machine learning model leveraging the Alzheimer’s KnowledgeBase (AlzKB); DR3, an LLM-based chatbot built on AlzKB; DR4, our ESCARGOT framework combining GoT-enhanced LLMs with AlzKB; and DR5, a general reasoning-driven LLM approach. Results showed that AlzKB significantly improved DR outcomes. ESCARGOT further enhanced performance while reducing the need for coding or advanced expertise in knowledge graph analysis. Because the architecture of AlzKB is easily adaptable to other diseases and ESCARGOT can integrate with various knowledge graph platforms, this framework offers a broadly applicable, innovative tool for accelerating drug discovery through repurposing.</p>

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Drug repurposing for Alzheimer’s disease using a graph-of-thoughts based large language model to infer drug-disease relationships in a comprehensive knowledge graph

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年8月5日

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  • Zhiping Paul Wang,
  • Xi Li,
  • Nicholas Matsumoto,
  • Mythreye Venkatesan,
  • Jui-Hsuan Chang,
  • Jay Moran,
  • Hyunjun Choi,
  • Binglan Li,
  • Yufei Meng,
  • Miguel E. Hernandez,
  • Jason H. Moore

摘要

Drug repurposing (DR) offers a promising alternative to the high cost and low success rate of traditional drug development, especially for complex diseases like Alzheimer’s disease (AD). This study addressed DR for AD from three key angles: (1) demonstrating how disease-specific knowledge graphs can improve DR performance, (2) evaluating the role of large language models (LLMs) in enhancing the usability and efficiency of these graphs, and (3) assessing whether Graph-of-Thoughts (GoT)-enhanced LLMs, when integrated with AD knowledge graphs, can outperform traditional machine learning and LLM-based approaches. We tested five distinct DR strategies (DR1–DR5) for AD: DR1, a machine learning method using TxGNN; DR2, a machine learning model leveraging the Alzheimer’s KnowledgeBase (AlzKB); DR3, an LLM-based chatbot built on AlzKB; DR4, our ESCARGOT framework combining GoT-enhanced LLMs with AlzKB; and DR5, a general reasoning-driven LLM approach. Results showed that AlzKB significantly improved DR outcomes. ESCARGOT further enhanced performance while reducing the need for coding or advanced expertise in knowledge graph analysis. Because the architecture of AlzKB is easily adaptable to other diseases and ESCARGOT can integrate with various knowledge graph platforms, this framework offers a broadly applicable, innovative tool for accelerating drug discovery through repurposing.