Taner, Nilüfer

Abstract Alzheimer’s Disease (AD) 1 is a progressive neurodegenerative disorder with limited therapeutic options, driving interest in drug repurposing to accelerate treatment discovery. Drug repurposing has emerged as a promising strategy to accelerate therapeutic discovery by repositioning existing drugs for new clinical indications. Recent computational repurposing approaches, including knowledge graph reasoning, transcriptomic signature analysis, and integrative literature mining, have demonstrated strong predictive capabilities 2 . However, these methods often yield divergent drug rankings, which makes it difficult to decide which candidates to advance for experimental follow-up and results in substantial gaps between computational predictions and feasible in vivo validation 2 .To bridge this computational-experimental gap, we proposed an advanced prioritization framework leveraging large language models (LLMs). Our method systematically evaluated three state-of-the-art (SOTA) and representative computational methods (TxGNN 3 , Composition-based Graph Convolutional Network (CompGCN) 4 , and a regularized logistic regression (RLR) 5 , to analyze both their predictive performance and pharmaceutical class distributions. By integrating the strengths and divergences of these models, we generated a unified, streamlined list of 90 candidate drugs for further prioritization. We then utilized an LLM-based agent to perform evidence synthesis from biomedical literature abstracts for each candidate. This process mimics expert manual curation but significantly reduces human effort and time by efficiently distilling vast textual data into actionable insights. Applying consistent and transparent selection criteria, we obtained a refined and prioritized list of drug candidates suitable for subsequent in vivo experimental validation. The robustness and clinical relevance of our framework were validated using real-world data from Alzheimer’s patient cohorts, clinical trial registries, and expert pharmacological reviews. This comprehensive validation confirmed that our LLM-driven approach enhances efficiency, consistency, scalability, and generalizability. By integrating computational predictions with scalable evidence synthesis and multifaceted validation, our framework facilitated rapid and informed prioritization of repurposed drugs. Our framework can potentially accelerate the translational pathway toward viable AD therapeutics. Moreover, the versatility of our framework can also be applied to drug repurposing efforts for other diseases beyond AD.