From Blood to Brain: Transcriptomic Drug Repurposing for Alzheimer's Disease

Abstract

Alzheimer’s disease (AD) is the leading cause of dementia worldwide and remains without curative or disease-modifying therapies. Conventional drug development approaches are hindered by high costs, lengthy timelines, and high failure rates. In this study, we employed a computational pipeline to identify existing compounds capable of reversing AD-associated gene expression signatures derived from peripheral blood. Differential gene expression analysis was performed on the GSE63060 dataset using GEO2R, comparing individuals with Alzheimer’s disease to cognitively normal controls. Disease-specific gene signatures were queried against the LINCS L1000 database using L1000FWD platform to identify drugs exhibiting transcriptional reversal. Candidate compounds were further evaluated through molecular target identification, pathway enrichment analysis, blood-brain barrier permeability assessment, and regulatory status screening. This approach yielded ten prioritized compounds with mechanistic relevance to Alzheimer’s pathology. Notably, Temsirolimus and Indirubin emerged as high-priority candidates due to their involvement in mTOR and GSK-3β signaling pathways, respectively. These findings demonstrate the utility of peripheral blood transcriptomic data for drug repurposing in Alzheimer’s disease and identify some drugs as potential options that justify future studies for experimental validation.