Drug repurposing for Alzheimer's disease integrating transcriptome-wide association study and biological network analysis

Background The accumulation of particular protein deposits connected to molecular mechanisms is one of the many brain abnormalities associated with Alzheimer's disease (AD), a complex neurodegenerative illness. There are currently no effective disease-modifying treatments for AD. Objective This study attempts to identify potential AD therapeutics through a biological network-based drug repurposing strategy, focusing on drugs targeting important proteins and biological pathways involved in AD pathology. Methods A comprehensive biological network of AD-associated molecules and their transcription regulatory interactions is constructed. This computational approach integrates data from genome-wide association studies, multiple AD-related magnetic resonance imaging (MRI) derived phenotypes, biomolecular interactions, and gene expression profiles. Results The constructed AD sub-regulatory network reveals significant correlations between transcription factors showing changed gene expression in AD patients relative to controls. This strategy prioritizes drug candidates based on their mechanisms of action, reducing the risk of clinical trial failures and enhancing patient outcomes related to AD. A total of 43 drug candidates have been identified, including 28 FDA-approved drugs, 15 experimental and investigational drugs that may alter biological processes pertaining to important facets of AD pathology. Baricitinib and Gabapentin emerge as promising candidates for targeting AD-related biological processes in the cerebral cortex and hippocampus regions. Conclusions By combining biological network analysis and MRI-driven transcriptome-wide association study, this systematic drug repurposing strategy demonstrates promise for identifying novel therapeutic options for AD and offers potential implications for addressing other complex neurological disorders.