Uncovering leading compounds for alzheimer’s disease treatment: mendelian randomization and virtual screening insights into plasma protein modulation

Abstract

Alzheimer's disease (AD) is a neurodegenerative disorder influenced by both genetic and environmental factors. Identifying therapeutic targets and interventions remains challenging. This study utilized Mendelian Randomization (MR) to investigate causal relationships between plasma proteins, lifestyle factors, and AD, along with virtual screening to identify potential drug compounds. A two-sample MR analysis assessed associations between plasma proteins, identified through genome-wide association studies (GWAS), and AD risk. Co-localization analysis (CA) confirmed the overlap between protein expression and AD susceptibility loci, and reverse MR ruled out reverse causality. A protein–protein interaction (PPI) network was constructed to explore therapeutic targets, followed by virtual screening to identify small-molecule inhibitors for selected proteins. The analysis found significant associations between eight plasma proteins and AD, with five proteins (GSTP1, BIN1, Siglec-3, SERPINF2, and GRN) showing strong evidence of involvement in AD pathogenesis. Virtual screening identified six compounds as potential inhibitors of GSTP1 and four compounds as potential inhibitors of BIN1. Furthermore, MR analysis of lifestyle factors, such as dietary behaviors and smoking cessation, indicated they may influence AD risk through their effects on specific proteins. These findings offer novel insights into the genetic mechanisms underlying AD and highlight the potential of combining MR with virtual screening to identify therapeutic targets. The study also suggests that lifestyle modifications could offer alternative prevention and treatment strategies for AD. Future research should focus on the experimental validation of the identified compounds and further explore the mechanisms linking lifestyle factors to AD.