Key Regulators of Alzheimer’s Disease: Network Biology and In-Silico Analysis with AChE and Glutamate Inhibitors

Alzheimer’s disease (AD) is a complex, progressive neurodegenerative disorder driven by both genetic and environmental factors, with hallmark features including amyloid-β plaques and neurofibrillary tangles. Despite advances in therapeutics, current treatments remain palliative, underscoring the urgent need for novel targets and multipathway interventions. This study employed a systems biology approach to identify central regulatory proteins in AD through protein−protein interaction (PPI) networks. Using six major biomedical databases, 85 overlapping AD-related genes were identified, and a primary PPI network was constructed and analyzed using CytoScape. Centrality metric (CytoNCA) and hub (CytoHubba) analyses led to the identification of seven key regulators: APP, BDNF, APOE, VEGFA, PSEN1, NOTCH1, and CASP1. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses revealed their involvement in key neurobiological functions including axon development, signaling receptor binding, and neurodegenerative pathways. These targets were further evaluated through molecular docking against four FDA-approved AD drugs i.e., donepezil, galantamine, rivastigmine, and memantine using AutoDock Vina. Notably, BDNF showed the strongest binding affinity across all the compounds, especially with donepezil, whereas APP exhibited the weakest interactions. This multilevel computational study reveals critical molecular targets in AD and explores their potential responsiveness to existing therapeutics, supporting drug repurposing strategies.