Evolution of Multitarget Strategies for Alzheimer’s Disease: From Cholinergic Inhibition to Network-Oriented Therapeutic Design (2006–2025)

Abstract

Background: Alzheimer’s disease (AD) is a complex neurodegenerative disorder and a major global health challenge. The traditional “one drug-one target” paradigm has shown limitations in addressing its multifactorial nature. Multitarget-directed ligands (MTDLs), designed to modulate multiple pathological pathways, have emerged as a promising therapeutic strategy. Objectives: To examine the structural, thematic, and temporal evolution of multitarget strategies for AD treatment between 2006 and 2025. Methods: A total of 1184 Web of Science-indexed articles were analyzed. Publication growth, h-index, author productivity, institutional and national contributions, and keyword co-occurrence networks were evaluated using VOSviewer. Bibliometric laws (Price, Bradford, Zipf, and Lotka) were applied to characterize productivity patterns and thematic organization. Results: Multitarget research shows exponential growth, suggesting a consolidation of the MTDL paradigm. China, India, the United States, Italy, and Spain were the most productive countries. Early studies focused on cholinesterase inhibition, particularly acetylcholinesterase-based hybrids. The field expanded to include β-amyloid aggregation, oxidative stress, metal chelation, and blood-brain barrier permeability. Recent trends emphasize integration of computational approaches, including molecular docking, molecular dynamics, virtual screening, and network pharmacology, alongside targets such as BACE1 and GSK-3β. Conclusions: Multitarget strategies have evolved toward a systems-oriented framework. Despite advances, challenges remain in reducing cholinesterase dependency and improving translational validation. This study provides a framework to interpret therapeutic evolution and guide future network-based drug design.