Beyond the Single-Target Approach: Polypharmacology and Multi-Target Therapeutics in Alzheimer's Disease.

Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder characterized by amyloid-beta aggregation, tau pathology, oxidative stress, neuroinflammation, mitochondrial dysfunction, and synaptic degeneration. The limited clinical success of traditional single-target therapeutic approaches has highlighted the need for more comprehensive treatment strategies. Polypharmacology has emerged as a promising paradigm that seeks to simultaneously modulate multiple pathological pathways involved in disease progression. In particular, multi-target-directed ligands (MTDLs) have gained considerable attention due to their ability to integrate multiple pharmacological activities within a single molecular entity. This review summarizes current advances in polypharmacology-based approaches for Alzheimer's disease, including rational drug design, ligand-based and network pharmacology strategies, artificial intelligence-assisted drug discovery, and emerging multi-target therapeutics. Representative synthetic and natural-productderived MTDLs are critically evaluated with respect to their mechanisms of action, pharmacokinetic limitations, blood-brain barrier penetration, and clinical development status. Finally, major translational challenges and future opportunities are discussed. Collectively, polypharmacology represents a promising framework for developing next-generation disease-modifying therapies for Alzheimer's disease, although significant challenges remain before widespread clinical implementation can be achieved.