Natural Products as a Pipeline for Next-Generation Neurodegenerative Drugs: From Single-Target Failure to Multi-Target Opportunity in Alzheimer’s and Parkinson’s Disease

Neurodegenerative diseases such as Alzheimer’s disease (AD) and Parkinson’s disease (PD) represent some of the most complex and therapeutically challenging disorders in modern medicine. Despite decades of research, the traditional one drug–one target paradigm has largely failed to deliver disease-modifying therapies. Increasing evidence suggests that these complex diseases arise from interconnected pathological networks involving protein aggregation, oxidative stress, mitochondrial dysfunction, neuroinflammation, and synaptic loss. In this context, natural products (NPs) have re-emerged as a promising pipeline for next-generation therapeutics. Unlike conventional small molecules, NPs inherently exhibit polypharmacology, targeting multiple pathways simultaneously. Recent advances (2019–2026) demonstrate a paradigm shift, from crude NPs and single-mechanism compounds toward engineered derivatives, network pharmacology, and multi-target drug design. Using AD and PD as case studies, this review critically evaluates how NPs are redefining drug discovery by highlighting key emerging NPs, translational strategies, and future directions.