Phytomolecules as Alzheimer's therapeutics: A comprehensive review

Alzheimer's disease (AD) is a leading neurodegenerative disorder recognized by progressive cognitive decline and behavioral changes. The pathology of AD is characterized by the accumulation of amyloid-β (Aβ) plaques and the hyperphosphorylation of tau protein, which leads to synaptic loss and subsequent neurodegeneration. Additional contributors to disease progression include metabolic, vascular, and inflammatory factors. Glycogen synthase kinase-3β (GSK-3β) is also implicated, as it plays a crucial role in tau phosphorylation and the progression of neurodegeneration. This review provides a comprehensive analysis of various phytomolecules and their potential to target multiple aspects of AD pathology. We examined natural products from diverse classes, including stilbenes, flavonoids, phenolic acids, alkaloids, coumarins, terpenoids, chromenes, cannabinoids, chalcones, phloroglucinols, and polycyclic polyprenylated acylphloroglucinols (PPAPs). The key mechanisms of action of these phytomolecules include modulating tau protein dynamics to reduce aggregation, inhibiting acetylcholinesterase (AChE) to maintain neurotransmitter levels and enhance cognitive function, and inhibiting β-secretase (BACE1) to decrease Aβ production. Additionally, some phytomolecules were found to influence GSK-3β activity, thereby impacting tau phosphorylation and neurodegeneration. By addressing multiple targets, Aβ production, tau hyperphosphorylation, AChE activity, and GSK-3β, these natural products offer a promising multi-targeted approach to AD therapy. This review highlights their potential to develop effective treatments that not only mitigate core pathological features but also manage the complex, multifactorial aspects of AD progression.