Cholinergic dysfunction in Alzheimer's disease: Mechanistic perspectives and multi-target effects of traditional Chinese medicine.

Abstract

Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder characterized by progressive cognitive decline and complex pathological changes. Cholinergic dysfunction is an early, clinically pivotal feature of AD closely associated with multiple pathological processes, including amyloid-β (Aβ) pathology, neuroinflammatory responses, mitochondrial dysfunction, metal-ion dyshomeostasis, and apolipoprotein E (APOE) ε4-related vulnerability. While disrupted cholinergic signaling impairs memory formation and synaptic function, its bidirectional interaction with AD-related pathological cascades further accelerates disease progression. Traditional Chinese medicine (TCM) has been investigated as a potential multitarget approach with which to modulate cholinergic deficits and related pathological processes. Some TCM-derived compounds, standardized extracts, and formulas have been reported to regulate cholinergic enzymes, acetylcholine levels, cholinergic receptors, oxidative stress, mitochondrial function, neuroinflammatory responses, and Aβ- or tau-related pathology. This review summarizes the role of cholinergic failure in AD pathophysiology and evaluates the evidence surrounding TCM-based interventions, with emphasis on direct cholinergic evidence, indirect collateral mechanisms, and current translational limitations. Indeed, the purpose of these insights is to inform future development of multitarget therapeutic strategies for AD.