Advances in Targeting Central Cholinergic Dysfunction for Neurodegenerative Diseases: From Pharmacotherapy to Neuromodulation

Abstract

ABSTRACT Background The central cholinergic system has long been a cornerstone therapeutic target for neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease dementia (PDD), and dementia with Lewy bodies (DLB). For decades, acetylcholinesterase inhibitors (AChEIs) have served as the standard symptomatic treatment, providing cognitive and functional relief by enhancing synaptic acetylcholine levels. However, their limited efficacy and inability to modify disease progression underscore the fundamental constraint of purely neurochemical enhancement, especially in the context of progressive cholinergic neuron loss. Results and Conclusion This review critically examines the evolution of cholinergic therapies beyond AChEIs. We first explore the shift from broad neurotransmitter enhancement toward precision targeting of receptor subtypes and the development of multi‐target pharmacological strategies. Furthermore, we highlight how neuromodulation techniques—including vagus nerve stimulation, deep brain stimulation, and non‐invasive brain stimulation—directly engage and restore dysfunctional neural circuits, moving beyond mere chemical enhancement. Emerging directions such as advanced cholinergic imaging, gene therapy, and cell‐based regeneration are also discussed as promising pathways toward true disease modification. Ultimately, the integration of sophisticated pharmacological agents with circuit‐level neuromodulation represents the next frontier in treating cholinergic dysfunction across the spectrum of neurodegenerative disorders, advancing the therapeutic goal from chemical enhancement to circuit repair and regeneration.