The Cholinergic System in the Pathophysiology and Treatment of Alzheimer's Disease

Harald Hampel; M.-Marsel Mesulam; A. Claudio Cuello; Martin R. Farlow; Ezio Giacobini; George T. Grossberg; Ara S. Khachaturian; Andrea Vergallo; Enrica Cavedo; Peter J. Snyder; Zaven S. Khachaturian


Brain. 2018;141(7):1917-1933. 

In This Article


The cholinergic system is important for neuronal function in memory, learning, and other essential aspects of cognition and plays a wider role in the promotion of neuronal plasticity. Multidisciplinary investigations are revealing how dysfunction in cholinergic networks arising from the basal forebrain, interact with other important pathophysiologic aspects of Alzheimer's disease—including amyloid-β plaques, neurofibrillary tangles, inflammation, oxidative stress, and vascular insufficiency to undermine cognition. A wealth of clinical literature supports the benefit of promoting cholinergic activity in Alzheimer's disease through the use of cholinesterase inhibitors. Moreover, new data based on MRI are showing evidence of hippocampal protection and, perhaps, disease course alterations in individuals who receive cholinesterase inhibitors for long periods of time. Interest remains high in understanding the temporal sequence and cascade of these complex interactions and their synergistic feedback mechanisms over the course of Alzheimer's disease. It is anticipated that optimal Alzheimer's disease management will integrate a systems biology approach based on precision medicine to help tailor combinatorial therapeutic regimens for different stages of Alzheimer's disease on the basis of genetic risks, brain imaging, and biomarkers. As we anticipate major developments in the treatment strategies of Alzheimer's disease, cholinergic interventions are likely to maintain their critical roles in the therapeutic armamentarium.