The cholinergic system in the pathophysiology and treatment of Alzheimer's disease

Harald Hampel*, Marek-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

*Corresponding author for this work

Research output: Contribution to journalReview article

56 Citations (Scopus)

Abstract

Cholinergic synapses are ubiquitous in the human central nervous system. Their high density in the thalamus, striatum, limbic system, and neocortex suggest that cholinergic transmission is likely to be critically important for memory, learning, attention and other higher brain functions. Several lines of research suggest additional roles for cholinergic systems in overall brain homeostasis and plasticity. As such, the brain's cholinergic system occupies a central role in ongoing research related to normal cognition and age-related cognitive decline, including dementias such as Alzheimer's disease. The cholinergic hypothesis of Alzheimer's disease centres on the progressive loss of limbic and neocortical cholinergic innervation. Neurofibrillary degeneration in the basal forebrain is believed to be the primary cause for the dysfunction and death of forebrain cholinergic neurons, giving rise to a widespread presynaptic cholinergic denervation. Cholinesterase inhibitors increase the availability of acetylcholine at synapses in the brain and are one of the few drug therapies that have been proven clinically useful in the treatment of Alzheimer's disease dementia, thus validating the cholinergic system as an important therapeutic target in the disease. This review includes an overview of the role of the cholinergic system in cognition and an updated understanding of how cholinergic deficits in Alzheimer's disease interact with other aspects of disease pathophysiology, including plaques composed of amyloid-β proteins. This review also documents the benefits of cholinergic therapies at various stages of Alzheimer's disease and during long-term follow-up as visualized in novel imaging studies. The weight of the evidence supports the continued value of cholinergic drugs as a standard, cornerstone pharmacological approach in Alzheimer's disease, particularly as we look ahead to future combination therapies that address symptoms as well as disease progression.

Original languageEnglish (US)
Pages (from-to)1917-1933
Number of pages17
JournalBrain
Volume141
Issue number7
DOIs
StatePublished - Jul 1 2018

Fingerprint

Cholinergic Agents
Alzheimer Disease
Therapeutics
Brain
Synapses
Cognition
Amyloidogenic Proteins
Limbic System
Cholinergic Neurons
Neocortex
Cholinesterase Inhibitors
Denervation
Prosencephalon
Thalamus
Research
Acetylcholine
Dementia
Disease Progression
Cause of Death
Homeostasis

Keywords

  • Alzheimer's disease
  • acetylcholine
  • cholinergic system
  • cholinesterase inhibitors
  • cognition

ASJC Scopus subject areas

  • Clinical Neurology

Cite this

Hampel, H., Mesulam, M-M., Cuello, A. C., Farlow, M. R., Giacobini, E., Grossberg, G. T., ... Khachaturian, Z. S. (2018). The cholinergic system in the pathophysiology and treatment of Alzheimer's disease. Brain, 141(7), 1917-1933. https://doi.org/10.1093/brain/awy132
Hampel, Harald ; Mesulam, Marek-Marsel ; Cuello, A. Claudio ; Farlow, Martin R. ; Giacobini, Ezio ; Grossberg, George T. ; Khachaturian, Ara S. ; Vergallo, Andrea ; Cavedo, Enrica ; Snyder, Peter J. ; Khachaturian, Zaven S. / The cholinergic system in the pathophysiology and treatment of Alzheimer's disease. In: Brain. 2018 ; Vol. 141, No. 7. pp. 1917-1933.
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Hampel, H, Mesulam, M-M, Cuello, AC, Farlow, MR, Giacobini, E, Grossberg, GT, Khachaturian, AS, Vergallo, A, Cavedo, E, Snyder, PJ & Khachaturian, ZS 2018, 'The cholinergic system in the pathophysiology and treatment of Alzheimer's disease', Brain, vol. 141, no. 7, pp. 1917-1933. https://doi.org/10.1093/brain/awy132

The cholinergic system in the pathophysiology and treatment of Alzheimer's disease. / Hampel, Harald; Mesulam, Marek-Marsel; Cuello, A. Claudio; Farlow, Martin R.; Giacobini, Ezio; Grossberg, George T.; Khachaturian, Ara S.; Vergallo, Andrea; Cavedo, Enrica; Snyder, Peter J.; Khachaturian, Zaven S.

In: Brain, Vol. 141, No. 7, 01.07.2018, p. 1917-1933.

Research output: Contribution to journalReview article

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AU - Hampel, Harald

AU - Mesulam, Marek-Marsel

AU - Cuello, A. Claudio

AU - Farlow, Martin R.

AU - Giacobini, Ezio

AU - Grossberg, George T.

AU - Khachaturian, Ara S.

AU - Vergallo, Andrea

AU - Cavedo, Enrica

AU - Snyder, Peter J.

AU - Khachaturian, Zaven S.

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Hampel H, Mesulam M-M, Cuello AC, Farlow MR, Giacobini E, Grossberg GT et al. The cholinergic system in the pathophysiology and treatment of Alzheimer's disease. Brain. 2018 Jul 1;141(7):1917-1933. https://doi.org/10.1093/brain/awy132