Reimagining cholinergic therapy for Alzheimer’s disease
Open accessAbstract
Currently, enhancement of cholinergic neurotransmission via cholinesterase inhibitors represents the main available approach to treat cognitive and behavioural symptoms of the early as well as late stages of Alzheimer's disease. Restoring the cholinergic system has been a primary means of improving cognition in Alzheimer's disease, as four of the six approved therapies are acetylcholinesterase inhibitors. Memantine is an N-methyl-d-aspartate antagonist with a well-documented clinical effect on behavioural symptoms, which is often added to cholinesterase inhibitors to potentiate their effect and aducanumab, targeting the amyloid pathology, has recently been approved. The early, progressive and selective degeneration of the cholinergic system together and its close relation to cognitive deficits supports the use of cholinergic therapy for Alzheimer's disease. This review provides an updated view of the basal forebrain cholinergic system, its relation to cognition and its relevance for therapy of Alzheimer's disease. It deals with the three main aspects that form the basis of the cholinergic-oriented therapy of Alzheimer's disease, its origin, its mechanism of action, its clinical effects, advantages and limits of a cholinergic therapeutic approach. It includes a new and updated overview of the involvement of muscarinic receptors in Alzheimer's disease as well as the recent development of new and highly selective M1 muscarinic receptor agonists with disease-modifying potential. It also addresses the discovery of a novel nerve growth factor metabolic pathway responsible for the trophic maintenance of the basal forebrain system and its deregulation in Alzheimer's disease. It discusses new clinical studies and provides evidence for the long-term efficacy of cholinesterase inhibitor therapy suggesting a disease-modifying effect of these drugs. The classical symptomatic cholinergic therapy based on cholinesterase inhibitors is judiciously discussed for its maximal efficacy and best clinical application. The review proposes new alternatives of cholinergic therapy that should be developed to amplify its clinical effect and supplement the disease-modifying effect of new treatments to slow down or arrest disease progression.
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The cholinergic hypothesis posits that degeneration of cholinergic neurons, particularly in the basal forebrain, is a central feature of AD and is closely linked to cognitive decline.
“The cholinergic hypothesis posits that the degeneration of cholinergic neurons, particularly in the basal forebrain, is a central feature of AD and is closely linked to cognitive decline.”
From Recent Advances in Therapeutics for the Treatment of Alzheimer’s Disease (2024) · cites this paper as [9]
AChE inhibitors donepezil, rivastigmine, and galantamine have limited efficacy and do not halt disease progression.
“AChE inhibitors, such as donepezil, rivastigmine, and galantamine, have been developed as treatments based on this hypothesis, although their efficacy is limited and they do not halt disease progression [7,9].”
From Recent Advances in Therapeutics for the Treatment of Alzheimer’s Disease (2024) · cites this paper as [9]
Decline in ChAT activity combined with detrimental effects of Aβ on cholinergic signaling leads to decreased ACh levels, contributing to cognitive deficits in AD patients.
“The decline in choline acetyltransferase (ChAT) activity, combined with the detrimental effects of amyloid beta (Aβ) on cholinergic signaling, leads to decreased ACh levels. Consequently, this reduction contributes to the cognitive deficits observed in AD patients.”
From Recent Advances in Therapeutics for the Treatment of Alzheimer’s Disease (2024) · cites this paper as [9]
A reduction in synthesis and release of ACh impairs its physiological functions, which are critical for learning, memory, and other cognitive processes.
“This hypothesis suggests that a reduction in the synthesis and release of ACh impairs its physiological functions, which are critical for learning, memory, and other cognitive processes.”
From Recent Advances in Therapeutics for the Treatment of Alzheimer’s Disease (2024) · cites this paper as [9]
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- Authors
- Giacobini, E., Cuello, A. C., & Fisher, A.
- Affiliations
- University of Geneva (CH)
- University of Oxford (GB)
- Israel Institute for Biological Research (IL)
- Corresponding author
- Giacobini, Ezio
- Venue
- Brain
- Publisher
- Oxford University Press (OUP)
- Published
- 2022-03-15
- Volume
- 145
- Issue
- 7
- Pages
- 2250-2275
- ISSN
- 0006-8950 (ISSN-L)
- 1460-2156
- OpenAlex
- W4220993307
- Cited by
- 187
- References
- 322
- Citations by year
- 2026: 36 · 2025: 63 · 2024: 43 · 2023: 29 · 2022: 16
- FWCI
- 5.48
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model (vor)
- Locations
- Brain (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- Canadian Institutes of Health Research
- Topics
- Health Sciences › Medicine › Pharmacology › Cholinesterase and Neurodegenerative Diseases
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- Alzheimer's disease, cholinergic therapy, cholinesterase inhibitors, muscarinic receptors, basal forebrain cholinergic system, nerve growth factor, memantine, aducanumab, disease-modifying therapy, cognitive impairment, behavioural symptoms
- MeSH terms
- Acetylcholinesterase, Alzheimer Disease, Cholinesterase Inhibitors, Humans, Cholinergic Agents, Receptor, Muscarinic M1
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