Cited by 189Cholinesterase and Neurodegenerative DiseasesAlzheimer's disease research and treatmentsDementia and Cognitive Impairment Research

Reimagining cholinergic therapy for Alzheimer’s disease

Open access
Giacobini, Ezio, Cuello, A Claudio, Fisher, Abraham·2022·Brain

Abstract

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.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1093/brain/awac096

Cites

322 of 323 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • 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.”
  • 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].”
  • 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.”
  • 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.”

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Part of this paper’s reference list could not be split into single entries.

1 retracted

Flagged first, then by citations

Cited by

Sorted by citations

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
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
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

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review