{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T03:01:06Z","timestamp":1791082866986,"version":"4.1.0"},"reference-count":325,"publisher":"Oxford University Press (OUP)","issue":"7","license":[{"start":{"date-parts":[[2022,3,15]],"date-time":"2022-03-15T00:00:00Z","timestamp":1647302400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2022,7,29]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>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\u2019s disease. Restoring the cholinergic system has been a primary means of improving cognition in Alzheimer\u2019s disease, as four of the six approved therapies are acetylcholinesterase inhibitors.<\/jats:p><jats:p>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.<\/jats:p><jats:p>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\u2019s disease.<\/jats:p><jats:p>This review provides an updated view of the basal forebrain cholinergic system, its relation to cognition and its relevance for therapy of Alzheimer\u2019s disease. It deals with the three main aspects that form the basis of the cholinergic-oriented therapy of Alzheimer\u2019s 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\u2019s 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\u2019s 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.<\/jats:p><jats:p>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.<\/jats:p>","DOI":"10.1093\/brain\/awac096","type":"journal-article","created":{"date-parts":[[2022,3,12]],"date-time":"2022-03-12T12:08:10Z","timestamp":1647086890000},"page":"2250-2275","source":"Crossref","is-referenced-by-count":187,"title":["Reimagining cholinergic therapy for Alzheimer\u2019s disease"],"prefix":"10.1093","volume":"145","author":[{"given":"Ezio","family":"Giacobini","sequence":"first","affiliation":[{"name":"Department of Internal Medicine, Readaptation and Geriatrics, Faculty of Medicine, University of Geneva Hospitals, University of Geneva , CH 1226 Geneva , Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7962-7433","authenticated-orcid":false,"given":"A Claudio","family":"Cuello","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, McGill University , H3G 1Y6 Montreal , Canada"},{"name":"Visiting Professor, Department of Pharmacology, Oxford University , Oxford OX1 3QT , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0931-3049","authenticated-orcid":false,"given":"Abraham","family":"Fisher","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry, Israel Institute for Biological Research , 74100 Ness Ziona , Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2022,3,15]]},"reference":[{"key":"2022072919095280800_awac096-B1","doi-asserted-by":"crossref","first-page":"5789","DOI":"10.3390\/molecules25245789","article-title":"Comprehensive review on Alzheimer\u2019s disease: Causes and 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