{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T04:41:40Z","timestamp":1784868100991,"version":"3.55.0"},"reference-count":163,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2021,12,22]],"date-time":"2021-12-22T00:00:00Z","timestamp":1640131200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research","doi-asserted-by":"publisher","award":["201603PJT-364544"],"award-info":[{"award-number":["201603PJT-364544"]}],"id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]},{"name":"National Institute of Health and Aging","award":["R01- AG056850"],"award-info":[{"award-number":["R01- AG056850"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>The cause of the loss of basal forebrain cholinergic neurons (BFCNs) and their terminal synapses in the cerebral cortex and hippocampus in Alzheimer\u2019s disease (AD) has provoked a decades-long controversy. The cholinergic phenotype of this neuronal system, involved in numerous cognitive mechanisms, is tightly dependent on the target-derived nerve growth factor (NGF). Consequently, the loss of BFCNs cholinergic phenotype in AD was initially suspected to be due to an NGF trophic failure. However, in AD there is a normal NGF synthesis and abundance of the NGF precursor (proNGF), therefore the NGF trophic failure hypothesis for the atrophy of BCNs was abandoned. In this review, we discuss the history of NGF-dependency of BFCNs and the atrophy of these neurons in Alzheimer\u2019s disease (AD). Further to it, we propose that trophic factor failure explains the BFCNs atrophy in AD. We discuss evidence of the occurrence of a brain NGF metabolic pathway, the dysregulation of which, in AD explains the severe deficiency of NGF trophic support for the maintenance of BFCNs cholinergic phenotype. Finally, we revise recent evidence that the NGF metabolic dysregulation in AD pathology starts at preclinical stages. We also propose that the alteration of NGF metabolism-related markers in body fluids might assist in the AD preclinical diagnosis.<\/jats:p>","DOI":"10.3390\/cells11010016","type":"journal-article","created":{"date-parts":[[2021,12,22]],"date-time":"2021-12-22T10:24:52Z","timestamp":1640168692000},"page":"16","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":27,"title":["The Nerve Growth Factor Metabolic Pathway Dysregulation as Cause of Alzheimer\u2019s Cholinergic Atrophy"],"prefix":"10.3390","volume":"11","author":[{"given":"Sonia","family":"Do Carmo","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Therapeutics, McGill University, Montreal, QC H3G 1Y6, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin","family":"Kannel","sequence":"additional","affiliation":[{"name":"Department of Neurology and Neurosurgery, McGill University, Montreal, QC H3A 2B4, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A. Claudio","family":"Cuello","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Therapeutics, McGill University, Montreal, QC H3G 1Y6, Canada"},{"name":"Department of Neurology and Neurosurgery, McGill University, Montreal, QC H3A 2B4, Canada"},{"name":"Department of Anatomy and Cell Biology, McGill University, Montreal, QC H3A 0C7, Canada"},{"name":"Department of Pharmacology, Oxford University, Oxford OX1 3QT, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,12,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"449","DOI":"10.1002\/jez.1400680305","article-title":"The effects of wing bud extirpation on the development of the central nervous system in chick embryos","volume":"68","author":"Hamburger","year":"1934","journal-title":"J. Exp. 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