TY - JOUR
T1 - The cholinergic system in the pathophysiology and treatment of Alzheimer's disease
AU - Hampel, Harald
AU - Mesulam, M. 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.
N1 - Funding Information:
H.H. is supported by the AXA Research Fund, the ‘Fondation partenariale Sorbonne Université’ and the ‘Fondation pour la Recherche sur Alzheimer’, Paris, France. Ce travail a bénéficié d’une aide de l’Etat ‘Investissements d’avenir’ ANR-10-IAIHU-06. The research leading to these results has received funding from the program ‘Investissements d’avenir’ ANR-10-IAIHU-06 (Agence Nationale de la Recherche-10-IA Agence Institut Hospitalo-Universitaire-6). A.C.C. is supported by the CIHR (Canadian Institutes of Health Research), the NSERC (National Research Council) and the Alzheimer Society of Canada. A.C.C. is a Member of the Canadian Consortium of Neurodegeneration in Aging and has received unrestricted support from Merck Canada, Dr. Alan Frosst and the Frosst Family. A.V. is supported by Rotary Club Livorno ‘Mascagni’/The Rotary Foundation (Global Grant No GG1758249). M.M.M. has received research support from the ADC grant (AG013854).
Funding Information:
Axovant supported the travel and lodging expenses of the authors for two meetings of the CWG in New York City. The authors were also paid as consultants at customary rates for the time spent at the two meetings of the CWG; there were no other honoraria provided to the authors. A science writer, paid by Axovant help to compile the contributions of the authors into a coherent document. However, the various sections of the paper were prepared exclusively by the authors who were not paid in any way or the time spent in writing-editing the manuscript. All proceedings of the CWG were independent from Axovant. The support for the meetings was accepted by the CWG with the stipulation that Axovant would have no input to the deliberations of the Workgroup and/or influence in anyway the final conclusions/recommendations of the WG. Thus, no member of the company participated in development, discussion or drafting of this manuscript. Axovant has had under development a compound RVT-101 (aka Intepirdine) an antagonist of the serotonin receptor 6 (5-HT6) (which was found to lack efficacy for the treatment of Alzheimer’s disease), as well as RVT-104 (combination of glycopyrrolate and high-dose rivastigmine) a compound that targets the cholinergic mechanism H.H. serves as Senior Associate Editor for Alzheimer’s & Dementia; he received lecture fees from Biogen and Roche, research grants from Pfizer, Avid, and MSD Avenir (paid to the institution), travel funding from Axovant, Eli Lilly and company, Takeda and Zinfandel, GE-Healthcare and Oryzon Genomics, consultancy fees from Jung Diagnostics, Cytox Ltd., Axovant, Anavex, Takeda and Zinfandel, GE Healthcare and Oryzon Genomics, and participated in scientific advisory boards of Axovant, Eli Lilly and company, Cytox Ltd., GE Healthcare, Takeda and Zinfandel, Oryzon Genomics and Roche Diagnostics. H.H. is co-inventor in the following patents as a scientific expert and has received no royalties: In Vitro Multiparameter Determination Method for The Diagnosis and Early Diagnosis of Neurodegenerative Disorders Patent Number: 8916388. In Vitro Procedure for Diagnosis and Early Diagnosis of Neurodegenerative Diseases Patent Number: 8298784. Neurodegenerative Markers for Psychiatric Conditions Publication Number: 20120196300. In Vitro Multiparameter Determination Method for The Diagnosis and Early Diagnosis of Neurodegenerative Disorders Publication Number: 20100062463. In Vitro Method for The Diagnosis and Early Diagnosis of Neurodegenerative Disorders Publication Number: 20100035286. In Vitro Procedure for Diagnosis and Early Diagnosis of Neurodegenerative Diseases Publication Number: 20090263822. In Vitro Method for The Diagnosis of Neurodegenerative Diseases Patent Number: 7547553. CSF Diagnostic in Vitro Method for Diagnosis of Dementias and Neuroinflammatory Diseases Publication Number: 20080206797. In Vitro Method for The Diagnosis of Neurodegenerative Diseases Publication Number: 20080199966. Neurodegenerative Markers for Psychiatric Conditions Publication Number: 20080131921. G.T.G. is a consultant for Acadia, Allergan, Avanir, Axovant, GE, Lundbeck, Novartis, Otsuka, Roche, Takeda. Research Support for Janssen, NIA. M.F. has received research support from Accera, Biogen, Eisai, Eli Lilly, Genentech, Roche, Lundbeck, Chase Pharmaceuticals, Boehringer Ingelheim, Novartis, and Suven Life Sciences, Ltd.; and has been a consultant and/or advisory or DSMB board member for Accera, AstraZeneca, Avanir, Axovant, AZTherapies, Eli Lilly & Company, FORUM Pharmaceuticals, INC Research, KCRN Research, Longeveron, Medavante, Merck and Co., Inc., Medtronic, Proclara (formerly Neurophage Pharmaceuticals), Neurotrope Biosciences, Novartis, Sanofi-Aventis, Stemedica Cell Technologies, Inc., Takeda, United Neuroscience Inc., and vTv Therapeutics. He also holds a patent for a transgenic mouse model that is licensed to Elan. A.C.C., E.G., P.J.S., E.C. and A.V. have nothing of relevance to declare.
PY - 2018/7/1
Y1 - 2018/7/1
N2 - 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.
AB - 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.
KW - Alzheimer's disease
KW - acetylcholine
KW - cholinergic system
KW - cholinesterase inhibitors
KW - cognition
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U2 - 10.1093/brain/awy132
DO - 10.1093/brain/awy132
M3 - Review article
C2 - 29850777
AN - SCOPUS:85048969248
VL - 141
SP - 1917
EP - 1933
JO - Brain
JF - Brain
SN - 0006-8950
IS - 7
ER -