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Pharmacological Drug Treatment of Alzheimer Disease: The Cholinergic Hypothesis Revisited
Abstract
Christopher J. Ladner, PhD, John M. Lee, MD, PhD; Pharmacological Drug Treatment of Alzheimer Disease: The Cholinergic Hypothesis Revisited, Journal of Neu
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“reduced ACh, is associated with an insufficient synthetic action of choline O-acetyltransferase (ChAt) and a high catalytic action of acetylcholinesterase (AChE), finally, lead to the loss of cholinergic transmission at the pre-synaptic level [15].”
From Multi-Target Mechanisms of Phytochemicals in Alzheimer’s Disease: Effects on Oxidative Stress, Neuroinflammation and Protein Aggregation (2022) · cites this paper as [15]
In the citing paper
“The cholinergic hypothesis argues that the reduction of learning and mnemonic processes at the base of the disease are due to low levels of ACh in neurons”
From Multi-Target Mechanisms of Phytochemicals in Alzheimer’s Disease: Effects on Oxidative Stress, Neuroinflammation and Protein Aggregation (2022) · cites this paper as [15]
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Synthesis of more potent analogues of the acetylcholinesterase inhibitor, huperzine B
Rajendran, V., Saxena, A., Doctor, B. P., et al. (2002) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/s0960-894x(02)00204-4 · Cited by 12
Rajendran, V., Prakash, K. R. C., Ved, H. S., et al. (2000) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/s0960-894x(00)00494-7 · Cited by 12
Tacrine-sugar mimetic conjugates as enhanced cholinesterase inhibitors
de Santana, Q. L. O., Evangelista, T. C. S., Imhof, P., Ferreira, S. B., Fernández‐Bolaños, J. G., Sydnes, M. O., López, Ó., & Lindbäck, E. (2021) · Organic & Biomolecular Chemistry · doi:10.1039/d0ob02588g · Cited by 10
Accelerating Alzheimer’s pathogenesis by GRK5 deficiency via cholinergic dysfunction
Suo, W. Z. (2013) · Advances in Alzheimer s Disease · doi:10.4236/aad.2013.24020 · Cited by 10
“Although the details of these two hypotheses may evolve over time with increasing insights into disease pathogenesis, the principal concepts of these distinct hypotheses appear to stand solidly [6,106-112].”
BackgroundKeleş, T., Bıyıklıoğlu, Z., Akkaya, D., et al. (2022) · TURKISH JOURNAL OF CHEMISTRY · doi:10.55730/1300-0527.3368 · Cited by 9
Association Analysis for the Muscarinic M1 Receptor Genetic Polymorphisms and Alzheimer’s Disease
Liu, H.-C., Hong, C., Liu, T., et al. (2004) · Dementia and Geriatric Cognitive Disorders · doi:10.1159/000080970 · Cited by 8
Lorme, K. C. D., Grant, M. K. O., Noetzel, M. J., et al. (2007) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.107.129940 · Cited by 8
“In contrast to the deterioration of presynaptic cholinergic input in Alzheimer’s disease, the M1 mAChR remains preserved throughout progression of the disease (Ladner and Lee, 1998).”
BackgroundRispoli, V., Marra, R., Costa, N., Rotiroti, D., Tirassa, P., Scipione, L., Vita, D. D., Liberatore, F., & Carelli, V. (2008) · Behavioural Brain Research · doi:10.1016/j.bbr.2008.02.002 · Cited by 7
Arruda, J. E., McInnis, M. C., & Steele, J. (2022) · Clinical EEG and Neuroscience · doi:10.1177/15500594211069727 · Cited by 6
Güngör, Ö., & Köse, M. (2022) · Journal of Biomolecular Structure and Dynamics · doi:10.1080/07391102.2022.2158945 · Cited by 6
“A decrease in ACh level in the body is the most prominent clinical findings in AD due to the rapid hydrolysis of acetylcholine (ACh), a neurotransmitter responsible for the transmission of electrical impulses to the nerve cell, by acetylcholinesterase (AChE) (Ladner & Lee, 1998).”
BackgroundProtective Effects of Statins against Alzheimer Disease
Rezakhani, L., Salimi, Z., Zarei, F., Moradpour, F., Khazaei, M. R., Khazaei, M., & Pourjalili, M. (2023) · Ewha Medical Journal · doi:10.12771/emj.2023.e17 · Cited by 6
“One strategy involves the use of acetylcholinesterase inhibitors, which prevent the breakdown or hydrolysis of ACh, thereby increasing its levels in the CNS [87].”
BackgroundOrmrod, D. J., & Spencer, C. M. (2000) · CNS Drugs · doi:10.2165/00023210-200013060-00006 · Cited by 6
Prasad, S., Kumar, Y. C. S., Kumar, C. S. A., et al. (2007) · The Open Medicinal Chemistry Journal · doi:10.2174/1874104500701010004 · Cited by 5
“These include the use of Acetylcholinesterase inhibitors, the administration of acetylcholine precursors, the investigation of acetylcholine releasers and direct acetylcholine receptor agonists [5].”
BackgroundPeptidyl epoxides as selective protease inactivators
Albeck, A. (2000) · Drug Development Research · doi:10.1002/1098-2299(200007/08)50:3/4 · Cited by 12
Soyer, Z. (2013) · MARMARA PHARMACEUTCAL JOURNAL · doi:10.12991/201317387 · Cited by 5
Soyer, Z., Parlar, S., & Alptüzün, V. (2014) · Dspace Repository (Marmara Üniversitesi) · doi:10.12991/mpj.61959 · Cited by 4
“Therefore, a promising treatment strategy for AD has been the use of acetylcholinesterase inhibitors (AChEIs) (1-4).”
Backgroundvon der Kammer, H., Mayhaus, M., Albrecht, C., Andresen, B., Klaudiny, J., Demiralay, C., & Nitsch, R. M. (2000) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.2000.tb06939.x · Cited by 3
Jasmin, S. B. (2011) · eScholarship@McGill (McGill) · doi:10.82308/52384 · Cited by 3
Cholinergic abnormalities in Alzheimer's disease: are there new targets for drug development?
Fodero, L. R., & Small, D. H. (2002) · Drug Development Research · doi:10.1002/ddr.10089 · Cited by 3
“This impaired coupling may lead to decreased signal transduction and to a reduction in the levels of sAPPa and the generation of more Ab [Jope, 1996; Kelly et al., 1996; Fisher, 1997; Ladner and Lee, 1998].”
BackgroundNanoparticle-mediated delivery of AChE inhibitors for the treatment of Alzheimer’s disease
Namdeo, P., Mathew, J., & Garg, A. (2022) · Elsevier eBooks · doi:10.1016/b978-0-323-85544-0.00004-6 · Cited by 5
GPCR, a rider of Alzheimer’s disease
Liu, X., & Zhao, J. (2011) · Frontiers in Biology · doi:10.1007/s11515-011-1129-3 · Cited by 3
“Further, the loss and dysfunction of cholinergic neurons correlate well with Aβ plaques, NFTs and clinical observation of AD ( Ladner and Lee, 1998 ), suggesting an interplay among the above three theories.”
BackgroundFisiopatología de la enfermedad de Alzheimer
Delacourte, A. (2002) · EMC - Tratado de Medicina · doi:10.1016/s1636-5410(02)70234-1 · Cited by 4
Therapeutic Role of Nanocurcumin in Alzheimer’s and Parkinson’s Disease
Barman, D. K., & Sahoo, H. (2023) · Springer eBooks · doi:10.1007/978-981-99-7731-4_16 · Cited by 1
Sarıkürkçü, C. (2025) · Selçuk Üniversitesi Fen Fakültesi Fen Dergisi · doi:10.35238/sufefd.1544595 · Cited by 1
Archive of SID NEUROPATHOLOGICAL CHANGES IN THE PDAPP TRANSGENIC MOUSE MODEL OF ALZHEIMER'S DISEASE
Pasbakhsh, P., Mehdizadeh, M., & Omidi, N. (2005) · Cited by 1
Les modèles pharmacologiques dans la recherche sur la maladie d’Alzheimer
Gilles, C., Ertle, S., & Macher, J. P. (2001) · Annales Médico-psychologiques revue psychiatrique · doi:10.1016/s0003-4487(00)00011-1 · Cited by 1
M1 Muscarinic Agonists as a Therapeutic Strategy in Alzheimer’s Disease
Fisher, A., Pittel, Z., Haring, R., Brandeis, R., Bar-Ner, N., Sonego, H., Marcovitch, I., Natan, N., Mestre‐Francés, N., & Bons, N. (2002) · Advances in behavioral biology · doi:10.1007/978-0-306-47593-1_34 · Cited by 1
(2000) · Time to knit · doi:10.1016/s0246-0378(19)30299-4 · Cited by 1
“Les agonistes muscariniques et nicotiniques pourraient avoir une activité pharmacologique intéressante [76], en cours d’exploration actuellement.”
Biomarkers and Surrogate Markers in Drug Development
Cutler, N. R., Sramek, J. J., Murphy, M. F., Riordan, H., Bieck, P. R., & Carta, A. (2010) · Wiley eBooks · doi:10.1002/9781444318579.ch4
Karn, S., Wei, Z., MacTavish, D., Kabogo, D., Song, M.-S., & Jhamandas, J. H. (2006) · Springer eBooks · doi:10.1007/978-1-84628-440-3_10
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Pasbakhsh, P., Mehdizadeh, M., & Omidi, N. (2005)
Investigação de associação entre a Butirilcolinesterase e a doença de Alzheimer
Bono, G. F. (2014) · LA Referencia (Red Federada de Repositorios Institucionales de Publicaciones Científicas)
Physiopathologie de la maladie d'Alzheimer
Delacourte, A. (2006) · EMC - Traité de médecine AKOS · doi:10.1016/s1634-6939(06)75448-5
Farooqui, A. A. (2016) · Springer eBooks · doi:10.1007/978-3-319-15889-1_2
“…of individuals with AD have indicated that a profound reduction in the activity of the ACh-synthesizing enzyme, choline acetyltransferase (ChAT), in the neocortex, which correlates positively with the severity of dementia (Geula and Mesulam 1994 ; Lander and Lee 1998 ; Davies and Maloney 1976 ).”
BackgroundRoles of GRK Dysfunction in Alzheimer’s Pathogenesis
Suo, W. Z. (2016) · Methods in pharmacology and toxicology · doi:10.1007/978-1-4939-3798-1_10
NEUROBIOLOGIA DA DOENÇA DE ALZHEIMER
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Metrifonateof its Use in Alzheimer's Disease
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Chung, J.-Y. (2015) · ERA: Education and Research Archive (University of Alberta) · doi:10.7939/r32h3s
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SEMI-SYNTHESIS AND EVALUATION OF HESPERETIN DERIVATIVES AS ACETYLCHOLINESTERASE INHIBITORS7
The, H. T., & Thanh, D. T. (2018) · Journal of Medicine and Pharmacy · doi:10.34071/jmp.2018.4.1
Identification and Screening of Novel ACE Inhibitors using Computational Approach
Mishra, M. M., & Kumar, P. (2023) · International Conference on Intelligent Communication and Computational Techniques (ICCT) · doi:10.1109/icct56969.2023.10075941
“This atrophy is characterized by the reduction in the amount of neurotransmitter such as acetylcholine which are accountable for the transmission of electrical impulsive signal from nerve cell to another due to the hydrolysis by acetylcholinesterase enzyme[6].”
Background(2000) · Time to knit · doi:10.1016/s0246-0378(19)30329-x
(2000) · Time to knit · doi:10.1016/s1293-2973(00)00119-x
Değirmenci, U. (2025) · Harran Üniversitesi Tıp Fakültesi Dergisi · doi:10.35440/hutfd.1555225
Metadata
- Authors
- Ladner, C. J., & Lee, J. M.
- Affiliations
- Loyola University Medical Center (US)
- Corresponding author
- Lee, John M.
- ORCID
- Lee, John M.
- Venue
- Journal of Neuropathology & Experimental Neurology
- Publisher
- Oxford University Press (OUP)
- Published
- 1998-08
- Volume
- 57
- Issue
- 8
- Pages
- 719-731
- ISSN
- 0022-3069 (ISSN-L)
- 1554-6578
- OpenAlex
- W2061570982
- Cited by
- 142
- References
- 0
- Citations by year
- 2025: 2 · 2023: 3 · 2022: 8 · 2021: 4 · 2020: 7 · 2019: 3 · 2018: 8 · 2017: 3 · 2016: 7 · 2015: 4 · 2014: 4 · 2013: 5 · 2012: 1
- FWCI
- 7.08
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Neuropathology & Experimental Neurology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Pharmacology (medical) › Cholinesterase and Neurodegenerative Diseases
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- Alzheimer's disease, cholinergic hypothesis, cholinesterase inhibitors, acetylcholinesterase, pharmacotherapy, cholinergic system
- MeSH terms
- Acetylcholine, Alzheimer Disease, Central Nervous System, Humans, Receptors, Muscarinic, Receptors, Nicotinic
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