The Cholinergic Hypothesis of Age and Alzheimer’s Disease-Related Cognitive Deficits: Recent Challenges and Their Implications for Novel Drug Development
Abstract
The cholinergic hypothesis was initially presented over 20 years ago and suggests that a dysfunction of acetylcholine containing neurons in the brain contributes substantially to the cognitive decline observed in those with advanced age and Alzheimer's disease (AD). This premise has since served as the basis for the majority of treatment strategies and drug development approaches for AD to date. Recent studies of the brains of patients who had mild cognitive impairment or early stage AD in which choline acetyltransferase and/or acetylcholinesterase activity was unaffected (or even up-regulated) have, however, led some to challenge the validity of the hypothesis as well as the rationale for using cholinomimetics to treat the disorder, particularly in the earlier stages. These challenges, primarily based on assays of post mortem enzyme activity, should be taken in perspective and evaluated within the wide range of cholinergic abnormalities known to exist in both aging and AD. The results of both post mortem and antemortem studies in aged humans and AD patients, as well as animal experiments suggest that a host of cholinergic abnormalities including alterations in choline transport, acetylcholine release, nicotinic and muscarinic receptor expression, neurotrophin support, and perhaps axonal transport may all contribute to cognitive abnormalities in aging and AD. Cholinergic abnormalities may also contribute to noncognitive behavioral abnormalities as well as the deposition of to…
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Oxidative stress and mitochondrial impairment are central amplifiers of cellular injury in AD.
“Cholinergic dysfunction has long been recognized as a correlate of cognitive decline, while oxidative stress and mitochondrial impairment are increasingly appreciated as central amplifiers of cellular injury [12, 13].”
From Toward a Unified Framework in Molecular Neurobiology of Alzheimer’s Disease: Revisiting the Pathophysiological Hypotheses (2026) · cites this paper as [13]
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- Authors
- Terry, A. V., & Buccafusco, J. J.
- Affiliations
- University of Georgia (US)
- Augusta University (US)
- ORCID
- Terry, A.V.
- Venue
- The Journal of Pharmacology and Experimental Therapeutics
- Publisher
- Elsevier BV
- Published
- 2003-09
- Volume
- 306
- Issue
- 3
- Pages
- 821-827
- ISSN
- 0022-3565 (ISSN-L)
- OpenAlex
- W2135134122
- Cited by
- 1,159
- References
- 2
- Citations by year
- 2026: 29 · 2025: 35 · 2024: 60 · 2023: 62 · 2022: 90 · 2021: 51 · 2020: 44 · 2019: 58 · 2018: 67 · 2017: 66 · 2016: 48 · 2015: 72 · 2014: 64 · 2013: 67 · 2012: 54
- FWCI
- 4.63
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Pharmacology and Experimental Therapeutics (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Pharmacology › Cholinesterase and Neurodegenerative Diseases
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- cholinergic hypothesis, Alzheimer's disease, aging, cognitive decline, acetylcholine, cholinergic drugs, choline acetyltransferase, acetylcholinesterase, mild cognitive impairment, nicotinic acetylcholine receptors, muscarinic receptors, choline transport, axonal transport, neurotrophins, neuritic plaques, behavioral abnormalities, drug development
- MeSH terms
- Acetylcholine, Aging, Alzheimer Disease, Cognition Disorders, Humans, Cholinergic Antagonists
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