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Research ArticlePERSPECTIVES IN PHARMACOLOGY

The Cholinergic Hypothesis of Age and Alzheimer's Disease-Related Cognitive Deficits: Recent Challenges and Their Implications for Novel Drug Development

A. V. Terry Jr and J. J. Buccafusco
Journal of Pharmacology and Experimental Therapeutics September 2003, 306 (3) 821-827; DOI: https://doi.org/10.1124/jpet.102.041616
A. V. Terry Jr
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J. J. Buccafusco
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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 toxic neuritic plaques in AD. Therefore, cholinergic-based strategies will likely remain valid as one approach to rational drug development for the treatment of AD other forms of dementia.

Footnotes

  • The authors of this work are supported by the National Institute of Mental Health, The Alzheimer's Association, The Institute for the Study of Aging, and the Office of Research and Development, Medical Research Service, Department of Veterans Affairs. The authors have also provided consultation or performed research (relevant to this article) either contractually or in collaboration with a number of pharmaceutical companies including Abbott Laboratories, Boehringer Ingelheim, Hoechst Marion Roussel, Janssen Pharmaceutica, Lilly, Merck, Pfizer, Roche Bioscience, SIBIA Neurosciences, Teva Pharmaceuticals, and Wyeth-Ayerst Research.

  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

  • DOI: 10.1124/jpet.102.041616.

  • ABBREVIATIONS: AD, Alzheimer's disease; MCI, mild cognitive impairment; AChE, acetylcholinesterase; ChAT, choline acetyl transferase; NGF, nerve growth factor; PET, positron emission tomography; APP, amyloid precursor protein; Aβ, amyloid-β.

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Journal of Pharmacology and Experimental Therapeutics: 306 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 306, Issue 3
1 Sep 2003
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Research ArticlePERSPECTIVES IN PHARMACOLOGY

The Cholinergic Hypothesis of Age and Alzheimer's Disease-Related Cognitive Deficits: Recent Challenges and Their Implications for Novel Drug Development

A. V. Terry and J. J. Buccafusco
Journal of Pharmacology and Experimental Therapeutics September 1, 2003, 306 (3) 821-827; DOI: https://doi.org/10.1124/jpet.102.041616

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Research ArticlePERSPECTIVES IN PHARMACOLOGY

The Cholinergic Hypothesis of Age and Alzheimer's Disease-Related Cognitive Deficits: Recent Challenges and Their Implications for Novel Drug Development

A. V. Terry and J. J. Buccafusco
Journal of Pharmacology and Experimental Therapeutics September 1, 2003, 306 (3) 821-827; DOI: https://doi.org/10.1124/jpet.102.041616
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    • The Cholinergic Hypothesis
    • Challenges to the Cholinergic Hypothesis
    • Aging and Brain Cholinergic Neurons
    • Anticholinergic Drugs in Elderly Subjects and AD Patients
    • Amyloid and the Cholinergic System
    • Cholinergic-Based Therapeutic Strategies (Present and Future Considerations)
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