The cholinergic hypothesis of age and Alzheimer's disease-related cognitive deficits

Recent challenges and their implications for novel drug development

Alvin V Terry, J. J. Buccafusco

Research output: Contribution to journalReview article

682 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)821-827
Number of pages7
JournalJournal of Pharmacology and Experimental Therapeutics
Volume306
Issue number3
DOIs
StatePublished - Sep 1 2003

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Cholinergic Agents
Alzheimer Disease
Pharmaceutical Preparations
Axonal Transport
Choline O-Acetyltransferase
Poisons
Amyloid Plaques
Nerve Growth Factors
Brain
Nicotinic Receptors
Muscarinic Receptors
Acetylcholinesterase
Choline
Acetylcholine
Dementia
Neurons
Enzymes
Therapeutics

ASJC Scopus subject areas

  • Pharmacology

Cite this

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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.",
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