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Cited by 2,198Alzheimer's disease research and treatmentsCholinesterase and Neurodegenerative DiseasesDementia and Cognitive Impairment Research

The cholinergic hypothesis of Alzheimer’s disease: A review of progress

Open access
Francis, P. T, Palmer, A. M, Snape, M., Wilcock, G. K·1999·Journal of Neurology, Neurosurgery & Psychiatry
DOI 10.1136/jnnp.66.2.137PMC PMC1736202
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Abstract

Alzheimer's disease is one of the most common causes of mental deterioration in elderly people, accounting for around 50%-60% of the overall cases of dementia among persons over 65 years of age. The past two decades have witnessed a considerable research effort directed towards discovering the cause of Alzheimer's disease with the ultimate hope of developing safe and effective pharmacological treatments. This article examines the existing scientific applicability of the original cholinergic hypothesis of Alzheimer's disease by describing the biochemical and histopathological changes of neurotransmitter markers that occur in the brains of patients with Alzheimer's disease both at postmortem and neurosurgical cerebral biopsy and the behavioural consequences of cholinomimetic drugs and cholinergic lesions. Such studies have resulted in the discovery of an association between a decline in learning and memory, and a deficit in excitatory amino acid (EAA) neurotransmission, together with important roles for the cholinergic system in attentional processing and as a modulator of EAA neurotransmission. Accordingly, although there is presently no "cure" for Alzheimer's disease, a large number of potential therapeutic interventions have emerged that are designed to correct loss of presynaptic cholinergic function. A few of these compounds have confirmed efficacy in delaying the deterioration of symptoms of Alzheimer's disease, a valuable treatment target considering the progressive nature of the disease. Indeed, three compounds have received European approval for the treatment of the cognitive symptoms of Alzheimer's disease, first tacrine and more recently, donepezil and rivastigmine, all of which are cholinesterase inhibitors.

AI snapshot

Written from the paper’s full text.

TL;DR

This narrative review re-evaluates the cholinergic hypothesis of Alzheimer’s disease, concluding that cholinergic dysfunction contributes to cognitive symptoms largely through attentional processing and may compound excitatory amino acid pyramidal neuron loss. It reports that cholinesterase inhibitors such as tacrine, donepezil, and rivastigmine provide symptomatic benefit, delaying decline by about 6–12 months, while noting that cholinergic loss is not a direct or sole cause of dementia.

Key findings

  • Alzheimer’s disease accounts for around 50%–60% of dementia cases among people over 65, affects an estimated 15 million people worldwide, and has a mean duration of around 8.5 years between clinical onset and death. Presynaptic cholinergic markers, including ChAT activity and ACh synthesis, are reduced early and correlate with cognitive impairment; glutamate concentration was reduced by 14% in temporal lobe biopsy samples from patients with Alzheimer’s disease.
  • The cholinergic hypothesis is refined to include a major role for excitatory amino acid pyramidal neurons: cholinergic dysfunction may not cause cognitive impairment directly but indirectly by interfering with attentional processing, and cholinergic hypofunction may compound loss of EAA function.
  • In a 30-week randomised, double-blind donepezil trial (5 or 10 mg/day versus placebo; n=150/group, 450 total), statistically significant improvements were obtained for both doses on ADAS-cog (p<0.001) and CIBIC plus (p<0.005); donepezil 10 mg/day delayed loss of activities of daily living by about 1 year, and cholinesterase inhibitors generally delay symptomatic decline by about 6–12 months.
  • Three compounds received European approval for cognitive symptoms—tacrine, donepezil, and rivastigmine—but less than half of patients receiving cholinesterase inhibitors achieve a clinically significant response. Tacrine caused cholinergic side effects in about 20% of patients within the therapeutic range; in one 30-week trial over 50% discontinued because of cholinergic side effects, and over 70% titrated to 160 mg/day failed to complete the study. Donepezil is over 1000-fold more selective for AChE than BuChE and showed no evidence of hepatotoxicity.

Methods

  • Narrative review re-evaluating the cholinergic hypothesis by synthesising biochemical and histopathological findings from postmortem and neurosurgical cerebral biopsy studies, behavioural studies of cholinomimetic drugs and cholinergic lesions, and preclinical and clinical development of cholinomimetic drugs.
  • Data sources include human brain tissue, animal and human pharmacological/behavioural studies, and clinical trials of cholinesterase inhibitors; no systematic search strategy or meta-analysis is described.

Limitations

  • Stated in the paper: an association between cholinergic loss and cognitive impairment does not prove causality; some patients with Alzheimer’s disease do not show large decreases in ChAT activity, and patients with inherited olivopontocerebellar atrophy have similarly diminished ChAT activity without cognitive deficits. Diagnostic inaccuracy may be as high as 20%, Alzheimer’s disease is heterogeneous, responders cannot yet be predicted, and no data have been reported on whether cholinomimetic drugs increase APP or reduce β-amyloid production in patients.
  • Stated in the paper: long-term studies needed to test effects on pathology may raise ethical problems, including serial lumbar puncture and placebo-controlled groups.
  • Evident from the text: this is a narrative review rather than a systematic review or meta-analysis, and the manuscript was supported by an educational grant from Eisai Inc and Pfizer Pharmaceuticals Group, makers of donepezil.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1136/jnnp.66.2.137

Cites

130 of 130 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 112 cited sources checked · 0 supported · 0 flagged

  • Findingreasoning

    The prediction that cholinomimetic drugs would improve cognitive function was not fully realised with compounds such as physostigmine and tacrine.

    “This prediction was not fully realised with compounds such as physostigmine and tacrine”
    Quote in the paperSubstantial claim
  • Premisecitation

    Subsequent discoveries of reduced choline uptake, acetylcholine release, and loss of cholinergic perikarya from the nucleus basalis of Meynert confirmed a substantial presynaptic cholinergic deficit in Alzheimer's disease.

    “Subsequent discoveries of reduced choline uptake, 5 ACh release 6 and loss of cholinergic perikarya from the nucleus basalis of Meynert 7 confirmed a substantial presynaptic cholinergic deficit.”
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  • Premisecitation

    Presynaptic markers of the cholinergic system appear uniformly reduced in Alzheimer's disease.

    “Specifically, presynaptic markers of the cholinergic system appear uniformly reduced.”
    Quote in the paperSubstantial claim
  • Premisecitation

    Reductions in ChAT activity and acetylcholine synthesis are strongly correlated with the degree of cognitive impairment in patients with Alzheimer's disease.

    “This is exemplified by reductions in ChAT activity and ACh synthesis which are strongly correlated with the degree of cognitive impairment in patients with Alzheimer's disease.[12][13][14][15]”
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  • Interpretationcitation

    Neocortical cholinergic innervation is probably lost at an early stage of Alzheimer's disease.

    “On the basis of the above evidence, neocortical cholinergic innervation is probably lost at an early stage of the disease, a conclusion substantiated by evidence for similar changes in patients that have displayed clinical symptoms for less than 1 year.22”
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  • May combine two claims. 38

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    Findingnone given

    Poor tolerability seems to be less of an issue for second generation compounds of the type now being licensed for the treatment of Alzheimer's disease.

    “Poor tolerability seems to be less of an issue for the second generation compounds of the type now being licensed for the treatment of Alzheimer's disease.”
    Quote in the paperNot a substantial claim

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    Premisecitation

    A few patients with Alzheimer's disease do not show large decreases in ChAT activity, although a small reduction is found in the amygdala.

    “Moreover, a few patients with Alzheimer's disease do not show large decreases in ChAT activity, albeit that a small reduction is found in the amygdala.24”
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    Premisecitation

    In Alzheimer's disease biopsy tissue, serotonergic and some noradrenergic markers are affected, whereas markers for dopamine, GABA, or somatostatin are not altered.

    “Whereas serotonergic and some noradrenergic markers are aVected, markers for dopamine, -aminobutyric acid (GABA), or somatostatin are not altered.12”
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    Interpretationreasoning

    Although loss of cholinergic function is correlated with cognitive impairment in Alzheimer's disease, an association between two such indices does not necessarily indicate a causal relation.

    “However, although the loss of cholinergic function is correlated with the cognitive impairment in Alzheimer's disease, an association between two such indices does not necessarily indicate a causal relation.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Disease-related changes in the Alzheimer's disease brain are focused on pyramidal neurons because these cells are lost, subject to tangle formation, represent a major source of APP, and are regulated by acetylcholine, which is affected early in the disease.

    “It is of interest here that disease related changes in the Alzheimer's disease brain are focused on pyramidal neurons in that these cells are lost in the disease, subject to tangle formation, represent a major source of APP (and hence, a site for its mismetabolism leading to increased -amyloid production) and are regulated by a neurotransmitter (ACh), aVected early in the disease.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    Compounds being developed for symptomatic treatment may have a serendipitous effect on the continuing emergence of pathology by reducing the production of beta-amyloid.

    “suggests that compounds being developed for symptomatic treatment may have a serendipitous eVect on the continuing emergence of pathology by reducing the production of -amyloid.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Interpretationreasoning

    If these neurotransmitter-protein interactions occur in the Alzheimer's disease brain, changes in the balance of neurotransmission may contribute to increased tau phosphorylation and beta-amyloid production and hence neurodegeneration in selectively vulnerable regions.

    “Thus, if these neurotransmitter-protein interactions occur in the Alzheimer's disease brain, it is not inconceivable that the changes in the balance of neurotransmission in the Alzheimer's disease brain may contribute to increased tau phosphorylation and -amyloid production and hence neurodegeneration in selectively vulnerable regions.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Loss of cortical pyramidal neurons, synapse loss, reduced glutamate concentration, and neurofibrillary tangle formation all correlate with the severity of dementia.

    “Loss of cortical pyramidal neurons, 23 40 41 synapse loss, 40 and reduced glutamate concentration, 17 together with the formation of neurofibrillary tangles, 42 all correlate with the severity of dementia.”
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    Interpretationreasoning

    These neurons therefore seem to have a central role in the clinical symptoms as well as in the pathophysiology of Alzheimer's disease.

    “These neurons therefore seem to have a central role in the clinical symptoms as well as in the pathophysiology of the disease.”
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    Premisecitation

    There is a reduction in the number of nicotinic and muscarinic (M2) acetylcholine receptors in Alzheimer's disease brains, most of which are considered to be located on presynaptic cholinergic terminals, but there is relative preservation of postsynaptic muscarinic (M1, M3) receptors.

    “Other studies have demonstrated a reduction in the number of nicotinic 26 and muscarinic (M2) ACh receptors in Alzheimer's disease brains, most of which are considered to be located on presynaptic cholinergic terminals, but a relative preservation of postsynaptic muscarinic (M1, M3) receptors. 27”
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    Premisecitation

    Electrophysiological studies show excitatory actions of cholinomimetic drugs in cortical pyramidal neurons from both rats and humans, and microdialysis studies in rats support this.

    “This is supported by electrophysiological studies showing the excitatory actions of cholinomimetic drugs in cortical pyramidal neurons from both rats and humans 30 31 and microdialysis studies in rats.32”
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    Premisecitation

    Cholinergic neurotransmission may be a specific target for beta-amyloid, as beta-amyloid has been shown to reduce both choline uptake and acetylcholine release in vitro.

    “Cholinergic neurotransmission may be a specific target for -amyloid, as it has been shown to reduce both choline uptake and ACh release in vitro.47 48”
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    Interpretationreasoning

    As a consequence of reduced cholinergic activity, reduced activation of protein kinase C may lead to a higher level of activity of GSK-3 and hence hyperphosphorylation of tau.

    “Therefore, as a consequence of reduced cholinergic activity, reduced activation of protein kinase C may lead to a higher level of activity of GSK-3 and hence hyperphosphorylation of tau.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    These findings indicate that pyramidal neurons and their transmitter glutamate (and/or aspartate) play a part in the cognitive symptoms of Alzheimer's disease and may therefore represent an additional therapeutic target.

    “These findings indicate that pyramidal neurons and their transmitter glutamate (and/or aspartate) play a part in the cognitive symptoms of Alzheimer's disease and may therefore represent an additional therapeutic target.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Excitatory amino acid (EAA) releasing cortical pyramidal neurons contribute to normal cognitive function and have a pivotal role in cholinergic function because they are cholinoceptive.

    “These neurons, considered to contribute to normal cognitive function in their own right, also seem to have a pivotal role in cholinergic function as they are cholinoceptive.[29][30][31][32]”
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    Premisecitation

    Neurochemical studies of EAA neurotransmission have failed to show profound or extensive alterations in EAA neuronal indices, possibly because of difficulty in distinguishing the transmitter pool of aspartate and glutamate from the metabolic pool.

    “Although neurochemical studies of EAA neurotransmission have failed to show profound or extensive alterations in EAA neuronal indices, 12 this may be related to the diYculty in distinguishing the transmitter pool of aspartate and glutamate from the metabolic pool.”
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    Interpretationreasoning

    Although diminished ChAT activity is a necessary correlate of Alzheimer's disease, additional factors other than impaired cholinergic function are likely to participate in the decline in cognitive function.

    “Thus, although diminished ChAT activity is a necessary correlate of Alzheimer's disease, additional factors other than impaired cholinergic function are likely to participate in the decline in cognitive function.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Interpretationreasoning

    Given that depression and aggression are important determinants of quality of life for patients with Alzheimer's disease and their carers, such effects may have clinical relevance.

    “Given that depression and aggression are important determinants of quality of life for patients with Alzheimer's disease and their carers, such eVects may have clinical relevance.1”
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    Premisecitation

    Injection of quisqualic acid and AMPA into the same site causes a greater loss of ChAT activity than ibotenate but only marginal impairments in the same range of cognitive tasks.

    “However, injection of the toxins quisqualic acid and -amino-3-hydroxy-5-methyl-4-isoxazole (AMPA) into the same site causes a greater loss of ChAT activity than ibotenate but only marginal impairments in the same range of cognitive tasks.62”
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    Premisecitation

    The inhibition produced by tacrine and donepezil is mutually exclusive, suggesting that both compounds act at similar sites within the enzyme, although donepezil is more potent and selective.

    “Further, the inhibition produced by these compounds is mutually exclusive, suggesting that both compounds act at similar sites within the enzyme, although donepezil is more potent and selective.70 71”
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    Premisecitation

    Both tacrine and donepezil displace the binding of selective ligands from muscarinic and nicotinic acetylcholine receptors, although neither compound has significant activity at other neurotransmitter receptors.

    “Both tacrine and donepezil displace the binding of selective ligands from muscarinic and nicotinic ACh receptors, 57 71 83-85 although neither compound has significant activity at other neurotransmitter receptors.”
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    Interpretationcitation

    These effects on muscarinic receptors only occur at concentrations significantly greater than those needed for cholinesterase inhibition and are not likely to have relevance in the clinic.

    “However, these eVects only occur at concentrations of the compounds significantly greater than those needed to produce the required degree of ChE inhibition and are not therefore likely to have relevance in the clinic.86”
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    Interpretationreasoning

    These effects might be expected to influence affective states, such as mood, in a positive manner.

    “These type of eVects might be expected to influence aVective states-for example, mood-in a positive manner.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    The cholinergic hypothesis may be refined to include the idea that a major target of cholinomimetic action is EAA pyramidal neurons, and that cholinergic hypofunction compounds the loss of EAA function.

    “Thus, the cholinergic hypothesis may be refined to include the idea that a major target of cholinomimetic action is EAA pyramidal neurons, and that cholinergic hypofunction compounds the loss of EAA function.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Methylscopolamine, which does not cross the blood-brain barrier, is as active as scopolamine in several models of cognitive function, indicating that peripheral changes induced by these compounds indirectly influence performance in cognitive tasks.

    “For example, methylscopolamine (which does not cross the blood-brain barrier) is as active as scopolamine in several models of cognitive function, 55 56 indicating that peripheral changes induced by these compounds indirectly influence performance in cognitive tasks.”
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    Premisecitation

    Intraventricular administration of nerve growth factor prevents lesion-induced loss of cholinergic neuronal cell bodies and accelerates recovery of behavioural deficits in learning.

    “Consequently, intraventricular administration of NGF has been shown to prevent the lesion induced loss of cholinergic neuronal cell bodies and to accelerate the recovery of behavioural deficits in learning.67”
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    Premisecitation

    At muscarinic receptors, both tacrine and donepezil act as antagonists.

    “At muscarinic receptors, both compounds act as antagonists.71”
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    Premisecitation

    Clinical data with selective and non-selective AChE inhibitors suggest that BuChE inhibition may be associated with unwanted peripheral side effects, although this remains an unproved empirical finding.

    “Although the function of BuChE remains unknown, 77 clinical data with selective and non-selective AChE inhibitors suggest the BuChE inhibition may be associated with unwanted peripheral side eVects, 78 79 although to date, this remains an unproved empirical finding.”
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    Premisecitation

    Compared with tacrine, less peripheral cholinergic-related side effects have been found with donepezil, as it is over 1000-fold more selective for AChE than BuChE.

    “However, compared with tacrine, less peripheral cholinergicrelated side eVects have been found with donepezil, as it is over 1000-fold more selective for AChE than BuChE.70 74 79 80”
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    Premisecitation

    Non-competitive inhibitors may produce only slowly reversible cholinesterase inhibition, and the rate at which this inhibition is reversed may be of the same order as the rate of enzyme synthesis.

    “Non-competitive inhibitors may produce only slowly reversible ChE inhibition.The rate at which this inhibition is reversed may be of the same order as the rate of enzyme synthesis.76”
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    Interpretationreasoning

    This revised cholinergic hypothesis provides a stronger case for the continued development of cholinomimetic drugs for the symptomatic treatment of Alzheimer's disease.

    “This revised cholinergic hypothesis provides a stronger case for the continued development of cholinomimetic drugs for the symptomatic treatment of Alzheimer's disease.”
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    Interpretationcitation

    Greater brain AChE inhibition may be achieved with donepezil at the therapeutically effective dose compared with tacrine, increasing donepezil's potential clinical efficacy.

    “Thus, greater brain AChE inhibition may be achieved with donepezil at the therapeutically eVective dose compared with tacrine, increasing donepezil's potential clinical eYcacy.71”
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    Premisecitation

    Metrifonate inhibits cholinesterase irreversibly; it is a prodrug converted into dichlorvos, an organophosphorus cholinesterase inhibitor with a very long duration of inhibition and a half-life of 52 days.

    “A further compound, metrifonate, inhibits ChE irreversibly.Metrifonate is a prodrug that is converted into dichlorvos, an organophosphorus ChE inhibitor with a very long duration of inhibition (the half life is 52 days).75”
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    Interpretationreasoning

    Together these systems may be largely responsible for the neuropsychological deficits and may contribute to the continuing emergence of pathology in patients with Alzheimer's disease.

    “Together these systems may be largely responsible for the neuropsychological deficits and may contribute to the continuing emergence of pathology in patients with Alzheimer's disease.”
    Quote in the paperSubstantial claim

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    Premisecitation

    Both tacrine and nicotine improve attentional functions in patients with Alzheimer's disease.

    “This is supported by a study showing that both tacrine and nicotine improve attentional functions in patients with Alzheimer's disease.66”
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    Interpretationcitation

    In addition to the established role for acetylcholine in learning and memory, there are data to suggest that acetylcholine also plays a critical part in attentional processing.

    “Thus, in addition to the established role for ACh in learning and memory, there are data to suggest that ACh also plays a critical part in attentional processing.[63][64][65]”
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    Premisecitation

    In the same 30-week study, statistically significant improvements were obtained with both 5 and 10 mg/day of donepezil for CIBIC plus (p<0.005).

    “In one 30 week randomised, double blind study of donepezil (5 or 10 mg/day) versus placebo (n=150/group, 450 total), statistically significant improvements were obtained with both 5 and 10 mg/day of donepezil for the intent to treat analysis of Alzheimer's disease assessment scale (ADAS-cog 104 ; p<0.001) and the clinician's interview based impression of change (CIBIC plus 105 ; p<0.005).97”
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    Premisecitation

    Donepezil (5 and 10 mg/day) is well tolerated with no evidence of hepatotoxicity.

    “Donepezil (5 and 10 mg/day) is well tolerated with no evidence of hepatotoxicity.70 96-98 108 and an incidence of side eVects (5 mg/day) similar to that of placebo.[96][97][98]”
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  • May combine two claims.

    Interpretationcitation

    ChE inhibitors delay the progression of symptoms of Alzheimer's disease and improve patients, on average, by the equivalent of 6-12 months deterioration.

    “This gen-eral thesis that ChE inhibitors will delay the progression of symptoms of Alzheimer's disease and improve patients, on average, by the equivalent of 6-12 months deterioration, is now receiving further support with the publication of results from the trials of rivastigmine and metrifonate.[99][100][101][102]”
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    Premisecitation

    Donepezil produces dose-related significant improvements in cognition and global function.

    “For example, donepezil has a once daily dosage schedule and produces dose related significant improvements in cognition and global function, with over 80% of patients experiencing an improvement or no deterioration in cognition.”
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    Interpretationreasoning

    Some patients respond considerably more than the mean reported in clinical trials, while others respond less.

    “Thus, whereas some patients, of course, respond considerably more than the mean reported in clinical trials, others similarly, will respond less.”
    Quote in the paperNot a substantial claim

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    Premisecitation

    Clinical improvement as determined by ADAS-cog was correlated with both donepezil plasma concentrations and AChE inhibition.

    “This clinical improvement (as determined by the ADAS-cog) was correlated with both donepezil plasma concentrations and AChE inhibition.96”
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  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given

    Cholinomimetic treatment may be beneficial in other dementias where a cholinergic deficit also exists, for example Lewy body disease.

    “Cholinomimetic treatment is targeted specifically at patients with Alzheimer's disease, albeit that such treatment may be beneficial in other dementias where a cholinergic deficit also exists-for example, Lewy body disease.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    It has not yet been possible to predict or distinguish responders from non-responders.

    “Unfortunately, however, it has not yet been possible to predict or distinguish responders from non-responders.”
    Quote in the paperNot a substantial claim
44 of 44

  • The paper relies on this without support.

    Diagnostic inaccuracy in Alzheimer's disease may be as high as 20%.

    “Diagnostic inaccuracy, which may be as high as 20%, can produce a strong bias in favour of non-response when the results in diVerent treatment arms are”

  • The paper relies on this without support.

    Alzheimer's disease is heterogeneous at a genetic, clinical, neurochemical, and neuropathological level.

    “The heterogeneity of Alzheimer's disease at a genetic, clinical, neurochemical, and neuropathological level may also contribute to differing response rates.”

  • The paper relies on this without support.

    Cholinergic dysfunction causes cognitive impairment indirectly by interfering with attentional processing rather than directly.

    “Although it is now clear that cholinergic dysfunction may not cause cognitive impairment directly, but rather indirectly, by interfering with attentional processing”
3 of 3

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Damage to cholinergic neurons is a critical pathological change associated with Alzheimer's disease-related cognitive impairment.

    “Damage to the cholinergic neurons has also been accepted as a critical pathological chance associated with AD-related cognitive impairment [25].”

    From The Multifaceted Role of Neuroprotective Plants in Alzheimer’s Disease Treatment (2022) · cites this paper as [25]

  • Cholinergic neuronal dysfunction in the brain could substantially contribute to Alzheimer's disease-related cognitive decline.

    “As such, the cholinergic hypothesis proposes that cholinergic neuronal dysfunction in the brain could substantially contribute to the AD-related cognitive decline [25].”

    From The Multifaceted Role of Neuroprotective Plants in Alzheimer’s Disease Treatment (2022) · cites this paper as [25]

Cites

Flagged first, then by citations

12 of the 142 references couldn’t be matched to a known paper.

Research works printed but not linked: 12

  1. Wilcock GK, Esiri MM, Bowen DM, et al. Alzheimer's dis- ease. Correlation of cortical choline acetyltransferase activ- ity with the severity of dementia and histological abnor- malities. J Neurol Sci 1982;57:407-17.
  2. McCormick DA, Prince DA. Two types of muscarinic responses to acetycholine in mammalian cortical neurones. Proc Natl Acad Sci USA 1985;82:6344-8.
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Authors
Francis, P. T., Palmer, A. M., Snape, M., & Wilcock, G. K.
Affiliations
King's College London (GB)
Corresponding author
Francis, P. T
ORCID
Venue
Journal of Neurology, Neurosurgery & Psychiatry
Publisher
BMJ
Published
1999-02-01
Volume
66
Issue
2
Pages
137-147
ISSN
0022-3050 (ISSN-L)
DOI
10.1136/jnnp.66.2.137
PMC
PMC1736202
OpenAlex
W2137777161
Semantic Scholar
1c514b0b0cb110ac1b7f1d209d119f2a5b1c93d5
Cited by
2,198
References
142
Citations by year
2026: 45 · 2025: 93 · 2024: 99 · 2023: 110 · 2022: 114 · 2021: 121 · 2020: 114 · 2019: 122 · 2018: 130 · 2017: 119 · 2016: 102 · 2015: 124 · 2014: 109 · 2013: 102 · 2012: 70
FWCI
6.43
Type
journal article
Language
en
Open access
Locations
  • Journal of Neurology Neurosurgery & Psychiatry (publishedVersion)
  • PubMed Central (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
Alzheimer's disease, cholinergic hypothesis, cholinergic system, acetylcholine, cholinesterase inhibitors, tacrine, donepezil, rivastigmine, excitatory amino acid neurotransmission, learning and memory, attention, cholinomimetic drugs, cholinergic lesions, dementia, postmortem neuropathology
MeSH terms
Alzheimer Disease, Cholinergic Fibers, Cholinesterase Inhibitors, Humans

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