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The cholinergic hypothesis of Alzheimer’s disease: A review of progress
Open accessAbstract
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.
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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.
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82 Not checked yet · 27 Own interpretation · 4 No basis given · 1 Own method
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“This prediction was not fully realised with compounds such as physostigmine and tacrine”
§ The cholinergic hypothesis of Alzheimer's disease: a review of progress > Conclusion
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“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.”
§ The cholinergic hypothesis of Alzheimer's disease: a review of progress > Abstract
What the sources say
- Not checked yetcites [5]
- Not checked yetcites [6]
- Not checked yetcites [7]
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In the paper
“Specifically, presynaptic markers of the cholinergic system appear uniformly reduced.”
§ The cholinergic hypothesis of Alzheimer's disease: a review of progress > Schematic diagram of a neuron representing (A) alterations in neurotransmission in Alzheimer's disease and (B) the hypothetical mode of action of AChE inhibitors. Key to figure (A): (1) reduced cortical cholinergic innervation; (2) reduced corticocortical glutamatergic neurotransmission due to neuron or synapse loss; (3) reduced coupling of muscarinic M1 receptors to second messenger system?; (4) shift of tau to the hyperphosphoryalted state-precursor of neurofibrillary tangles; (5) reduced secretion of soluble APP; (6) increased production of -amyloid protein; (7) decreased glutamate production.
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In the paper
“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]”
§ The cholinergic hypothesis of Alzheimer's disease: a review of progress > Schematic diagram of a neuron representing (A) alterations in neurotransmission in Alzheimer's disease and (B) the hypothetical mode of action of AChE inhibitors. Key to figure (A): (1) reduced cortical cholinergic innervation; (2) reduced corticocortical glutamatergic neurotransmission due to neuron or synapse loss; (3) reduced coupling of muscarinic M1 receptors to second messenger system?; (4) shift of tau to the hyperphosphoryalted state-precursor of neurofibrillary tangles; (5) reduced secretion of soluble APP; (6) increased production of -amyloid protein; (7) decreased glutamate production.
What the sources say
- Not checked yetcites [12][13][14][15]
boostedcorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“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”
§ The cholinergic hypothesis of Alzheimer's disease: a review of progress > Schematic diagram of a neuron representing (A) alterations in neurotransmission in Alzheimer's disease and (B) the hypothetical mode of action of AChE inhibitors. Key to figure (A): (1) reduced cortical cholinergic innervation; (2) reduced corticocortical glutamatergic neurotransmission due to neuron or synapse loss; (3) reduced coupling of muscarinic M1 receptors to second messenger system?; (4) shift of tau to the hyperphosphoryalted state-precursor of neurofibrillary tangles; (5) reduced secretion of soluble APP; (6) increased production of -amyloid protein; (7) decreased glutamate production.
What the sources say
- Not checked yetcites [22]
hedged- Asserted: passes — The authors put it forward as true.
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In the paper
“Support for this perspective came in the mid-1970s with reports of substantial neocortical deficits in the enzyme responsible for the synthesis of acetylcholine (ACh), choline acetyltransferase (ChAT).[2][3][4]”
§ The cholinergic hypothesis of Alzheimer's disease: a review of progress > Abstract
What the sources say
- Not checked yetcites [2][3][4]
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“Based on postmortem studies, however, changes in serotonergic neurotransmission may be linked to the behavioural disturbances of Alzheimer's disease such as depression, rather than cognitive dysfunction. 1 20 21”
§ The cholinergic hypothesis of Alzheimer's disease: a review of progress > Schematic diagram of a neuron representing (A) alterations in neurotransmission in Alzheimer's disease and (B) the hypothetical mode of action of AChE inhibitors. Key to figure (A): (1) reduced cortical cholinergic innervation; (2) reduced corticocortical glutamatergic neurotransmission due to neuron or synapse loss; (3) reduced coupling of muscarinic M1 receptors to second messenger system?; (4) shift of tau to the hyperphosphoryalted state-precursor of neurofibrillary tangles; (5) reduced secretion of soluble APP; (6) increased production of -amyloid protein; (7) decreased glutamate production.
What the sources say
- Not checked yetcites 1 20 21
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“In addition, patients with inherited olivopontocerebellar atrophy have diminished ChAT activity of a magnitude similar to that seen in Alzheimer's disease in the absence of cognitive deficits.25”
§ The cholinergic hypothesis of Alzheimer's disease: a review of progress > Schematic diagram of a neuron representing (A) alterations in neurotransmission in Alzheimer's disease and (B) the hypothetical mode of action of AChE inhibitors. Key to figure (A): (1) reduced cortical cholinergic innervation; (2) reduced corticocortical glutamatergic neurotransmission due to neuron or synapse loss; (3) reduced coupling of muscarinic M1 receptors to second messenger system?; (4) shift of tau to the hyperphosphoryalted state-precursor of neurofibrillary tangles; (5) reduced secretion of soluble APP; (6) increased production of -amyloid protein; (7) decreased glutamate production.
What the sources say
- Not checked yetcites [25]
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“Biochemical investigations of biopsy tissue taken from patients with Alzheimer's disease 3.5 years (on average) after the onset of symptoms indicate that a selective neurotransmitter pathology occurs early in the course of the disease.12”
§ The cholinergic hypothesis of Alzheimer's disease: a review of progress > Schematic diagram of a neuron representing (A) alterations in neurotransmission in Alzheimer's disease and (B) the hypothetical mode of action of AChE inhibitors. Key to figure (A): (1) reduced cortical cholinergic innervation; (2) reduced corticocortical glutamatergic neurotransmission due to neuron or synapse loss; (3) reduced coupling of muscarinic M1 receptors to second messenger system?; (4) shift of tau to the hyperphosphoryalted state-precursor of neurofibrillary tangles; (5) reduced secretion of soluble APP; (6) increased production of -amyloid protein; (7) decreased glutamate production.
What the sources say
- Not checked yetcites [12]
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
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None of the sources cited for this claim have been checked yet.
In the paper
“When postmortem studies of Alzheimer's disease brain are considered (typically representing a later stage of the disease) many more neurotransmitter systems are involved or are aVected to a greater extent.These include GABA 16 17 and somatostatin 18 19”
§ The cholinergic hypothesis of Alzheimer's disease: a review of progress > Schematic diagram of a neuron representing (A) alterations in neurotransmission in Alzheimer's disease and (B) the hypothetical mode of action of AChE inhibitors. Key to figure (A): (1) reduced cortical cholinergic innervation; (2) reduced corticocortical glutamatergic neurotransmission due to neuron or synapse loss; (3) reduced coupling of muscarinic M1 receptors to second messenger system?; (4) shift of tau to the hyperphosphoryalted state-precursor of neurofibrillary tangles; (5) reduced secretion of soluble APP; (6) increased production of -amyloid protein; (7) decreased glutamate production.
What the sources say
- Not checked yetcites 16 17
- Not checked yetcites 18 19
plaincorrelational- Asserted: passes — The authors put it forward as true.
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- Probably not a substantial claim. 8
- It may state two separate claims as one. 38
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“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.”
§ The cholinergic hypothesis of Alzheimer's disease: a review of progress > Conclusion
hedged- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper may give no reason why it holds.
In the paper
“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”
§ The cholinergic hypothesis of Alzheimer's disease: a review of progress > Schematic diagram of a neuron representing (A) alterations in neurotransmission in Alzheimer's disease and (B) the hypothetical mode of action of AChE inhibitors. Key to figure (A): (1) reduced cortical cholinergic innervation; (2) reduced corticocortical glutamatergic neurotransmission due to neuron or synapse loss; (3) reduced coupling of muscarinic M1 receptors to second messenger system?; (4) shift of tau to the hyperphosphoryalted state-precursor of neurofibrillary tangles; (5) reduced secretion of soluble APP; (6) increased production of -amyloid protein; (7) decreased glutamate production.
What the sources say
- Not checked yetcites [24]
plain- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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It may state two separate claims as one.
In the paper
“Whereas serotonergic and some noradrenergic markers are aVected, markers for dopamine, -aminobutyric acid (GABA), or somatostatin are not altered.12”
§ The cholinergic hypothesis of Alzheimer's disease: a review of progress > Schematic diagram of a neuron representing (A) alterations in neurotransmission in Alzheimer's disease and (B) the hypothetical mode of action of AChE inhibitors. Key to figure (A): (1) reduced cortical cholinergic innervation; (2) reduced corticocortical glutamatergic neurotransmission due to neuron or synapse loss; (3) reduced coupling of muscarinic M1 receptors to second messenger system?; (4) shift of tau to the hyperphosphoryalted state-precursor of neurofibrillary tangles; (5) reduced secretion of soluble APP; (6) increased production of -amyloid protein; (7) decreased glutamate production.
What the sources say
- Not checked yetcites [12]
plain- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ The cholinergic hypothesis of Alzheimer's disease: a review of progress > Schematic diagram of a neuron representing (A) alterations in neurotransmission in Alzheimer's disease and (B) the hypothetical mode of action of AChE inhibitors. Key to figure (A): (1) reduced cortical cholinergic innervation; (2) reduced corticocortical glutamatergic neurotransmission due to neuron or synapse loss; (3) reduced coupling of muscarinic M1 receptors to second messenger system?; (4) shift of tau to the hyperphosphoryalted state-precursor of neurofibrillary tangles; (5) reduced secretion of soluble APP; (6) increased production of -amyloid protein; (7) decreased glutamate production.
plaincorrelational- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ The cholinergic hypothesis of Alzheimer's disease: a review of progress > CHOLINERGIC AND NON-CHOLINERGIC NEURONS AND ALZHEIMER'S DISEASE NEUROPATHOLOGY
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ The cholinergic hypothesis of Alzheimer's disease: a review of progress > CHOLINERGIC AND NON-CHOLINERGIC NEURONS AND ALZHEIMER'S DISEASE NEUROPATHOLOGY
hedgedconditional- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ The cholinergic hypothesis of Alzheimer's disease: a review of progress > CHOLINERGIC AND NON-CHOLINERGIC NEURONS AND ALZHEIMER'S DISEASE NEUROPATHOLOGY
hedgedconditional- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. It may state two separate claims as one.
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In the paper
“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.”
§ The cholinergic hypothesis of Alzheimer's disease: a review of progress > Schematic diagram of a neuron representing (A) alterations in neurotransmission in Alzheimer's disease and (B) the hypothetical mode of action of AChE inhibitors. Key to figure (A): (1) reduced cortical cholinergic innervation; (2) reduced corticocortical glutamatergic neurotransmission due to neuron or synapse loss; (3) reduced coupling of muscarinic M1 receptors to second messenger system?; (4) shift of tau to the hyperphosphoryalted state-precursor of neurofibrillary tangles; (5) reduced secretion of soluble APP; (6) increased production of -amyloid protein; (7) decreased glutamate production.
What the sources say
- Not checked yetcites 23 40 41
- Not checked yetcites [40]
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plaincorrelational- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“These neurons therefore seem to have a central role in the clinical symptoms as well as in the pathophysiology of the disease.”
§ The cholinergic hypothesis of Alzheimer's disease: a review of progress > CHOLINERGIC AND NON-CHOLINERGIC NEURONS AND ALZHEIMER'S DISEASE NEUROPATHOLOGY
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“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”
§ The cholinergic hypothesis of Alzheimer's disease: a review of progress > Schematic diagram of a neuron representing (A) alterations in neurotransmission in Alzheimer's disease and (B) the hypothetical mode of action of AChE inhibitors. Key to figure (A): (1) reduced cortical cholinergic innervation; (2) reduced corticocortical glutamatergic neurotransmission due to neuron or synapse loss; (3) reduced coupling of muscarinic M1 receptors to second messenger system?; (4) shift of tau to the hyperphosphoryalted state-precursor of neurofibrillary tangles; (5) reduced secretion of soluble APP; (6) increased production of -amyloid protein; (7) decreased glutamate production.
What the sources say
- Not checked yetcites [26]
- Not checked yetcites [27]
boostedcorrelational- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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”
§ The cholinergic hypothesis of Alzheimer's disease: a review of progress > Schematic diagram of a neuron representing (A) alterations in neurotransmission in Alzheimer's disease and (B) the hypothetical mode of action of AChE inhibitors. Key to figure (A): (1) reduced cortical cholinergic innervation; (2) reduced corticocortical glutamatergic neurotransmission due to neuron or synapse loss; (3) reduced coupling of muscarinic M1 receptors to second messenger system?; (4) shift of tau to the hyperphosphoryalted state-precursor of neurofibrillary tangles; (5) reduced secretion of soluble APP; (6) increased production of -amyloid protein; (7) decreased glutamate production.
What the sources say
- Not checked yetcites 30 31
- Not checked yetcites [32]
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“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”
§ The cholinergic hypothesis of Alzheimer's disease: a review of progress > CHOLINERGIC AND NON-CHOLINERGIC NEURONS AND ALZHEIMER'S DISEASE NEUROPATHOLOGY
What the sources say
- Not checked yetcites 47 48
hedgedconditional- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ The cholinergic hypothesis of Alzheimer's disease: a review of progress > CHOLINERGIC AND NON-CHOLINERGIC NEURONS AND ALZHEIMER'S DISEASE NEUROPATHOLOGY
hedgedconditional- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ The cholinergic hypothesis of Alzheimer's disease: a review of progress > Schematic diagram of a neuron representing (A) alterations in neurotransmission in Alzheimer's disease and (B) the hypothetical mode of action of AChE inhibitors. Key to figure (A): (1) reduced cortical cholinergic innervation; (2) reduced corticocortical glutamatergic neurotransmission due to neuron or synapse loss; (3) reduced coupling of muscarinic M1 receptors to second messenger system?; (4) shift of tau to the hyperphosphoryalted state-precursor of neurofibrillary tangles; (5) reduced secretion of soluble APP; (6) increased production of -amyloid protein; (7) decreased glutamate production.
hedgedconditional- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“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]”
§ The cholinergic hypothesis of Alzheimer's disease: a review of progress > Schematic diagram of a neuron representing (A) alterations in neurotransmission in Alzheimer's disease and (B) the hypothetical mode of action of AChE inhibitors. Key to figure (A): (1) reduced cortical cholinergic innervation; (2) reduced corticocortical glutamatergic neurotransmission due to neuron or synapse loss; (3) reduced coupling of muscarinic M1 receptors to second messenger system?; (4) shift of tau to the hyperphosphoryalted state-precursor of neurofibrillary tangles; (5) reduced secretion of soluble APP; (6) increased production of -amyloid protein; (7) decreased glutamate production.
What the sources say
- Not checked yetcites [29][30][31][32]
hedgeddirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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It may state two separate claims as one.
In the paper
“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.”
§ The cholinergic hypothesis of Alzheimer's disease: a review of progress > Schematic diagram of a neuron representing (A) alterations in neurotransmission in Alzheimer's disease and (B) the hypothetical mode of action of AChE inhibitors. Key to figure (A): (1) reduced cortical cholinergic innervation; (2) reduced corticocortical glutamatergic neurotransmission due to neuron or synapse loss; (3) reduced coupling of muscarinic M1 receptors to second messenger system?; (4) shift of tau to the hyperphosphoryalted state-precursor of neurofibrillary tangles; (5) reduced secretion of soluble APP; (6) increased production of -amyloid protein; (7) decreased glutamate production.
What the sources say
- Not checked yetcites [12]
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ The cholinergic hypothesis of Alzheimer's disease: a review of progress > Schematic diagram of a neuron representing (A) alterations in neurotransmission in Alzheimer's disease and (B) the hypothetical mode of action of AChE inhibitors. Key to figure (A): (1) reduced cortical cholinergic innervation; (2) reduced corticocortical glutamatergic neurotransmission due to neuron or synapse loss; (3) reduced coupling of muscarinic M1 receptors to second messenger system?; (4) shift of tau to the hyperphosphoryalted state-precursor of neurofibrillary tangles; (5) reduced secretion of soluble APP; (6) increased production of -amyloid protein; (7) decreased glutamate production.
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“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”
§ The cholinergic hypothesis of Alzheimer's disease: a review of progress > PRECLINICAL STUDIES OF CHOLINESTERASE INHIBITORS
What the sources say
- Not checked yetcites [1]
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
In the paper
“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”
§ The cholinergic hypothesis of Alzheimer's disease: a review of progress > Behavioural consequences of cholinomimetic drugs and cholinergic lesions
What the sources say
- Not checked yetcites [62]
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“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”
§ The cholinergic hypothesis of Alzheimer's disease: a review of progress > PRECLINICAL STUDIES OF CHOLINESTERASE INHIBITORS
What the sources say
- Not checked yetcites 70 71
hedgeddirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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It may state two separate claims as one.
In the paper
“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.”
§ The cholinergic hypothesis of Alzheimer's disease: a review of progress > PRECLINICAL STUDIES OF CHOLINESTERASE INHIBITORS
What the sources say
- Not checked yetcites 57 71 83-85
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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It may state two separate claims as one.
In the paper
“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”
§ The cholinergic hypothesis of Alzheimer's disease: a review of progress > PRECLINICAL STUDIES OF CHOLINESTERASE INHIBITORS
What the sources say
- Not checked yetcites [86]
hedged- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“These type of eVects might be expected to influence aVective states-for example, mood-in a positive manner.”
§ The cholinergic hypothesis of Alzheimer's disease: a review of progress > PRECLINICAL STUDIES OF CHOLINESTERASE INHIBITORS
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ The cholinergic hypothesis of Alzheimer's disease: a review of progress > CHOLINERGIC AND NON-CHOLINERGIC NEURONS AND ALZHEIMER'S DISEASE NEUROPATHOLOGY
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“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.”
§ The cholinergic hypothesis of Alzheimer's disease: a review of progress > Behavioural consequences of cholinomimetic drugs and cholinergic lesions
What the sources say
- Not checked yetcites 55 56
hedgeddirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“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”
§ The cholinergic hypothesis of Alzheimer's disease: a review of progress > Cholinomimetic therapy in Alzheimer's disease
What the sources say
- Not checked yetcites [67]
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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It may state two separate claims as one.
In the paper
“At muscarinic receptors, both compounds act as antagonists.71”
§ The cholinergic hypothesis of Alzheimer's disease: a review of progress > PRECLINICAL STUDIES OF CHOLINESTERASE INHIBITORS
What the sources say
- Not checked yetcites [71]
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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.”
§ The cholinergic hypothesis of Alzheimer's disease: a review of progress > PRECLINICAL STUDIES OF CHOLINESTERASE INHIBITORS
What the sources say
- Not checked yetcites [77]
- Not checked yetcites 78 79
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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It may state two separate claims as one.
In the paper
“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”
§ The cholinergic hypothesis of Alzheimer's disease: a review of progress > PRECLINICAL STUDIES OF CHOLINESTERASE INHIBITORS
What the sources say
- Not checked yetcites 70 74 79 80
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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It may state two separate claims as one.
In the paper
“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”
§ The cholinergic hypothesis of Alzheimer's disease: a review of progress > PRECLINICAL STUDIES OF CHOLINESTERASE INHIBITORS
What the sources say
- Not checked yetcites [76]
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“This revised cholinergic hypothesis provides a stronger case for the continued development of cholinomimetic drugs for the symptomatic treatment of Alzheimer's disease.”
§ The cholinergic hypothesis of Alzheimer's disease: a review of progress > CHOLINERGIC AND NON-CHOLINERGIC NEURONS AND ALZHEIMER'S DISEASE NEUROPATHOLOGY
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: fails — It may be too vague to check against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. It may be too vague to check against evidence.
In the paper
“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”
§ The cholinergic hypothesis of Alzheimer's disease: a review of progress > PRECLINICAL STUDIES OF CHOLINESTERASE INHIBITORS
What the sources say
- Not checked yetcites [71]
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“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”
§ The cholinergic hypothesis of Alzheimer's disease: a review of progress > PRECLINICAL STUDIES OF CHOLINESTERASE INHIBITORS
What the sources say
- Not checked yetcites [75]
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ The cholinergic hypothesis of Alzheimer's disease: a review of progress > CHOLINERGIC AND NON-CHOLINERGIC NEURONS AND ALZHEIMER'S DISEASE NEUROPATHOLOGY
hedgedconditional- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“This is supported by a study showing that both tacrine and nicotine improve attentional functions in patients with Alzheimer's disease.66”
§ The cholinergic hypothesis of Alzheimer's disease: a review of progress > Behavioural consequences of cholinomimetic drugs and cholinergic lesions
What the sources say
- Not checked yetcites [66]
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“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]”
§ The cholinergic hypothesis of Alzheimer's disease: a review of progress > Behavioural consequences of cholinomimetic drugs and cholinergic lesions
What the sources say
- Not checked yetcites [63][64][65]
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“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”
§ The cholinergic hypothesis of Alzheimer's disease: a review of progress > Second generation cholinesterase inhibitors
What the sources say
- Not checked yetcites [97]
plaindirectn = 150 ·- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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]”
§ The cholinergic hypothesis of Alzheimer's disease: a review of progress > Second generation cholinesterase inhibitors
What the sources say
- Not checked yetcites [70]
- Not checked yetcites [96]
- Not checked yetcites [97]
- Not checked yetcites [98]
- Not checked yetcites [108]
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“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]”
§ The cholinergic hypothesis of Alzheimer's disease: a review of progress > Second generation cholinesterase inhibitors
What the sources say
- Not checked yetcites [99][100][101][102]
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“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.”
§ The cholinergic hypothesis of Alzheimer's disease: a review of progress > Second generation cholinesterase inhibitors
What the sources say
- Not checked yetcites [97]
plaindirectn = 150 ·- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Thus, whereas some patients, of course, respond considerably more than the mean reported in clinical trials, others similarly, will respond less.”
§ The cholinergic hypothesis of Alzheimer's disease: a review of progress > Second generation cholinesterase inhibitors
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“This clinical improvement (as determined by the ADAS-cog) was correlated with both donepezil plasma concentrations and AChE inhibition.96”
§ The cholinergic hypothesis of Alzheimer's disease: a review of progress > Second generation cholinesterase inhibitors
What the sources say
- Not checked yetcites [96]
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ The cholinergic hypothesis of Alzheimer's disease: a review of progress > Choosing the right patient
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Unfortunately, however, it has not yet been possible to predict or distinguish responders from non-responders.”
§ The cholinergic hypothesis of Alzheimer's disease: a review of progress > Decisions on continuing long term cholinesterase inhibitor treatment
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The paper may give no reason why it holds.
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”
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?
In the citing paper
“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]
In the citing paper
“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]
Citations
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Rattray, M. (2001) · Biological Psychiatry · doi:10.1016/s0006-3223(00)01047-7 · Cited by 33
“In AD there is extensive loss of cholinergic and glutamatergic input into the hippocampus (reviewed in Francis et al 1993, 1999).”
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“shown that acetylcholinesterase inhibiting drugs treat cognitive symptoms of Alzheimer’s disease [123].”
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“Similarly, striking loss of cholinergic cells and AChRs in the cerebral cortex and hippocampus (HPC) are neurochemical features of Alzheimer’s disease (AD; Francis et al., 1999; Oddo & LaFerla, 2006).”
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Effects of Boswellia Papyrifera Gum Extract on Learning and Memory in Mice and Rats
Farshchi, A., Ghiasi, G., Farshchi, S., et al. (2010) · Iranian journal of basic medical sciences. · doi:10.22038/ijbms.2010.5075 · Cited by 32
“Moreover, age, stress and emotions are conditions that may lead to impaired learning, memory loss, amnesia, and dementia or to more ominous threats like Schizophrenia and Alzheimer’s disease (2).”
BackgroundJunaid, M., Almuqri, E. A., Liu, J., et al. (2016) · PLoS ONE · doi:10.1371/journal.pone.0147761 · Cited by 32
Guerram, M., Zhang, L., & Jiang, Z. (2016) · Neurochemistry International · doi:10.1016/j.neuint.2016.09.005 · Cited by 32
Tùng, B. T., Hải, N. T., & Thu, D. K. (2016) · Journal of Ethnopharmacology · doi:10.1016/j.jep.2016.12.037 · Cited by 32
Novel Coumarin‐Quinoline Hybrids: Design of Multitarget Compounds for Alzheimer's Disease
Duarte, Y., Fonseca, A., Gutiérrez, M., Adasme‐Carreño, F., Muñoz‐Gutierrez, C., Alzate‐Morales, J. H., Santana, L., Uriarte, E., Álvarez, R., & Matos, M. J. (2019) · ChemistrySelect · doi:10.1002/slct.201803222 · Cited by 32
Overview on Rodent Models of Alzheimer's Disease
Dodart, J., & May, P. C. (2005) · Current Protocols in Neuroscience · doi:10.1002/0471142301.ns0922s33 · Cited by 32
“Loss of cholinergic nerve cells within the basal forebrain is typical of AD (Bartus et al., 1982; Coyle et al., 1983; Giacobini, 1990; Francis et al., 1999).”
BackgroundButyrylcholinesterase and Cognitive Function
Darvesh, S., MacKnight, C., & Rockwood, K. J. (2001) · International Psychogeriatrics · doi:10.1017/s1041610201007876 · Cited by 32
Décossas, M., Bloch, B., & Bernard, V. (2003) · The Journal of Comparative Neurology · doi:10.1002/cne.10734 · Cited by 32
“…is known to play a major role in the pathophysiology of Alzheimer’s disease (Nagai et al., 1983), and it has been proposed to use acetylcholinesterase (AChE) inhibitors, which increase acetylcholine levels, in the treatment of the symptoms of this pathologic condition (Francis et al., 1999).”
BackgroundBuccafusco, J. J., Terry, A. V., Goren, T., & Blaugrun, E. (2003) · Neuroscience · doi:10.1016/s0306-4522(02)00937-5 · Cited by 32
“Among the host of degenerative processes occurring in Alzheimer’s disease, reproducible cholinergic deficits have been consistently reported, they appear early in the disease process, and correlate well with the degree of dementia (for review, Francis et al., 1999 ).”
Potentiation of α7-Containing Nicotinic Acetylcholine Receptors by Select Albumins
Conroy, W. G., Liu, Q., Nai, Q., Margiotta, J. F., & Berg, D. K. (2003) · Molecular Pharmacology · doi:10.1124/mol.63.2.419 · Cited by 32
“Examples include compounds to treat nicotine addiction, generate nociception, and ameliorate Alzheimer’s disease (for reviews, see Francis et al., 1999; Dani et al., 2001).”
BackgroundPharmacokinetic and Safety Assessments of Concurrent Administration of Risperidone and Donepezil
Zhao, Q., Xie, C. X., Pesco‐Koplowitz, L., et al. (2003) · The Journal of Clinical Pharmacology · doi:10.1177/0091270002239827 · Cited by 32
Guo, H., Wang, G., Zhai, Z., Huang, J., Huang, Z., Zhou, Y., Xia, X., Yao, Z., Huang, Y., Zhao, Z., et al. (2024) · International Journal of Pharmaceutics · doi:10.1016/j.ijpharm.2024.123809 · Cited by 31
Asiatic acid derivatives enhance cognitive performance partly by improving acetylcholine synthesis
Kim, S. R., Koo, K. A., Lee, M. K., Park, H.-G., Jew, S.-S., Cha, K.-H., & Kim, Y. C. (2004) · Journal of Pharmacy and Pharmacology · doi:10.1211/0022357044391 · Cited by 31
“The most consistent features of Alzheimer’s disease are cholinergic deficits (Francis et al 1999; Frolich 2002) including: (i) decreased numbers of cholinergic neurons in the basal forebrain nuclei; (ii) decreased acetylcholine (ACh) production; (iii) enhanced levels of acetylcholinesterase (AChE);…”
BackgroundMethodJi, Y. B., Lee, S., Ju, H. J., Kim, H., Noh, J. H., Choi, S., Park, K., Lee, H. B., & Kim, M. S. (2023) · Journal of Controlled Release · doi:10.1016/j.jconrel.2023.02.024 · Cited by 32
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“Acetylcholine (ACh), which is synthesized by choline acetyltransferase, is a neurotransmitter that is responsible for the establishment and maintenance of memory as the decider between the encoding and retrieval modes in memory processing [7].”
BackgroundRecent Advances in Medicinal Chemistry of Memantine Against Alzheimer's Disease
Singh, Y. P., & Kumar, H. (2024) · Chemical Biology & Drug Design · doi:10.1111/cbdd.14638 · Cited by 35
“The basic hallmarks of the disease include the loss of neurons, particularly cholinergic neurons, in the brain regions responsible for learning, memory, cognition, and normal neuronal functions (Paul et al. 1999; Singh and Kumar 2023a; Umar et al. 2022).”
Çetin, E., Top, E. C., Şahin, G., Özkaya, Y. G., Aydın, H. A., & Toraman, N. F. (2010) · The journal of nutrition health & aging · doi:10.1007/s12603-010-0256-x · Cited by 31
“The present study is not intended to, and can not, draw definitive conclusions on the effect of vitamin E in Alzheimer Diasease, because Alzheimer Disease is a multifaceted progressive disorder characterized by both cognitive and behavioral dysfunctions (48).”
Ray, R. S., Rai, S., & Katyal, A. (2014) · Nitric Oxide · doi:10.1016/j.niox.2014.08.009 · Cited by 31
Blaikie, L., Kay, G., & Lin, P. K. T. (2020) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2020.127505 · Cited by 33
Tacrines as Therapeutic Agents for Alzheimer's Disease. V. Recent Developments
Bautista‐Aguilera, Ó. M., Ismaïli, L., Iriepa, I., Diez‐Iriepa, D., Chabchoub, F., Marco, J. L., & Pérez, M. (2020) · The Chemical Record · doi:10.1002/tcr.202000107 · Cited by 34
Morales, G. G., Huerta‐Reyes, M., González‐Cortazar, M., Zamilpa, A., Jiménez‐Ferrer, E., Silva‐García, R., Román‐Ramos, R., & Aguilar‐Rojas, A. (2015) · Archives of Pharmacal Research · doi:10.1007/s12272-015-0587-6 · Cited by 32
“In conjunction, all of these aspects promote profound neural damage and the typical symptomatology of AD (Francis et al. 1999; Weiner et al. 2012).”
BackgroundCholine reverses scopolamine-induced memory impairment by improving memory reconsolidation
Blake, M. G., Boccia, M. M., Krawczyk, M. C., Delorenzi, A., & Baratti, C. M. (2012) · Neurobiology of Learning and Memory · doi:10.1016/j.nlm.2012.07.001 · Cited by 31
Hiraoka, K., Okamura, N., Funaki, Y., et al. (2009) · NeuroImage · doi:10.1016/j.neuroimage.2009.03.006 · Cited by 31
“The cholinergic system is one of the most crucial neurotransmitter systems in the brain, and it has very profound links with the manifestations of dementia (Francis et al., 1999; Perry et al., 1999).”
Rivastigmine blocks voltage‐activated K+ currents in dissociated rat hippocampal neurons
Pan, Y., Xu, X., & Wang, X. (2003) · British Journal of Pharmacology · doi:10.1038/sj.bjp.0705503 · Cited by 31
“A reduction of acetylcholine (ACh) and a central cholinergic deficit have been consistently identified in the development of AD (Francis et al., 1999), which provides the rationale for the treatment of AD by enhancing ACh in the brain.”
BackgroundFiore, M., Korf, J., Angelucci, F., Talamini, L. M., & Aloe, L. (2000) · Physiology & Behavior · doi:10.1016/s0031-9384(00)00310-3 · Cited by 31
Drug therapy in Alzheimer disease: an update for the oral health care provider
Turner, L. N., Balasubramaniam, R., Hersh, E. V., & Stoopler, E. T. (2008) · Oral Surgery Oral Medicine Oral Pathology Oral Radiology and Endodontology · doi:10.1016/j.tripleo.2008.06.009 · Cited by 31
Scopolamine impairs behavioural function and arginine metabolism in the rat dentate gyrus
Knox, L. T., Yu, J. H., Fleete, M. S., Collie, N. D., Zhang, H., & Liu, P. (2011) · Neuropharmacology · doi:10.1016/j.neuropharm.2011.08.042 · Cited by 31
Response to cholinesterase inhibitors affects lifespan in Alzheimer's disease
Wattmo, C., Londos, E., & Minthon, L. (2014) · BMC Neurology · doi:10.1186/s12883-014-0173-4 · Cited by 30
“A modest post-treatment improvement in cognitive rating scales for about 6–12 months before the score returned to baseline value was reported by previous AD studies [32-34].”
Alzheimer′s disease: A review of recent developments
Salawu, F., Umar, J., & Olokoba, A. (2011) · Annals of African Medicine · doi:10.4103/1596-3519.82057 · Cited by 29
Mohamed, T., Mann, M. K., & Rao, P. P. N. (2017) · RSC Advances · doi:10.1039/c7ra02889j · Cited by 30
Dobryakova, Y. V., Kasianov, A. S., Zaichenko, M. I., Stepanichev, M. Y., Chesnokova, E., Kolosov, P. M., Markevich, V. A., & Bolshakov, A. P. (2018) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2017.00429 · Cited by 30
“Another important event that occurs in AD is degeneration of cholinergic neurons in the basal nuclei including septal neurons that form inputs to the hippocampus (Francis et al., 1999).”
BackgroundStem cell therapies for Alzheimer's disease
Wang, S., Lee, C., & Lim, H. K. (2018) · Current Opinion in Psychiatry · doi:10.1097/yco.0000000000000478 · Cited by 32
“The initial cholinergic hypothesis and neuromodulation theory proposed that Alzheimer’s disease was caused by reduced synthesis of the neurotransmitter acetylcholine and excitotoxicity from glutamate accumulation, respectively [3,4].”
Acetylcholinesterase inhibitors in Alzheimer's disease influence Zinc and Copper homeostasis
Giacconi, R., Giuli, C., Casoli, T., Balietti, M., Costarelli, L., Provinciali, M., Basso, A., Piacenza, F., Postacchini, D., Galeazzi, R., et al. (2019) · Journal of Trace Elements in Medicine and Biology · doi:10.1016/j.jtemb.2019.06.001 · Cited by 30
Mahgoub, M. Y., Elmaghraby, A. M., Harb, A.-E. A., da Silva, J. F., Justino, G. C., & Marques, M. M. (2019) · Molecules · doi:10.3390/molecules24122306 · Cited by 31
“According to the cholinergic hypothesis, depleted levels of ACh are associated with AD [2,3].”
BackgroundKim, S., Nam, Y., Jeong, Y.-O., Park, H. H., Lee, S.-K., Shin, S. J., Jung, H., Kim, B., Hong, S. B., Park, Y., et al. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20163992 · Cited by 31
“Based on cholinergic hypothesis in AD, although connectivity between the MS and hippocampus has been established in AD patients at the macroscale level, the mesoscale connectome of the SHS loop has not yet been elucidated during disease progress in the AD brain [55].”
BackgroundAcetylcholine acts on songbird premotor circuitry to invigorate vocal output
Jaffe, P. I., & Brainard, M. S. (2020) · eLife · doi:10.7554/elife.53288 · Cited by 31
Dehydroepiandrosterone (DHEA) and its Sulphate (DHEAS) in Alzheimer’s Disease
Štrac, D. Š., Konjevod, M., Perković, M. N., Tudor, L., Erjavec, G. N., & Pivac, N. (2020) · Current Alzheimer Research · doi:10.2174/1567205017666200317092310 · Cited by 31
Rhodamine-Based Metal Chelator: A Potent Inhibitor of Metal-Catalyzed Amyloid Toxicity
Pradhan, K., Das, G., Kar, C., Mukherjee, N., Khan, J., Mahata, T., Barman, S., & Ghosh, S. (2020) · ACS Omega · doi:10.1021/acsomega.0c02235 · Cited by 30
Enzymes inhibition profiles and antibacterial activities of benzylidenemalononitrile derivatives
Güller, P., Dağalan, Z., Güller, U., Çalışır, U., & Nişancı, B. (2021) · Journal of Molecular Structure · doi:10.1016/j.molstruc.2021.130498 · Cited by 31
Mak, S., Li, W., Fu, H., Luo, J., Cui, W., Hu, S., Pang, Y., Carlier, P. R., Tsim, K. W. K., Pi, R., et al. (2021) · Journal of Neurochemistry · doi:10.1111/jnc.15379 · Cited by 30
“…derived from the herbal medicine Huperzia Serrata (also known as Qian Ceng Ta), has been approved for treating AD in China, also exhibited potent inhibitory effects on AChE and provided neuroprotective effects (Francis et al., 1999; McGleenon et al., 1999; Wang et al., 1986; Zhang & Tang, 2006).”
BackgroundWang, Y., Xiong, B., Lin, H., Li, Q., Yang, H., Qiao, Y., Li, Q., Xu, Z., Lyu, W., Qu, W., et al. (2022) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2022.114806 · Cited by 32
Advances in the Design of 5-HT6 Receptor Ligands with Therapeutic Potential
Witty, D. R., Ahmed, M., & Chuang, T. T. (2009) · Progress in medicinal chemistry · doi:10.1016/s0079-6468(09)04805-x · Cited by 30
Peña, I. D., Yoon, S. Y., Kim, H. J., Park, S., Hong, E. Y., Ryu, J. H., Park, I. H., & Cheong, J. H. (2014) · Journal of Ginseng Research · doi:10.1016/j.jgr.2013.11.003 · Cited by 30
Araújo, J. Q., de Brito, M. A., Hoelz, L. V. B., de Alencastro, R. B., Castro, H. C., Rodrigues, C. R., & Albuquerque, M. G. (2010) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2010.10.009 · Cited by 30
Alzheimer’s Disease and Herbal Combination Therapy: A Comprehensive Review
Pradeep, S., Jain, A. S., Dharmashekara, C., Prasad, S. K., Kollur, S. P., Syed, A., & Shivamallu, C. (2020) · Journal of Alzheimer s Disease Reports · doi:10.3233/adr-200228 · Cited by 30
“This is the oldest known hypothesis and the currently available therapies for AD are mostly based on this [21].”
BackgroundThe Multifaceted Role of Neuroprotective Plants in Alzheimer’s Disease Treatment
Zieneldien, T., Kim, J., & Cao, C. (2022) · Geriatrics · doi:10.3390/geriatrics7020024 · Cited by 29
“As such, the cholinergic hypothesis proposes that cholinergic neuronal dysfunction in the brain could substantially contribute to the AD-related cognitive decline [25].”
BackgroundBiologically active compounds from cyanobacteria extracts:in vivo and in vitro aspects
de Carvalho, L. R., da Costa‐Neves, A., Conserva, G. A. A., et al. (2013) · Revista Brasileira de Farmacognosia · doi:10.1590/s0102-695x2013005000037 · Cited by 29
“…potential drug candidates against Alzheimer disease (AD); this neurodegenerative condition is associated with brain neurotransmitter defi cits and its symptomatic treatment is the restoration of cholinergic function by inhibiting acetylcholinesterase (Francis et al., 1999; Trevisan et al., 2003).”
BackgroundGonzalez, S., McHugh, T. L. M., Yang, T., Syriani, W., Massa, S. M., Longo, F. M., & Simmons, D. A. (2021) · Neurobiology of Disease · doi:10.1016/j.nbd.2021.105563 · Cited by 29
Recent Developments of Coumarin-based Hybrids in Drug Discovery
Xia, D.-G., Liu, H., Cheng, X., et al. (2022) · Current Topics in Medicinal Chemistry · doi:10.2174/1568026622666220105105450 · Cited by 31
Naseem, S., & Ismail, H. (2022) · BMC Complementary Medicine and Therapies · doi:10.1186/s12906-022-03520-5 · Cited by 30
“It is well known that neurodegenerative disorders are primarily associated with degeneration of the cholinergic system [65].”
BackgroundSammi, S. R., Jameson, L. E., Conrow, K. D., Leung, M. C. K., & Cannon, J. R. (2022) · Frontiers in Toxicology · doi:10.3389/ftox.2022.826488 · Cited by 27
Zhang, H., Wang, Y., Liu, D., Li, J., Feng, Y., Lu, Y., Yin, G., Zhao, L., Shi, T., & Wang, Z. (2022) · Bioorganic Chemistry · doi:10.1016/j.bioorg.2022.105844 · Cited by 32
Qin, P., Ran, Y., Xie, F., Liu, Y., Wei, C., Luan, X., & Wu, J. (2023) · Bioorganic & Medicinal Chemistry · doi:10.1016/j.bmc.2023.117178 · Cited by 30
Undertreatment of patients with Alzheimer's disease in an elderly United States population
Sano, M., Amatniek, J. C., Feely, M., et al. (2005) · Alzheimer s & Dementia · doi:10.1016/j.jalz.2005.09.011 · Cited by 29
“Acetylcholinesterase inhibitors (AChEIs) enhance ognitive function by increasing cholinergic neurotransmision [4] and have been approved for therapeutic use in the nited States [5].”
BackgroundBöttger, D., Ullrich, C., & Humpel, C. (2009) · Brain Research · doi:10.1016/j.brainres.2009.11.062 · Cited by 29
“All rights reserved with cognitive decline (Francis et al., 1999; Schliebs and Arendt, 2006).”
Deer Bone Extract Prevents Against Scopolamine-Induced Memory Impairment in Mice
Du, C. N., Min, A. Y., Kim, H. J., Shin, S. K., Yu, H. N., Sohn, E. J., Ahn, C.-W., Jung, S. U., Park, S.-H., & Kim, M. R. (2014) · Journal of Medicinal Food · doi:10.1089/jmf.2014.3187 · Cited by 29
Rajesh, V., Riju, T., Sellamuthu, V., & Babu, G. (2017) · Oriental Pharmacy and Experimental Medicine · doi:10.1007/s13596-017-0268-8 · Cited by 28
Nanotherapeutic strategies for the treatment of neurodegenerative diseases
Huang, M., Gu, X. Q., & Gao, X. (2018) · Elsevier eBooks · doi:10.1016/b978-0-12-814001-7.00013-5 · Cited by 34
Ha, J. S., Jin, D. E., Park, S. K., Park, C. H., Seung, T. W., Bae, D., Kim, D., & Heo, H. J. (2015) · Evidence-based Complementary and Alternative Medicine · doi:10.1155/2015/876484 · Cited by 28
“Neurodegenerative diseases are related to reduced ACh levels as well as relatively high AChE levels resulting from the loss of cholinergic neurons [1].”
BackgroundInfluentialFaster cognitive decline in elders without dementia and decreased risk of cancer mortality
Benito‐León, J., Romero, J. P., Louis, E. D., & Bermejo‐Pareja, F. (2014) · Neurology · doi:10.1212/wnl.0000000000000350 · Cited by 28
“The cholinergic system deficit that occurs in patients with ADmay explain, at least in part, the decreased risk of cancer.(4) Because acetylcholine stimulates cell proliferation, the association suggests that the degeneration of acetylcholine-secreting cells may have a protective role on cancer onset, as this neurotra…”
BackgroundGenesis of Neuroprotective Peptoid from Aβ30–34 Inhibits Aβ Aggregation and AChE Activity
Pradhan, K., Das, G., Mondal, P., Khan, J., Barman, S., & Ghosh, S. (2018) · ACS Chemical Neuroscience · doi:10.1021/acschemneuro.8b00071 · Cited by 27
Therapeutic Potential of Photobiomodulation In Alzheimer’s Disease: A Systematic Review
Cardoso, F. D. S., Lopes‐Martins, R. Á. B., & da Silva, S. G. (2020) · Journal of lasers in medical sciences · doi:10.34172/jlms.2020.s3 · Cited by 28
Yamazaki, D. A. D. S., Rozada, A. M. F., Baréa, P., Reis, E. C., Basso, E. A., Sarragiotto, M. H., Seixas, F. A. V., & Gauze, G. F. (2021) · Bioorganic & Medicinal Chemistry · doi:10.1016/j.bmc.2020.115991 · Cited by 29
Meng, H. Y. H., Mak, C. C. H., Mak, J. W. Y., Zuo, T., Ko, H., & Chan, F. K. L. (2022) · European Journal of Nutrition · doi:10.1007/s00394-021-02760-4 · Cited by 31
“Current understanding regarding the causes of and pathological changes in AD include (1) the amyloid-β (Aβ) cascade, with extracellular deposits of neurotoxic Aβ oligomers as the initiating pathological change [4], (2) hyperphosphorylated tau forming intracellular neurofibrillary tangles [5], (3) neuroinflammation enc…”
BackgroundSpatz, P., Steinmüller, S. A. M., Tutov, A., Poeta, E., Morilleau, A., Carles, A., Deventer, M. H., Hofmann, J., Stove, C. P., Monti, B., et al. (2023) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.3c00541 · Cited by 31
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Sensory Gating in Patients With Alzheimer’s Disease and Their Biological Children
Ally, B. A., Jones, G. E., Cole, J. A., & Budson, A. E. (2007) · American Journal of Alzheimer s Disease & Other Dementias® · doi:10.1177/1533317506292282 · Cited by 28
Bouger, P., & van der Staay, F. J. (2005) · European Neuropsychopharmacology · doi:10.1016/j.euroneuro.2004.11.006 · Cited by 28
The pharmacology and therapeutic potential of (-)-huperzine A
Herzon, S. B., & Tun, M. K. M. (2012) · Journal of Experimental Pharmacology · doi:10.2147/jep.s27084 · Cited by 30
“R = CH3 CH3 Ph CH3 methacrolein (9) TMG”
InfluentialGibson, R. H., Gander, P. H., Dowell, A. C., & Jones, L. (2016) · Dementia · doi:10.1177/1471301215625821 · Cited by 28
Role of Traditional Medicine in Neuropsychopharmacology
Tripathi, A. C., Dua, J. S., Prasad, D., & Gupta, R. (2009) · Cited by 28
Mintzer, J. E., & Kershaw, P. R. (2003) · International Journal of Geriatric Psychiatry · doi:10.1002/gps.826 · Cited by 28
Anesthesia, the aging brain, and the surgical patient
Crosby, G. J., & Culley, D. J. (2003) · Canadian Journal of Anesthesia/Journal canadien d anesthésie · doi:10.1007/bf03018158 · Cited by 28
Treatment of mild cognitive impairment: rationale, present and future strategies
Jelić, V., & Winblad, B. G. (2003) · Acta Neurologica Scandinavica · doi:10.1034/j.1600-0404.107.s179.12.x · Cited by 27
“This intervention is based on the cholinergic hypothesis of AD (8), which is built on the findings of cholinergic deafferentation of the cerebral cortex as a result of the selective loss of cholinergic neurons in the basal forebrain (9, 10) as well as on the positive effects of double-blind placebo-controlled trials o…”
Methodp97 as a biomarker for alzheimer disease
Ujiie, M. (2002) · Frontiers in bioscience · doi:10.2741/ujiie · Cited by 28
Leukoencephalopathy associated with khat misuse
Morrish, P., NICOLAOU, N., BRAKKENBERG, P., et al. (1999) · Journal of Neurology Neurosurgery & Psychiatry · doi:10.1136/jnnp.67.4.556 · Cited by 28
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Nizari, S., Carare, R. O., Romero, I. A., & Hawkes, C. A. (2019) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2019.00172 · Cited by 29
“The loss of cholinergic neurons in the basal forebrain and the areas innervated by their fiber projections is a hallmark of Alzheimer’s disease (AD; Whitehouse et al., 1982; Francis et al., 1999).”
BackgroundDorababu, A. (2019) · Bioorganic Chemistry · doi:10.1016/j.bioorg.2019.103299 · Cited by 28
“and medications are designed to treat acetylcholine deficiency) [8,9], amyloid hypothesis (hypothesizes that extracellular beta (Aβ) deposit/ amyloid plaques are responsible for AD) [10,11], Tau hypothesis (proposes that the AD is caused by tau protein abnormality) [11].”
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“Alzheimer’s disease (AD) is a chronic neurodegenerative disease characterized by continuous exacerbation in cognitive, language, executive, and behavioral functions.1 Its pathological hallmarks are extracellular plaques and intracellular neurofibrillary tangles, which consist of b-amyloid (Ab) and hyperphosphorylated…”
BackgroundInfluentialGene Polymorphisms Affecting the Pharmacokinetics and Pharmacodynamics of Donepezil Efficacy
Lu, J., Wang, X., Wan, L., Fu, J., Huo, Y., Zhao, Y., & Guo, C. (2020) · Frontiers in Pharmacology · doi:10.3389/fphar.2020.00934 · Cited by 29
“DNP plays an important role in the treatment of Alzheimer's disease, but its individual efficacy varies widely, leading to treatment failure and economic waste in clinical therapy (Francis et al., 1999).”
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Thiadiazole – A promising structure in design and development of anti-Alzheimer agents
Hatami, M., Basri, Z., Sakhvidi, B. K., & Mortazavi, M. (2023) · International Immunopharmacology · doi:10.1016/j.intimp.2023.110027 · Cited by 27
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Metadata
- Authors
- Francis, P. T., Palmer, A. M., Snape, M., & Wilcock, G. K.
- Affiliations
- King's College London (GB)
- Corresponding author
- Francis, P. T
- Venue
- Journal of Neurology, Neurosurgery & Psychiatry
- Publisher
- BMJ
- Published
- 1999-02-01
- Volume
- 66
- Issue
- 2
- Pages
- 137-147
- ISSN
- 0022-3050 (ISSN-L)
- 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
- bronze
- doi.org
- Locations
- Journal of Neurology Neurosurgery & Psychiatry (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Pharmacology (medical) › 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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
A language model drew the claims from the paper on 2026-10-10, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-10-10 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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