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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.
- 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
“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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- 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
“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.
- 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
“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.
- Based: passes — The paper gives a reason why it holds.
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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It may state two separate claims as one.
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.
- 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
“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.
- 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
“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.
- 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
“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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Cited by
Sorted by citations
Items 201–300 of 1,002
Hajlaoui, H., Mighri, H., Aouni, M., Gharsallah, N., & Kadri, A. (2016) · Microbial Pathogenesis · doi:10.1016/j.micpath.2016.03.003 · Cited by 124
“Acetylcholinesterase (AChE) in hibitors can restore the level of 56 acetylcholine by inhibiting acetylcholinesterase [7 ,8].”
BackgroundMajdi, A., Sadigh‐Eteghad, S., Aghsan, S. R., Farajdokht, F., Vatandoust, S. M., Abbas-Abad, A. N., & Mahmoudi, J. (2020) · Reviews in the Neurosciences · doi:10.1515/revneuro-2019-0089 · Cited by 130
“Accordingly, because of the alterations in muscarinic and nicotinic AChRs, tau hyperphosphorylation, NFT formation, altered APP metabolism, and increased Aβ production occur, possibly leading to AD (Babic 1999; Sivaprakasam, 2006).”
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“Thus, the cholinergic de®cit in AD patients (Bartus et al., 1982; Francis et al., 1999) could modify the excitability and function of M1.”
BackgroundGalantamine Prolonged-Release Formulation in the Treatment of Mild to Moderate Alzheimer’s Disease
Brodaty, H., Corey‐Bloom, J., Potocnik, F. C. V., Truyen, L., Gold, M., & Damaraju, C. V. (2005) · Dementia and Geriatric Cognitive Disorders · doi:10.1159/000086613 · Cited by 122
“and Alzheimer’s disease (AD) in particular, represents for patients, their families, and the health care system, there is great interest in the development of therapeutic approaches that will lessen the human and financial costs associated with these disease states. Neuronal loss and subsequent disruption of brain neu…”
BackgroundPharmacological Treatment of Alzheimer Disease
Massoud, F., & Léger, G. C. (2011) · The Canadian Journal of Psychiatry · doi:10.1177/070674371105601003 · Cited by 130
Kim, D. H., Yoon, B. H., Kim, Y.-W., Lee, S.-J., Shin, B. Y., Jung, J. W., Kim, H. J., Lee, Y. S., Choi, J. S., Kim, S. Y., et al. (2007) · Journal of Pharmacological Sciences · doi:10.1254/jphs.fp0061565 · Cited by 120
Zuo, L., Hemmelgarn, B. T., Chuang, C., & Best, T. M. (2015) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2015/604658 · Cited by 122
Blood-Based Proteomic Biomarkers of Alzheimer’s Disease Pathology
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Spread spectrum SERS allows label-free detection of attomolar neurotransmitters
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“Although early studies uncovered an association between deficits in excitatory neurotransmission and AD progression (Francis et al. 1999), a mechanistic understanding of how cell death pathways are more readily activated in excitatory neurons remains elusive.”
BackgroundJaved, H., Vaibhav, K., Ahmed, M. E., Khan, A., Tabassum, R., Islam, F., Safhi, M. M., & Islam, F. (2014) · Journal of the Neurological Sciences · doi:10.1016/j.jns.2014.10.044 · Cited by 119
“It is well recognized that the brain cholinergic system, which is important for learning and memory, is closely related to age related diseases such as AD and particularly important in the pathogenesis of AD [33].”
Bhuvanendran, S., Kumari, Y., Othman, I., & Shaikh, M. F. (2018) · Frontiers in Pharmacology · doi:10.3389/fphar.2018.00665 · Cited by 120
“In AD patients, pathological changes affecting glutamatergic, cholinergic, noradrenergic, and serotonergic systems have been revealed (Francis et al., 1999).”
BackgroundPharmacotherapy for Alzheimer's disease: progress and prospects
Palmer, A. M. (2002) · Trends in Pharmacological Sciences · doi:10.1016/s0165-6147(02)02056-4 · Cited by 118
Self-citationLoganin improves learning and memory impairments induced by scopolamine in mice
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“alzheimer’s disease, Parkinson’s disease, schizophrenia, and recently expanded to ASD [11,12,13,14].”
BackgroundThe ameliorating effects of stigmasterol on scopolamine-induced memory impairments in mice
Park, S. J., Kim, D. H., Jung, J. M., Kim, J. M., Cai, M., Liu, X., Hong, J. G., Lee, C. H., Lee, K. R., & Ryu, J. H. (2011) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2011.11.050 · Cited by 116
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“In human AD cases, decreased NGF levels have been shown in the nucleus basalis of Meynert [126], a group of neurons in the basal forebrain which has wide ascending projections to the neocortex, is rich in acetylcholine (Ach) and choline acetyltransferase (ChAT), and is well known to undergo degeneration in AD [127].”
BackgroundSzutowicz, A., Bielarczyk, H., Jankowska-Kulawy, A., Pawełczyk, T., & Ronowska, A. (2013) · Neurochemical Research · doi:10.1007/s11064-013-1060-x · Cited by 117
“On the other hand, several noncholinergic transmitter systems were not or much less suppressed by these conditions [109, 110, 111].”
BackgroundPsychosis of Alzheimer’s disease is associated with elevated muscarinic M 2 binding in the cortex
Lai, M. K. P., Lai, O. –., Keene, J., Esiri, M. M., Francis, P. T., Hope, T., & Chen, C. (2001) · Neurology · doi:10.1212/wnl.57.5.805 · Cited by 114
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“The acetylcholine hypothesis: loss of cholinergic neurons and neurotransmission causes AD [2].”
BackgroundThe Pupil as Marker of Cognitive Processes
Einhäuser, W. (2016) · Cognitive science and technology · doi:10.1007/978-981-10-0213-7_7 · Cited by 117
Serotonin 5-HT2A and 5-HT6 receptors in the prefrontal cortex of Alzheimer and normal aging patients
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“Whereas the decline in cognitive functions can be largely related to cholinergic dysfunction arising from disruption of basal forebrain cholinergic pathways (cholinergic hypothesis) [1,3,4], impaired balance between several neurotransmitters has been implicated in the pathogenesis of BPSP [2, 5- 7 ], with serotonin (5…”
BackgroundCho, N., Lee, K. Y., Huh, J., Choi, J. H., Yang, H., Jeong, E. J., Kim, H. P., & Sung, S. H. (2013) · Food and Chemical Toxicology · doi:10.1016/j.fct.2013.05.007 · Cited by 115
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“Loss of cholinergic neurons and reduced activity of choline acetyltransferase in the cerebral cortex and hippocampus have also been consistent findings in AD (Cummings et al. 1998; Francis et al. 1999; West and Gundersen 1990; Mullan 2000).”
ResultInfection, systemic inflammation, and Alzheimer's disease
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“A large body of research carried out from the late 60's to the mid 80's placed neurotransmitters dysregulation, specifically acetylcholine, as the major contributor to the deterioration of the mental abilities observed in AD [3].”
BackgroundAltered synaptic function in Alzheimer's disease
Bell, K. F. S., & Cuello, A. C. (2006) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2006.06.045 · Cited by 117
“, 1990), for review see (Francis et al., 1993b; Francis et al., 1999)] and GABAergic systems [(Seidl et al.”
BackgroundZhao, Y., Dang, M., Zhang, W., Lei, Y., Ramesh, T., Veeraraghavan, V. P., & Hou, X. (2020) · Journal of Functional Foods · doi:10.1016/j.jff.2020.104009 · Cited by 116
Mechanisms of Metal-Induced Mitochondrial Dysfunction in Neurological Disorders
Cheng, H., Yang, B., Ke, T., Li, S., Yang, X., Aschner, M., & Chen, P. (2021) · Toxics · doi:10.3390/toxics9060142 · Cited by 120
“The etiological hypotheses for AD mainly include genetics [18], decreased acetylcholine synthesis [19], accumulation of neurotoxic protein plaques of amyloid-β (Aβ) peptide [20], fibrous tangles with high phosphorylation of tau protein (P-tau) [21], or irregular mitochondrial function and dynamics [2].”
BackgroundAlbasanz, J. L., Dalfó, E., Ferrer, I., & Martı́n, M. (2005) · Neurobiology of Disease · doi:10.1016/j.nbd.2005.05.001 · Cited by 111
Selective vulnerability to neurodegenerative disease: the curious case of Prion Protein
Jackson, W. S. (2014) · Disease Models & Mechanisms · doi:10.1242/dmm.012146 · Cited by 109
“example, cholinergic neurons of the cerebral cortex as well as hippocampal neurons are targeted in AD (Francis et al., 1999), whereas dopaminergic neurons of the substantia nigra are targeted”
BackgroundThe molecular basis of the prevention of Alzheimer’s disease through healthy nutrition
Steele, M. L., Stuchbury, G., & Münch, G. W. (2006) · Experimental Gerontology · doi:10.1016/j.exger.2006.06.002 · Cited by 110
“Final stages of the disease show profuse neuronal loss and neurofibrillary tangle formation in the neocortical and cerebral cortex, primarily in pyramidal neurons and their synapses (Francis et al., 1999).”
BackgroundThe benefits and risks associated with cholinesterase inhibitor therapy in Alzheimer’s disease
Thompson, S., Lanctôt, K. L., & Herrmann, N. (2004) · Expert Opinion on Drug Safety · doi:10.1517/14740338.3.5.425 · Cited by 109
“Donepezil, rivastigmine and galantamine have been studied extensively in numerous double-blind, placebo-controlled studies, and the benefits of ChEIs have been pointed out by various qualitative reviews [43-46].”
BackgroundCavedo, E., Grothe, M. J., Olivier Colliot, A., Lista, S., Marie Chupin, A., Dormont, D., Houot, M., Lehéricy, S., Teipel, S. J., Dubois, B., et al. (2017) · Scientific Reports · doi:10.1038/s41598-017-09780-3 · Cited by 112
Multifunctional Neuroprotective Derivatives of Rasagiline as Anti-Alzheimer's Disease Drugs
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Plants-derived neuroprotective agents: cutting the cycle of cell death through multiple mechanisms
Elufioye, T. O., Berida, T. I., & Habtemariam, S. (2017) · Evidence-based Complementary and Alternative Medicine · doi:10.1155/2017/3574012 · Cited by 107
“Reports of substantial neocortical deficits in choline acetyltransferase (ChAT), the enzyme responsible for the synthesis of acetylcholine (ACh), discoveries of reduced choline uptake, ACh release, and loss of cholinergic perikarya from the nucleus basalis ofMeynert, along with the emerging roles of ACh in learning an…”
BackgroundInfluentialMultiple Central Nervous System Targets for Eliciting Beneficial Effects on Memory and Cognition
Buccafusco, J. J., & Terry, A. V. (2000) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1016/s0022-3565(24)38924-4 · Cited by 106
Dong, H., Yuede, C. M., Coughlan, C. A., Murphy, K. M., & Csernansky, J. G. (2009) · Brain Research · doi:10.1016/j.brainres.2009.09.097 · Cited by 106
“…the brains of individuals with Alzheimer's disease (AD) formed the rationale for the development of acetylcholinesterase inhibitors as drugs to ameliorate the dementia associated with AD (Davis et al., 1992; Rogers et al., 1998a; Francis et al., 1999; Tariot et al., 2000; Csernansky et al., 2002).”
Spatial Navigation (Water Maze) Tasks
Terry, A. V. (2008) · Frontiers in neuroscience · doi:10.1201/noe1420052343.ch13 · Cited by 116
Taste and smell perception in the elderly: Effect of medications and disease
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Nampoothiri, M., John, J., Kumar, N., Mudgal, J., Nampurath, G. K., & Chamallamudi, M. R. (2015) · Behavioural Neurology · doi:10.1155/2015/210169 · Cited by 104
“The neurodegeneration in frontal cortex and hippocampus areas of the brain [45] resulting in impaired cholinergic transmission occurs by two ways.”
BackgroundChang, L. Y. L., Lowe, J., Ardiles, A., Lim, J., Grey, A. C., Robertson, K., Danesh‐Meyer, H., Palacios, A. G., & Acosta, M. L. (2014) · Alzheimer's & Dementia · doi:10.1016/j.jalz.2013.06.004 · Cited by 106
“Acetylcholine deficiency is part of the pathology in AD patients [19].”
BackgroundAllosteric Modulation of Nicotinic Receptors as a Treatment Strategy for Alzheimer’s Disease
Maelicke, A. (2000) · Dementia and Geriatric Cognitive Disorders · doi:10.1159/000051227 · Cited by 106
Ahmed, M. E., Khan, M. M., Javed, H., Vaibhav, K., Khan, A., Tabassum, R., Ashafaq, M., Islam, F., Safhi, M. M., & Islam, F. (2013) · Neurochemistry International · doi:10.1016/j.neuint.2013.02.006 · Cited by 103
“There is growing evidence that the brain cholinergic system, which plays an important role in learning and memory, may be closely linked to human aging diseases, like AD and it seems to be more prone to oxidative damage and pathogenesis of AD (Francis et al., 1999; Khan et al., 2012).”
Cao, Z., Wang, F., Xiu, C., Zhang, J., & Li, Y. (2017) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2017.05.022 · Cited by 107
Neurochemical basis for symptomatic treatment of Alzheimer's disease
Francis, P. T., Ramírez, M. J., & Lai, M. K. P. (2010) · Neuropharmacology · doi:10.1016/j.neuropharm.2010.02.010 · Cited by 104
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Adult hippocampal neurogenesis and its impairment in Alzheimer’s disease
Kim, T. A., Syty, M. D., Wu, K., & Ge, S. (2022) · 动物学研究 · doi:10.24272/j.issn.2095-8137.2021.479 · Cited by 116
“In AD patients, cholinergic neurons were found to degenerate and β-amyloid inhibited choline uptake and ACh release (Babic, 1999; Breijyeh & Karaman, 2020).”
A lzheimer's disease and chronic periodontitis: Is there an association?
Gaur, S., & Agnihotri, R. (2014) · Geriatrics and gerontology international/Geriatrics & gerontology international · doi:10.1111/ggi.12425 · Cited by 116
Bedse, G., Romano, A., Lavecchia, A. M., Cassano, T., & Gaetani, S. (2014) · Journal of Alzheimer s Disease · doi:10.3233/jad-141635 · Cited by 109
“degradation of neurotransmitter acetylcholine (ACh), which is reduced in AD [174].”
Zheng, X.-Y., Zhang, Z., Chou, G., et al. (2009) · Archives of Pharmacal Research · doi:10.1007/s12272-009-1910-x · Cited by 102
“Alzheimer's disease (AD) is a progressive, neurodegenerative disease, which primarily affects the elderly population, and is estimated to account for 50-60 percent of dementia cases in those over 65 years of age (Francis et al., 1999).”
BackgroundAlkaloids from Piper: A Review of its Phytochemistry and Pharmacology
Gutiérrez, R. M. P., González, A. M. N., & Hoyo‐Vadillo, C. (2013) · Mini-Reviews in Medicinal Chemistry · doi:10.2174/138955713804805148 · Cited by 102
“The number of patients suffering from Alzheimer’s disease (AD) condition all over the world is rising continually and becomes one of the biggest challenge for most societies throughout the world [156].”
BackgroundDietary Patterns and Alzheimer’s Disease: An Updated Review Linking Nutrition to Neuroscience
Ellouze, I., Sheffler, J., Nagpal, R., & Arjmandi, B. (2023) · Nutrients · doi:10.3390/nu15143204 · Cited by 104
“The neurological regions, such as the hippocampus and neocortex, are particularly affected early in the disease [4].”
BackgroundMcDermott, B., Porter, E., Hughes, D., McGinley, B., Lang, M. J., O’Halloran, M., & Jones, M. (2018) · Journal of Alzheimer s Disease · doi:10.3233/jad-180391 · Cited by 105
Siddiqi, K. S., Husen, A., Sohrab, S. S., & Yassin, M. O. (2018) · Nanoscale Research Letters · doi:10.1186/s11671-018-2638-7 · Cited by 104
The “ins” and “outs” of the high‐affinity choline transporter CHT1
Ribeiro, F. M., Black, S. A. G., Prado, V. F., Rylett, R. J., Ferguson, S. S. G., & Prado, M. A. M. (2006) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2006.03695.x · Cited by 110
“…effects of the cholinesterase inhibitors used in the treatment of AD are not fully understood at the molecular level, as there appears to be effects on disease progression that are distinct from the immediate effects of increased longevity of ACh in the synaptic cleft (Francis et al. 1999).”
BackgroundDysregulation of Astrocyte–Neuronal Communication in Alzheimer’s Disease
Nanclares, C., Baraibar, A. M., Araque, A., & Kofuji, P. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22157887 · Cited by 103
“The systematic biochemical investigation of the brains of patients with AD in the late 1960s and early 1970s led to the cholinergic hypothesis [7].”
BackgroundThe cellular model for Alzheimer's disease research: PC12 cells
Xie, D., Deng, T., Zhai, Z., Sun, T., & Xu, Y. D. (2023) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2022.1016559 · Cited by 107
A Clinical Overview of Cholinesterase Inhibitors in Alzheimer’s Disease
Farlow, M. R. (2002) · International Psychogeriatrics · doi:10.1017/s1041610203008688 · Cited by 100
Cerebral blood flow and cognitive responses to rivastigmine treatment in Alzheimer’s disease
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Misane, I., & Ögren, S. O. (2003) · Neuropsychopharmacology · doi:10.1038/sj.npp.1300024 · Cited by 100
“In addition to a deficit in cholinergic transmission, dementia is also related to degeneration of glutamatergic hippocampal and cortical pyramidal neurons (Aronica et al, 1998; Francis et al, 1999), which are targets for cholinergic and serotonergic innervation.”
Gouveia, F., Camins, A., Ettcheto, M., Bicker, J., Falcão, A. C., Cruz, M. T., & Fortuna, A. C. (2022) · Ageing Research Reviews · doi:10.1016/j.arr.2022.101612 · Cited by 99
Neuronal histamine and cognitive symptoms in Alzheimer's disease
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“A central hallmark of this disease is a deterioration of learning and memory as well as other cognitive symptoms leading to a profound negative impact on the patient's daily life (Babic, 1999; Bianchetti et al., 2006; Brodaty et al., 2001).”
Batool, Z., Sadir, S., Liaquat, L., Tabassum, S., Madiha, S., Rafiq, S., Tariq, S., Batool, T. S., Saleem, S., Naqvi, F. F., et al. (2015) · Brain Research Bulletin · doi:10.1016/j.brainresbull.2015.11.001 · Cited by 100
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Pathoconnectomics of cognitive impairment in small vessel disease: A systematic review
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“According to the cholinergic hypothesis, deterioration of cognitive function in those with AD can be attributed in part to degeneration of basal forebrain cholinergic neurons and reduced cholinergic neurotransmission [117].”
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Alzheimer’s Disease: Etiology, Neuropathology and Pathogenesis
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“Neocortical deficit of choline acetyltransferase, reduction of choline uptake and acetylcholine release, as well as loss of cholinergic neurons from the nucleus basalis of Meynert, together with the established role of acetylcholine in learning and memory, led to the cholinergic hypothesis of AD [19].”
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Vision function abnormalities in Alzheimer disease
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Long-Term Efficacy and Toxicity of Cholinesterase Inhibitors in the Treatment of Alzheimer Disease
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Rossini, P. M., Buscema, M., Capriotti, M., Grossi, E., Rodriguez, G., Percio, C. D., & Babiloni, C. (2008) · Clinical Neurophysiology · doi:10.1016/j.clinph.2008.03.026 · Cited by 91
“An important but not exclusive role might be played by a lack of the excitatory neurotransmitter acetylcholine into cholinergic neural projections from basal forebrain to hippocampus/amygdala and cortex reported in previous post-mortem AD studies (Francis et al., 1999; Mesulam, 2004).”
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“jectured to be linked with cognitive impairment through execution of cholinergic hypofunction, reactive oxygen/ nitrogen species (ROS/ RNS) generation, inflammation in neurons and eventual forfeiture of neuronal cells [4,11].”
Mitochondrial function in ageing: coordination with signalling and transcriptional pathways
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“…of Alzheimer’s disease has been hypothesized by several theories such as the β-amyloid hypothesis (Tanzi & Bertram, 2005), cholinergic hypothesis (Francis et al. 1999), tau hypothesis (Maccioni et al. 2010), oxidative stress hypothesis (Markesbery, 1997), and mitochondrial cascade hypothesis…”
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BackgroundInfluentialN a+‐ K +‐ ATP ase, a potent neuroprotective modulator against A lzheimer disease
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“AD is supposed to be account for 50–60% of dementia cases in elderly patients (Francis et al., 1999).”
BackgroundHippocampal estrogen β-receptor immunoreactivity is increased in Alzheimer’s disease
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Efficacy and Safety of Memantine in Moderate-to-Severe Alzheimer Disease: The Evidence to Date
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“In particular, excitotoxic reactions related to excess glutamate release in the CNS are thought to play a major role in cell death.(23) Nmethyl-D-aspartate (NMDA) postsynaptic receptors are stimulated by glutamate and have been implicated in the pathogenesis of AD.”
BackgroundNeurotransmitter Imbalance in the Brain and Alzheimer’s Disease Pathology
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The cerebrovascular role of the cholinergic neural system in Alzheimer's disease
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“In addition, the hippocampus and cortical regions of the brain are main sites for cholinergic transmission to monitor learning and memory processing, and seem to be more sensitive to oxidative damage [8] which contributes neuronal damage and establishing of cognitive deficit [9].”
Classics in Chemical Neuroscience: Donepezil
Brewster, J. T., Dell’Acqua, S., Thach, D. Q., & Sessler, J. L. (2018) · ACS Chemical Neuroscience · doi:10.1021/acschemneuro.8b00517 · Cited by 94
Zhang, R., Zhang, J., Fang, L., Li, X., Zhao, Y., Shi, W., & An, L. (2014) · International Journal of Molecular Sciences · doi:10.3390/ijms150814396 · Cited by 88
“To slow down the progression of AD and improve cognitive function, researchers have attempted to restore the cholinergic balance through inhibition of cholinesterase-mediated ACh breakdown [6,8].”
BackgroundMultifunctional drugs with different CNS targets for neuropsychiatric disorders
der Schyf, C. J. V., Geldenhuys, W. J., & Youdim, M. B. H. (2006) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2006.04141.x · Cited by 88
Nootropic, anxiolytic and CNS-depressant studies on different plant sources ofshankhpushpi
Malik, J., Karan, M., & Vasisht, K. (2011) · Pharmaceutical Biology · doi:10.3109/13880209.2011.584539 · Cited by 89
“Moreover, scopolamine is a muscarinic antagonist, and it has been reported that blockade/or decreased muscarinic activity causes excess phosphorylation of tau proteins leading to the formation of β-amyloid in the brain leading to memory impairment (Francis et al., 1999).”
BackgroundKarimipour, M., Rahbarghazi, R., Nasrabadi, H. T., Shimia, M., Ghanadian, M., Mahmoudi, J., & Bagheri, H. S. (2019) · International Journal of Developmental Neuroscience · doi:10.1016/j.ijdevneu.2019.02.005 · Cited by 90
“In human with the AD, the NGF level is decreased and contributed to neural tissue degeneration (Francis et al., 1999; Scott et al., 1995).”
Background
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
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