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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.
- 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
“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.
- Based: passes — The paper gives a reason why it holds.
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.
- 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, 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.
- Based: passes — The paper gives a reason why it holds.
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.
- Based: passes — The paper gives a reason why it holds.
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.
- Based: passes — The paper gives a reason why it holds.
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.
- 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
“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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Diagnostic and Statistical Manual of Mental Disorders
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Older Adults' Reasons for Using Technology while Aging in Place
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A 5-month, randomized, placebo-controlled trial of galantamine in AD
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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
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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