The DOI matches its Crossref record; 59 of the 59 references it cites were found in a registry or an index; none of the 55 sources its claims cite is checked for support yet.
Autism, Alzheimer disease, and fragile X
Open accessAbstract
The present review highlights an association between autism, Alzheimer disease (AD), and fragile X syndrome (FXS). We propose a conceptual framework involving the amyloid-β peptide (Aβ), Aβ precursor protein (APP), and fragile X mental retardation protein (FMRP) based on experimental evidence. The anabolic (growth-promoting) effect of the secreted α form of the amyloid-β precursor protein (sAPPα) may contribute to the state of brain overgrowth implicated in autism and FXS. Our previous report demonstrated that higher plasma sAPPα levels associate with more severe symptoms of autism, including aggression. This molecular effect could contribute to intellectual disability due to repression of cell-cell adhesion, promotion of dense, long, thin dendritic spines, and the potential for disorganized brain structure as a result of disrupted neurogenesis and migration. At the molecular level, APP and FMRP are linked via the metabotropic glutamate receptor 5 (mGluR5). Specifically, mGluR5 activation releases FMRP repression of APP mRNA translation and stimulates sAPP secretion. The relatively lower sAPPα level in AD may contribute to AD symptoms that significantly contrast with those of FXS and autism. Low sAPPα and production of insoluble Aβ would favor a degenerative process, with the brain atrophy seen in AD. Treatment with mGluR antagonists may help repress APP mRNA translation and reduce secretion of sAPP in FXS and perhaps autism.
Overview
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Written from the paper’s full text.
TL;DR
This review proposes that amyloid-β precursor protein (APP), fragile X mental retardation protein (FMRP), and metabotropic glutamate receptor 5 (mGluR5) form molecular links among autism, Alzheimer disease (AD), and fragile X syndrome (FXS). It hypothesizes that excess secreted α form of APP (sAPPα) contributes to brain overgrowth in severe autism and FXS, whereas relatively lower sAPPα and insoluble Aβ production favor degeneration and atrophy in AD.
Key findings
- In a small sample of young children with severe autism and aggression, plasma total sAPP (including sAPPα) was 2 or more times the levels in children without autism and up to 4 times higher than in children with mild autism; an independent laboratory found elevated plasma sAPPα in 60% of known autistic children (n = 25) versus healthy age-matched controls, and a larger follow-up sample confirmed elevated sAPPα in severe autism without coexistent aggression plus significantly reduced Aβ-40 and Aβ-42 (unpublished data, 2011).
- FMRP inhibits APP mRNA translation by binding G quartets in the APP coding region; mGluR5 activation releases this repression and stimulates sAPP secretion. In Fmr1 knockout mice, basal APP translation was increased, mGluR agonist treatment did not increase APP translation, and soluble Aβ-40 and Aβ-42 were significantly higher than in wild-type mice due to elevated APP expression.
- The authors propose that high sAPPα via nonamyloidogenic processing may contribute to macrocephaly and severe autism/FXS phenotypes, while low sAPPα and insoluble Aβ-40/42 would favor a catabolic, degenerative process leading to brain atrophy in AD.
- Seizures are seen in 10%–30% of individuals with autism and frequently in FXS and AD; based on mouse models, the authors speculate seizure etiology may involve overproduction of APP. Macrocephaly affects up to 20% of children with autism.
Methods
- Narrative review and conceptual synthesis of published literature plus the authors’ laboratory data, proposing a framework involving Aβ, APP, and FMRP.
- Evidence discussed includes human plasma samples from autistic and control children, Fmr1 knockout and wild-type mouse synaptoneurosomes, cell culture studies, and unpublished data (2011); no systematic review, meta-analysis, or formal statistical analysis is described.
- Main analysis is interpretive: linking APP/FMRP/mGluR5 signaling to autism, AD, and FXS phenotypes and comparing anabolic versus catabolic APP processing.
Limitations
- Stated: the original autism plasma finding was based on a small sample; some supporting data are unpublished (2011); elevated sAPPα was not found in mild autism and may not be applicable to that population.
- Stated: the model is speculative and hypothesis-generating, and the authors recognize that effects of developmental perturbations can differ from those of FMRP deficiency.
- Evident from the text: as a narrative review, it lacks a systematic search or quality assessment, relies partly on unpublished and cited data, and the independent replication involved only n = 25 autistic children with elevated sAPPα in 60%.
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Claims the paper makes
44 Sources not found · 16 Own interpretation · 5 Own result · 1 Not checked yet
None of the sources cited for this claim have been checked yet.
In the paper
“Our previous report demonstrated that higher plasma sAPP␣ levels associate with more severe symptoms of autism, including aggression.”
§ Autism, Alzheimer disease, and fragile X APP, FMRP, and mGluR5 are molecular links > Abstract
boostedcorrelational- 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.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Unlike our original study, we also observed significantly reduced levels of A-40 and A-42 in severe autism (unpublished data, 2011).”
§ Autism, Alzheimer disease, and fragile X APP, FMRP, and mGluR5 are molecular links > LINKING SAPP WITH AUTISM
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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None of the sources cited for this claim could be matched to a paper in Crossref, so there is nothing to check it against.
In the paper
“Our findings of high levels of sAPP␣ in some children with autism (unpublished data, 2011) 13,43 recently were corroborated in an independent laboratory.6”
§ Autism, Alzheimer disease, and fragile X APP, FMRP, and mGluR5 are molecular links > SUMMARY, POSSIBLE DRUG TARGETS, AND FUTURE PERSPECTIVES
What the sources say
- Not matchedcites [13]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not matchedcites [43]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not matchedcites [6]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
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In the paper
“We have reported high levels of total sAPP (including sAPP␣) in plasma of a small sample of young children with severe autism and aggression.13”
§ Autism, Alzheimer disease, and fragile X APP, FMRP, and mGluR5 are molecular links > LINKING SAPP WITH AUTISM
What the sources say
- Not matchedcites [13]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
plaincorrelational- 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.
- Not matched
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Furthermore, a recent follow-up study by our laboratory in a separate, larger set of autistic and control patient plasma samples confirms our original finding of elevated sAPP␣ in the plasma of severely autistic patients without requiring coexistent aggression (unpublished data, 2011).”
§ Autism, Alzheimer disease, and fragile X APP, FMRP, and mGluR5 are molecular links > LINKING SAPP WITH AUTISM
boostedcorrelational- 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.
None of the sources cited for this claim could be matched to a paper in Crossref, so there is nothing to check it against.
In the paper
“There have been recent genetic associations found between cases of autism with pronounced macrocephaly and mutations in the PTEN gene.[40][41]”
§ Autism, Alzheimer disease, and fragile X APP, FMRP, and mGluR5 are molecular links > RELATIONSHIPS AMONG NEURONAL PRO-TEINS IN AUTISM, AD, AND FXS
What the sources say
- Not matchedcites [40]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not matchedcites [41]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
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.
- Not matched
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
“Despite our contention that autism spectrum and AD may arise from converse disease mechanisms (especially with respect to APP metabolism), this does not preclude certain therapeutic modalities from proving beneficial in both disorders.”
§ Autism, Alzheimer disease, and fragile X APP, FMRP, and mGluR5 are molecular links > SUMMARY, POSSIBLE DRUG TARGETS, AND FUTURE PERSPECTIVES
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: unclear — It is unclear why the paper says 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
“Elevated neural proliferation is not balanced by increased neural pruning, in part due to FMRP deficiency.”
§ Autism, Alzheimer disease, and fragile X APP, FMRP, and mGluR5 are molecular links > ROLE OF GENE-ENVIRONMENT INTERACTION IN THE ETIOLOGY OF NEURODEVELOPMENTAL AND NEURODEGENERATIVE DISORDERS
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: unclear — It is unclear why the paper says it holds.
In the paper
“A recent study 4 showed head growth rate at 30 months was greater for FXS boys with autism (n ϭ 22) than for FXS boys without autism (n ϭ 22).”
§ Autism, Alzheimer disease, and fragile X APP, FMRP, and mGluR5 are molecular links > FXS.
What the sources say
- Not matchedcites [4]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
plaincorrelationaln = 22- 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.
- Not matched
In the paper
“Further, autism has been associated with DNA hypomethylation in parents.e41”
§ Autism, Alzheimer disease, and fragile X APP, FMRP, and mGluR5 are molecular links > ROLE OF GENE-ENVIRONMENT INTERACTION IN THE ETIOLOGY OF NEURODEVELOPMENTAL AND NEURODEGENERATIVE DISORDERS
What the sources say
- Not matchedcites e41
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
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.
- Not matched
- It may state two separate claims as one. 21
- Probably not a substantial claim. 5
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Elevation in sAPP␣ was not found for children with mild autism in either study and may not be applicable to this population.”
§ Autism, Alzheimer disease, and fragile X APP, FMRP, and mGluR5 are molecular links > LINKING SAPP WITH AUTISM
hedged- 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 result the paper reports from its own data — 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 children expressed sAPP at 2 or more times the levels of children without autism and up to 4 times more than children with mild autism.”
§ Autism, Alzheimer disease, and fragile X APP, FMRP, and mGluR5 are molecular links > LINKING SAPP WITH AUTISM
plaincorrelational- 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 result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Overall, there was a trend toward higher levels of both sAPP␣ and total sAPP (sAPP is not a significant component of plasma total sAPP and was not measured) within children with autism, combined with a nonsignificant decrease in A-40.”
§ Autism, Alzheimer disease, and fragile X APP, FMRP, and mGluR5 are molecular links > LINKING SAPP WITH AUTISM
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.
None of the sources cited for this claim could be matched to a paper in Crossref, so there is nothing to check it against.
In the paper
“Macrocephaly has been one of the most widely replicated biological findings in autism, affecting up to 20% of all children with the condition 22 and confirmed by MRI volumetric studies.23”
§ Autism, Alzheimer disease, and fragile X APP, FMRP, and mGluR5 are molecular links > FEATURES OF AUTISM, AD, AND FXS Autism.
What the sources say
- Not matchedcites [22]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not matchedcites [23]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
boostedcorrelational- 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.
- Not matched
In the paper
“When APP is processed alternatively via the nonamyloidogenic (␣-secretase) pathway, the secreted alpha form of APP (sAPP␣) is produced.”
§ Autism, Alzheimer disease, and fragile X APP, FMRP, and mGluR5 are molecular links > Abstract
What the sources say
- Not matchedcites e1
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
plaindirect- 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.
- Not matched
In the paper
“In this model, environmental agents epigenetically disturb gene regulation in a long-term manner, beginning at early developmental stages, but these perturbations might not have pathologic results until significantly later in life.”
§ Autism, Alzheimer disease, and fragile X APP, FMRP, and mGluR5 are molecular links > ROLE OF GENE-ENVIRONMENT INTERACTION IN THE ETIOLOGY OF NEURODEVELOPMENTAL AND NEURODEGENERATIVE DISORDERS
What the sources say
- Not matchedcites [44]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
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.
- Not matched
None of the sources cited for this claim could be matched to a paper in Crossref, so there is nothing to check it against.
In the paper
“These results point to an activity-dependent regulatory relationship between FMRP and APP mediated by mGluR5 signaling and to loss of this FMRP-based regulation in FXS, thereby providing a link between neuronal proteins associated with AD and FXS (unpublished data, 2011).6,13,43”
§ Autism, Alzheimer disease, and fragile X APP, FMRP, and mGluR5 are molecular links > The relationship of APP to FMRP is mediated by mGluR.
What the sources say
- Not matchedcites [6]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not matchedcites [13]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not matchedcites [43]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
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.
- Not matched
In the paper
“In mice, sAPP␣ has been shown to increase neurite outgrowth and memory and protect against multiple insults.11”
§ Autism, Alzheimer disease, and fragile X APP, FMRP, and mGluR5 are molecular links > Abstract
What the sources say
- Not matchedcites [11]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
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.
- Not matched
None of the sources cited for this claim could be matched to a paper in Crossref, so there is nothing to check it against.
In the paper
“mGluR induce activity-dependent protein synthesis by activating several pathways including the PI3K/mTOR pathway, e35,e36 which is a FMRPdependent pathway.”
§ Autism, Alzheimer disease, and fragile X APP, FMRP, and mGluR5 are molecular links > RELATIONSHIPS AMONG NEURONAL PRO-TEINS IN AUTISM, AD, AND FXS
What the sources say
- Not matchedcites e35
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not matchedcites e36
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
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.
- Not matched
None of the sources cited for this claim could be matched to a paper in Crossref, so there is nothing to check it against.
In the paper
“Studies of children with FXS have shown macrocephaly 4 and derangement of white matter frontal-striatal pathways.32”
§ Autism, Alzheimer disease, and fragile X APP, FMRP, and mGluR5 are molecular links > FXS.
What the sources say
- Not matchedcites [4]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not matchedcites [32]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
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.
- Not matched
In the paper
“Autism, FXS, and AD share uncertain etiologies, with opaque relationships between genes and the environment consistent with the recently proposed latent earlylife associated regulation (LEARn) model, positing latent changes in expression of specific genes initially primed at the developmental stage of life.44”
§ Autism, Alzheimer disease, and fragile X APP, FMRP, and mGluR5 are molecular links > ROLE OF GENE-ENVIRONMENT INTERACTION IN THE ETIOLOGY OF NEURODEVELOPMENTAL AND NEURODEGENERATIVE DISORDERS
What the sources say
- Not matchedcites [44]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
plaincorrelational- 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.
- Not matched
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
“In FXS, where FMRPdependent translational repression of APP is absent, high basal levels of APP and elimination of activitydependent regulation of APP levels would be expected.”
§ Autism, Alzheimer disease, and fragile X APP, FMRP, and mGluR5 are molecular links > The relationship of APP to FMRP is mediated by mGluR.
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.
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
“Specifically, we postulate that high levels of sAPP␣ may contribute to macrocephaly, observed in both FXS and autism, through its associated neurotrophic activity.”
§ Autism, Alzheimer disease, and fragile X APP, FMRP, and mGluR5 are molecular links > LINKING SAPP WITH AUTISM
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: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The paper may give no reason why it holds.
- Rests on an assumption: Plasma sAPPα levels reflect brain sAPPα levels or activity relevant to brain overgrowth in autism and FXS.
In the paper
“Activation of metabotropic glutamate receptor 5 (mGluR5) releases FMRP-mediated translation repression and results in protein synthesis-dependent LTD.”
§ Autism, Alzheimer disease, and fragile X APP, FMRP, and mGluR5 are molecular links > RELATIONSHIPS AMONG NEURONAL PRO-TEINS IN AUTISM, AD, AND FXS
What the sources say
- Not matchedcites [5]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
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.
- Not matched
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 activity of sAPP␣ may be partially mediated by interactions with adhesion modulators, such as -catenin, thereby altering adhesion and migration of cortical neurons and promoting overgrowth.”
§ Autism, Alzheimer disease, and fragile X APP, FMRP, and mGluR5 are molecular links > LINKING SAPP WITH AUTISM
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: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The paper may give no reason why it holds.
- Rests on an assumption: Cell adhesion suppresses brain growth, while abnormalities in adhesion promote growth or contribute to aberrant growth.
In the paper
“Specifically, FMRP inhibits APP translation under basal conditions, but when mGluR5 receptors are activated, this inhibitory effect is released.”
§ Autism, Alzheimer disease, and fragile X APP, FMRP, and mGluR5 are molecular links > The relationship of APP to FMRP is mediated by mGluR.
What the sources say
- Not matchedcites [5]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
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.
- Not matched
In the paper
“APP is the parental molecule of neurotoxic amyloid- peptide (A), produced by amyloidogenic processing of APP and secreted in excess in AD. e1”
§ Autism, Alzheimer disease, and fragile X APP, FMRP, and mGluR5 are molecular links > Abstract
What the sources say
- Not matchedcites e1
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
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.
Probably not a substantial claim. It may state two separate claims as one.
- Not matched
None of the sources cited for this claim could be matched to a paper in Crossref, so there is nothing to check it against.
In the paper
“Fmr1-knockout mice show reduced LTP in cortex and amygdala e28-e30 and exaggerated mGluRdependent LTD in hippocampus and cerebellum.e31-e34”
§ Autism, Alzheimer disease, and fragile X APP, FMRP, and mGluR5 are molecular links > RELATIONSHIPS AMONG NEURONAL PRO-TEINS IN AUTISM, AD, AND FXS
What the sources say
- Not matchedcites e28-e30
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not matchedcites e31-e34
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
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.
- Not matched
In the paper
“Specifically, mGluR5 activation releases FMRP repression of APP mRNA translation and stimulates sAPP secretion.”
§ Autism, Alzheimer disease, and fragile X APP, FMRP, and mGluR5 are molecular links > Abstract
What the sources say
- Not matchedcites [5]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
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.
- Not matched
None of the sources cited for this claim could be matched to a paper in Crossref, so there is nothing to check it against.
In the paper
“Some of the known functions of APP in these processes include promotion of proliferation, cell-cell adhesion and migration, 10 and synaptogenesis.33”
§ Autism, Alzheimer disease, and fragile X APP, FMRP, and mGluR5 are molecular links > RELATIONSHIPS AMONG NEURONAL PRO-TEINS IN AUTISM, AD, AND FXS
What the sources say
- Not matchedcites [10]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not matchedcites [33]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
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.
- Not matched
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
“The finding of exaggerated mGluR-LTD in the absence of FMRP suggests that LTD becomes uncoupled from mGluR5 activation and persists independent of FMRP-dependent new protein synthesis.”
§ Autism, Alzheimer disease, and fragile X APP, FMRP, and mGluR5 are molecular links > RELATIONSHIPS AMONG NEURONAL PRO-TEINS IN AUTISM, AD, AND FXS
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.
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 could result in CNS neural overgrowth and leads to the symptoms of fragile X syndrome (FXS) or autism.”
§ Autism, Alzheimer disease, and fragile X APP, FMRP, and mGluR5 are molecular links > ROLE OF GENE-ENVIRONMENT INTERACTION IN THE ETIOLOGY OF NEURODEVELOPMENTAL AND NEURODEGENERATIVE DISORDERS
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.
- Rests on an assumption: APP has been implicated in neurogenesis, which may set the stage for later prenatal to early postnatal overproliferation of neurons.
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
“When FMRP is eliminated or diminished, translation of amyloid- (A) precursor protein (APP) mRNA is disinhibited resulting in elevated basal levels of APP protein and the elimination of activity-dependent dynamic APP production.”
§ Autism, Alzheimer disease, and fragile X APP, FMRP, and mGluR5 are molecular links > ROLE OF GENE-ENVIRONMENT INTERACTION IN THE ETIOLOGY OF NEURODEVELOPMENTAL AND NEURODEGENERATIVE DISORDERS
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: unclear — It is unclear why the paper says 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 wide-spectrum changes in APP processing modulate protein product levels in a direction that would be beneficial in both disorders according to our model and could partially explain the observed salutary effect of memantine in both disorders, aside from classic NMDAR antagonism.”
§ Autism, Alzheimer disease, and fragile X APP, FMRP, and mGluR5 are molecular links > SUMMARY, POSSIBLE DRUG TARGETS, AND FUTURE PERSPECTIVES
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.
The paper relies on this without support.
Plasma sAPPα levels reflect brain sAPPα levels or activity relevant to brain overgrowth in autism and FXS.
“We have reported high levels of total sAPP (including sAPP␣) in plasma of a small sample of young children with severe autism and aggression.13”
The paper relies on this without support.
Cell adhesion suppresses brain growth, while abnormalities in adhesion promote growth or contribute to aberrant growth.
“Cell adhesion suppresses brain growth, while abnormalities in adhesion promote growth or contribute to aberrant growth.”
The paper relies on this without support.
Findings from mouse models and cell culture about APP, FMRP, and mGluR5 apply to human autism, FXS, and AD.
“In mice, sAPP␣ has been shown to increase neurite outgrowth and memory and protect against multiple insults.11”
“Fmr1-knockout mice show reduced LTP in cortex and amygdala e28-e30 and exaggerated mGluRdependent LTD in hippocampus and cerebellum.e31-e34”
The paper relies on this without support.
PTEN is a tumor suppressor that regulates cell cycle through its antagonistic actions on the PI3K/Akt/mTOR pathway.
“PTEN is a tumor suppressor that regulates cell cycle through its antagonistic actions on the PI3K/Akt/mTOR pathway.”
The paper relies on this without support.
PTEN is a phosphatase that counteracts PI3K by dephosphorylating PIP3.
“Specifically, PTEN is a phosphatase that counteracts PI3K by dephoshorylating PIP3.”
The paper relies on this without support.
The mTOR signaling pathway is a central regulator of cell growth and proliferation that also regulates synaptic plasticity by modulating protein synthesis in an activity-dependent manner.
“The mTOR signaling pathway is a central regulator of cell growth and proliferation that also regulates synaptic plasticity by modulating protein synthesis in an activity-dependent manner.”
The paper relies on this without support.
In a healthy system, FMRP activity and mGluR5 activity work in homeostasis and neural proliferation is balanced, leading to a neurotypical condition.
“In a healthy system, FMRP activity and mGluR5 activity work in homeostasis and neural proliferation is balanced, leading to a neurotypical condition.”
The paper relies on this without support.
APP has been implicated in neurogenesis, which may set the stage for later prenatal to early postnatal overproliferation of neurons.
“APP has been implicated in neurogenesis, which may set the stage for later prenatal to early postnatal overproliferation of neurons.”
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Rated major: it would touch a result — a value a result rests on, reported and recomputed p-values on opposite sides of the significance level, two passages that conflict with no sign which is right, or a cited work retracted before this paper was published.
In the paper
§ Autism, Alzheimer disease, and fragile X APP, FMRP, and mGluR5 are molecular links > Abstract
“Treatment with mGluR antagonists may help repress APP mRNA translation and reduce secretion of sAPP in FXS and perhaps autism.”
§ Autism, Alzheimer disease, and fragile X APP, FMRP, and mGluR5 are molecular links > SUMMARY, POSSIBLE DRUG TARGETS, AND FUTURE PERSPECTIVES
“mGluR5 activity in amyloid- (A) precursor protein (APP) mRNA translation is disinhibitory, so blocking mGluR5 is not likely to alter APP translation levels.”
Citations
Cites
The mGluR theory of fragile X mental retardation
Bear, M. F., Huber, K. M., & Warren, S. T. (2004) · Trends in Neurosciences · doi:10.1016/j.tins.2004.04.009 · Cited by 1,580
Autism genome-wide copy number variation reveals ubiquitin and neuronal genes
Glessner, J. T., Wang, K., Cai, G., Korvatska, O., Kim, C. E., Wood, S., Zhang, H., Estes, A., Brune, C. W., Bradfield, J. P., et al. (2009) · Nature · doi:10.1038/nature07953 · Cited by 1,421
Intention tremor, parkinsonism, and generalized brain atrophy in male carriers of fragile X
Hagerman, R. J., Leehey, M. A., Heinrichs, W. L., Tassone, F., Wilson, R., Hills, J. D., Grigsby, J., Gage, B. F., & Hagerman, P. J. (2001) · Neurology · doi:10.1212/wnl.57.1.127 · Cited by 966
Neuroanatomic observations of the brain in autism: a review and future directions
Bauman, M. L., & Kemper, T. L. (2005) · International Journal of Developmental Neuroscience · doi:10.1016/j.ijdevneu.2004.09.006 · Cited by 919
Elevated immune response in the brain of autistic patients
Li, X., Chauhan, A., Sheikh, A. M., Patil, S., Chauhan, V., Li, X.-M., Ji, L., Brown, T., & Malik, M. (2009) · Journal of Neuroimmunology · doi:10.1016/j.jneuroim.2008.12.002 · Cited by 786
Butler, M. G., Dasouki, M. J., Zhou, X.-P., Talebizadeh, Z., Brown, M., Takahashi, T. N., Miles, J. H., Wang, C. H., Stratton, R., Pilarski, R., et al. (2005) · Journal of Medical Genetics · doi:10.1136/jmg.2004.024646 · Cited by 778
Synapse Formation and Function Is Modulated by the Amyloid Precursor Protein
Priller, C., Bauer, T., Mitteregger, G., Krebs, B., Kretzschmar, H. A., & Herms, J. W. (2006) · Journal of Neuroscience · doi:10.1523/jneurosci.1450-06.2006 · Cited by 574
Geschwind, D. H. (2009) · Annual Review of Medicine · doi:10.1146/annurev.med.60.053107.121225 · Cited by 512
The epidemiology of the dementias: an update
Qiu, C., Ronchi, D. D., & Fratiglioni, L. (2007) · Current Opinion in Psychiatry · doi:10.1097/yco.0b013e32816ebc7b · Cited by 434
Elevated cytokine levels in children with autism spectrum disorder
Molloy, C. A., Morrow, A. L., Meinzen-Derr, J., Schleifer, K., Dienger, K., Manning-Courtney, P., Altaye, M., & Wills-Karp, M. (2006) · Journal of Neuroimmunology · doi:10.1016/j.jneuroim.2005.11.007 · Cited by 386
Research works printed but not linked: 1
- Sokol DK, Long J, Maloney B, Chen D, Lahiri DK. Potential Alzheimer's disease markers for autism? Beta amyloid precursor protein and acetylcholinesterase correlated with aggression in autism. Presented at the American Academy of Neurology, Seattle, 2009.
Cited by
Sorted by citations
Amyloid Beta: Structure, Biology and Structure-Based Therapeutic Development
Chen, G.-F., Xu, T.-H., Yan, Y., Zhou, Y.-R., Jiang, Y., Melcher, K., & Xu, H. E. (2017) · Acta Pharmacologica Sinica · doi:10.1038/aps.2017.28 · Cited by 1,965
Um, J. W., Kaufman, A. C., Kostylev, M., Heiss, J. K., Stagi, M., Takahashi, H., Kerrisk, M. E., Vortmeyer, A., Wisniewski, T., Koleske, A. J., et al. (2013) · Neuron · doi:10.1016/j.neuron.2013.06.036 · Cited by 572
“Shared pathways between AD and Fragile X have been reported (Sokol et al., 2011).”
Glutamate, Glutamate Receptors, and Downstream Signaling Pathways
Willard, S. S., & Koochekpour, S. (2013) · International Journal of Biological Sciences · doi:10.7150/ijbs.6426 · Cited by 323
An epigenetic framework for neurodevelopmental disorders: From pathogenesis to potential therapy
Millan, M. J. (2013) · Neuropharmacology · doi:10.1016/j.neuropharm.2012.11.015 · Cited by 229
Neurological phenotypes for Down syndrome across the life span
Lott, I. T. (2012) · Progress in Brain Research · doi:10.1016/b978-0-444-54299-1.00006-6 · Cited by 225
“Treatment with glutamate receptor antagonists may help repress APP and serve as a therapeutic target for AD (Sokol et al., 2011).”
Background
Metadata
- Authors
- Sokol, D. K., Maloney, B., Long, J. M., Ray, B., & Lahiri, D. K.
- Affiliations
- Indiana University Indianapolis (US)
- Venue
- Neurology
- Published
- 2011-04-12
- Volume
- 76
- Issue
- 15
- Pages
- 1344-1352
- ISSN
- 0028-3878 (ISSN-L)
- 1526-632X
- PMC
- PMC3090060
- OpenAlex
- W2042211936
- Cited by
- 141
- References
- 58
- Citations by year
- 2026: 5 · 2025: 4 · 2024: 7 · 2023: 4 · 2022: 10 · 2021: 8 · 2020: 7 · 2019: 11 · 2018: 8 · 2017: 8 · 2016: 11 · 2015: 10 · 2014: 12 · 2013: 17 · 2012: 16
- FWCI
- 8.76
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Neurology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (submittedVersion)
- Funders
- Alzheimer's Association (AG18379)
- National Institutes of Health (AG18379)
- National Institute on Aging (R01 AG018379, AG 18379, R01AG018884, AG18884)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
- Keywords
- autism spectrum disorder, Alzheimer's disease, fragile X syndrome, amyloid precursor protein, sAPPα, FMRP, metabotropic glutamate receptor 5, amyloid-beta, intellectual disability, dendritic spines, brain overgrowth, mGluR antagonists, plasma biomarkers
- MeSH terms
- Alzheimer Disease, Autistic Disorder, Fragile X Syndrome, Humans, Amyloid beta-Protein Precursor, Receptors, Metabotropic Glutamate, Fragile X Mental Retardation Protein, Fragile X Messenger Ribonucleoprotein 1, Receptor, Metabotropic Glutamate 5
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