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Cited by 141Genetics and Neurodevelopmental DisordersAlzheimer's disease research and treatmentsAutism Spectrum Disorder Research

Autism, Alzheimer disease, and fragile X

Open access
Sokol, D.K., Maloney, B., Long, J.M., Ray, B., Lahiri, D.K.·2011·Neurology
DOI 10.1212/wnl.0b013e3182166dc7PMC PMC3090060
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Abstract

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.

AI snapshot

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%.

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

Integrity signals

Registry

Crossref · 10.1212/wnl.0b013e3182166dc7

Cites

59 of 59 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 55 cited sources checked · 0 supported · 0 flagged

  • Findingcitation

    Higher plasma sAPPα levels associate with more severe symptoms of autism, including aggression.

    “Our previous report demonstrated that higher plasma sAPP␣ levels associate with more severe symptoms of autism, including aggression.”
    Quote in the paperSubstantial claim
  • Findingown data

    In severe autism, levels of Aβ-40 and Aβ-42 are significantly reduced.

    “Unlike our original study, we also observed significantly reduced levels of A␤-40 and A␤-42 in severe autism (unpublished data, 2011).”
    Quote in the paperSubstantial claim
  • Findingown data

    High levels of sAPPα are present in some children with autism.

    “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”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [13]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [43]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [6]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Findingcitation

    In a small sample of young children with severe autism and aggression, plasma total sAPP (including sAPPα) levels were high.

    “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”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [13]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Findingown data

    A follow-up study in a separate, larger set of autistic and control plasma samples confirms elevated sAPPα in plasma of severely autistic patients without requiring coexistent aggression.

    “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).”
    Quote in the paperSubstantial claim
  • May combine two claims. 21
  • Classified as probably not a substantial claim. 5

  • May combine two claims.

    Findingown data

    Elevation in sAPPα was not found for children with mild autism in either study and may not be applicable to this population.

    “Elevation in sAPP␣ was not found for children with mild autism in either study and may not be applicable to this population.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Children with severe autism and aggression expressed sAPP at 2 or more times the levels of children without autism and up to 4 times more than children with mild autism.

    “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.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Within children with autism, there was a trend toward higher levels of both sAPPα and total sAPP, combined with a nonsignificant decrease in Aβ-40.

    “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.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    Macrocephaly is one of the most widely replicated biological findings in autism, affecting up to 20% of all children with the condition and confirmed by MRI volumetric studies.

    “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”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [22]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [23]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

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

    Premisecitation

    When APP is processed alternatively via the nonamyloidogenic (α-secretase) pathway, the secreted alpha form of APP (sAPPα) is produced.

    “When APP is processed alternatively via the nonamyloidogenic (␣-secretase) pathway, the secreted alpha form of APP (sAPP␣) is produced.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites e1

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation

    In the LEARn 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.

    “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.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [44]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Interpretationreasoning

    The 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, providing a link between neuronal proteins associated with AD and FXS.

    “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”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [6]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [13]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [43]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation

    In mice, sAPPα has been shown to increase neurite outgrowth and memory and protect against multiple insults.

    “In mice, sAPP␣ has been shown to increase neurite outgrowth and memory and protect against multiple insults.11”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [11]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation

    mGluR induce activity-dependent protein synthesis by activating several pathways including the PI3K/mTOR pathway, which is a FMRP-dependent pathway.

    “mGluR induce activity-dependent protein synthesis by activating several pathways including the PI3K/mTOR pathway, e35,e36 which is a FMRPdependent pathway.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites e35

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites e36

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation

    Studies of children with FXS have shown macrocephaly and derangement of white matter frontal-striatal pathways.

    “Studies of children with FXS have shown macrocephaly 4 and derangement of white matter frontal-striatal pathways.32”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [4]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [32]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation

    Autism, FXS, and AD share uncertain etiologies, with opaque relationships between genes and the environment consistent with the LEARn model, which posits latent changes in expression of specific genes initially primed at the developmental stage of life.

    “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”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [44]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Interpretationreasoning

    In FXS, where FMRP-dependent translational repression of APP is absent, high basal levels of APP and elimination of activity-dependent regulation of APP levels are expected.

    “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.”
    Quote in the paperSubstantial claim

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

    Interpretationreasoning

    High levels of sAPPα may contribute to macrocephaly observed in both FXS and autism through its associated neurotrophic activity.

    “Specifically, we postulate that high levels of sAPP␣ may contribute to macrocephaly, observed in both FXS and autism, through its associated neurotrophic activity.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Plasma sAPPα levels reflect brain sAPPα levels or activity relevant to brain overgrowth in autism and FXS.

  • May combine two claims.

    Premisecitation

    Activation of mGluR5 releases FMRP-mediated translation repression and results in protein synthesis-dependent LTD.

    “Activation of metabotropic glutamate receptor 5 (mGluR5) releases FMRP-mediated translation repression and results in protein synthesis-dependent LTD.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [5]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

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

    Interpretationreasoning

    The activity of sAPPα may be partially mediated by interactions with adhesion modulators, such as β-catenin, thereby altering adhesion and migration of cortical neurons and promoting overgrowth.

    “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.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Cell adhesion suppresses brain growth, while abnormalities in adhesion promote growth or contribute to aberrant growth.

  • May combine two claims.

    Premisecitation

    FMRP inhibits APP translation under basal conditions, but when mGluR5 receptors are activated, this inhibitory effect is released.

    “Specifically, FMRP inhibits APP translation under basal conditions, but when mGluR5 receptors are activated, this inhibitory effect is released.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [5]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

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

    Premisecitation

    APP is the parental molecule of neurotoxic Aβ, produced by amyloidogenic processing of APP and secreted in excess in AD.

    “APP is the parental molecule of neurotoxic amyloid-␤ peptide (A␤), produced by amyloidogenic processing of APP and secreted in excess in AD. e1”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites e1

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation

    Fmr1-knockout mice show reduced LTP in cortex and amygdala and exaggerated mGluR-dependent LTD in hippocampus and cerebellum.

    “Fmr1-knockout mice show reduced LTP in cortex and amygdala e28-e30 and exaggerated mGluRdependent LTD in hippocampus and cerebellum.e31-e34”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites e28-e30

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites e31-e34

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation

    mGluR5 activation releases FMRP repression of APP mRNA translation and stimulates sAPP secretion.

    “Specifically, mGluR5 activation releases FMRP repression of APP mRNA translation and stimulates sAPP secretion.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [5]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation

    Some known functions of APP include promotion of proliferation, cell-cell adhesion and migration, and synaptogenesis.

    “Some of the known functions of APP in these processes include promotion of proliferation, cell-cell adhesion and migration, 10 and synaptogenesis.33”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [10]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [33]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Interpretationreasoning

    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.

    “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.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    FMRP deficiency can result in CNS neural overgrowth and lead to symptoms of fragile X syndrome or autism.

    “This could result in CNS neural overgrowth and leads to the symptoms of fragile X syndrome (FXS) or autism.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: APP has been implicated in neurogenesis, which may set the stage for later prenatal to early postnatal overproliferation of neurons.

  • May combine two claims.

    Interpretationreasoning

    When FMRP is eliminated or diminished, translation of APP mRNA is disinhibited, resulting in elevated basal levels of APP protein and elimination of activity-dependent dynamic APP production.

    “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.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    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.

    “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.”
    Quote in the paperSubstantial claim
24 of 24

  • 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.”
8 of 8

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.

  • Opposite predictions for mGluR antagonists and APP translation in FXS

    Major

    The abstract predicts that mGluR antagonists may repress APP translation in FXS, whereas the figure 3 description says blocking mGluR5 is not likely to alter APP translation when addressing FMRP deficiency.

1 of 1

Cites

Flagged first, then by citations

Research works printed but not linked: 1

  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.

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Related

Authors
Sokol, D. K., Maloney, B., Long, J. M., Ray, B., & Lahiri, D. K.
Affiliations
Indiana University Indianapolis (US)
ORCID
Venue
Neurology
Publisher
Ovid Technologies (Wolters Kluwer Health)
Published
2011-04-12
Volume
76
Issue
15
Pages
1344-1352
ISSN
  • 0028-3878 (ISSN-L)
  • 1526-632X
DOI
10.1212/wnl.0b013e3182166dc7
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
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
  • Health Sciences › Medicine › Physiology › 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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