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Cited by 141Alzheimer's disease research and treatmentsNeuroscience and Neuropharmacology ResearchNeuroinflammation and Neurodegeneration Mechanisms

Apolipoprotein E in Synaptic Plasticity and Alzheimer’s Disease: Potential Cellular and Molecular Mechanisms

Open access
Kim, Jaekwang, Yoon, Hyejin, Basak, Jacob, Kim, Jungsu·2014·Molecules and Cells
DOI 10.14348/molcells.2014.0248PMC PMC4255096
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Abstract

Alzheimer's disease (AD) is clinically characterized with progressive memory loss and cognitive decline. Synaptic dysfunction is an early pathological feature that occurs prior to neurodegeneration and memory dysfunction. Mounting evidence suggests that aggregation of amyloid-β (Aβ) and hyperphosphorylated tau leads to synaptic deficits and neurodegeneration, thereby to memory loss. Among the established genetic risk factors for AD, the ɛ4 allele of apolipoprotein E (APOE) is the strongest genetic risk factor. We and others previously demonstrated that apoE regulates Aβ aggregation and clearance in an isoform-dependent manner. While the effect of apoE on Aβ may explain how apoE isoforms differentially affect AD pathogenesis, there are also other underexplored pathogenic mechanisms. They include differential effects of apoE on cerebral energy metabolism, neuroinflammation, neurovascular function, neurogenesis, and synaptic plasticity. ApoE is a major carrier of cholesterols that are required for neuronal activity and injury repair in the brain. Although there are a few conflicting findings and the underlying mechanism is still unclear, several lines of studies demonstrated that apoE4 leads to synaptic deficits and impairment in long-term potentiation, memory and cognition. In this review, we summarize current understanding of apoE function in the brain, with a particular emphasis on its role in synaptic plasticity and the underlying cellular and molecular mechanisms, involving low-density lipoprotein receptor-related protein 1 (LRP1), syndecan, and LRP8/ApoER2.

AI snapshot

Written from the paper’s full text.

TL;DR

This review summarizes how apolipoprotein E (APOE) isoforms, especially apoE4, influence synaptic plasticity and Alzheimer’s disease (AD) risk, with emphasis on potential cellular and molecular mechanisms. It concludes that apoE4 is generally associated with detrimental synaptic effects relative to other isoforms, but the mechanisms and several findings remain unresolved.

Key findings

  • APOE ε4 is the strongest genetic risk factor for late-onset AD; apoE4 is found in 65–80% of sporadic and familial AD cases and increases AD occurrence by ∼12-fold in two ε4 allele carriers compared with those with no ε4 allele. The rare apoE2 allele has a protective effect against late-onset AD.
  • ApoE isoforms affect synaptic plasticity in an isoform-dependent manner: apoE3 promotes neurite outgrowth in primary embryonic and adult cortical neurons and neuronal cell lines, whereas apoE4 effects are inconsistent across studies (detrimental, no effect, or stimulating). In mouse models, apoE4 knock-in mice showed reduced excitatory synaptic transmission and dendritic arborization without noticeable neuropathological changes; LTP was reduced in apoE4 knock-in mice compared with apoE3 mice, although another study found young apoE4 mice had enhanced LTP. ApoE2 knock-in mice had LTP significantly less than apoE3 mice and comparable with apoE4 mice.
  • Potential mechanisms include LRP1-mediated neurite outgrowth, syndecan family heparan sulfate proteoglycans, and LRP8/ApoER2–reelin signaling that stabilizes actin via n-cofilin inactivation. ApoE3 binds avidly to tau, whereas apoE4 does not interact strongly with tau; apoE2 caused the strongest decrease in GSK3β and tau phosphorylation, and apoE4 the least.
  • A human subject with no detectable apoE due to an APOE frameshift mutation had familial dysbetalipoproteinemia but no severe cognitive or neurological abnormality, and normal CSF Aβ42, total tau, and phospho-tau levels, suggesting that reducing apoE levels may not cause adverse cognitive effects, though this does not directly address AD pathogenesis.

Methods

  • Narrative review synthesizing published in vitro, transgenic/knock-in mouse, and human case literature; no new experimental data are presented.
  • Main analysis is a qualitative synthesis of apoE isoform-dependent effects on Aβ aggregation/clearance, synaptic plasticity, cognition, and candidate receptor/cytoskeletal pathways.

Limitations

  • The paper states that the underlying mechanism for increased AD risk by apoE4 is still unclear, that there are conflicting findings in isoform-dependent roles of apoE in synaptic plasticity, and that whether mouse model findings are directly relevant to human AD remains unknown.
  • The paper notes that the human apoE-null case addresses normal physiological function of apoE, not direct AD pathogenesis, and that follow-up during aging and CSF lipoprotein profiles are needed.
  • Evident from the text: as a narrative review, it does not systematically search or quantify the evidence, and several mechanistic links are speculative and lack in vivo confirmation.

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

Integrity signals

Registry

Crossref · 10.14348/molcells.2014.0248

Cites

97 of 97 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

39 of 92 cited sources checked · 29 supported · 0 flagged · accuracy not yet measured

  • Premisecitation

    ApoE is a major carrier of cholesterols that are required for neuronal activity and injury repair in the brain.

    “ApoE is a major carrier of cholesterols that are required for neuronal activity and injury repair in the brain.”
    • Also stated in: § GENERAL FUNCTION AND STRUCTURE OF APOE · plain
      “ApoE transports cholesterol and other lipids in the plasma and brain through cell surface apoE binding receptors (Lane-Donovan et al., 2014).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites Lane-Donovan et al., 2014 source

      In “The Lipoprotein Receptors and Cholesterol Metabolism” (page unavailable), the paper says astrocytes release ApoE-containing particles that transport cholesterol to neurons and that glia-derived cholesterol is essential for mature synapses. This supports cholesterol transport and its importance to neuronal function, but our copy does not state that the transported cholesterol is required for injury repair. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
  • Premisecitation

    Aβ species, including the most abundant Aβ40 and more toxic Aβ42, are produced by two sequential proteolytic cleavages of amyloid precursor protein (APP) by β- and γ-secretases.

    “Aβ species, including the most abundant Aβ40 and more toxic Aβ42, are produced by two sequential proteolytic cleavages of amyloid precursor protein (APP) by β- and γ-secretases (Kim et al., 2007; McGowan et al., 2005).”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites Kim et al., 2007 source

      The Introduction (page not provided) states that sequential β- and γ-secretase processing of APP produces Aβ1-40 as a major species and Aβ1-42 as a minor species. It also reports that Aβ42 aggregates more rapidly and has a greater role in amyloid deposition, but it does not establish the claim that Aβ42 is more toxic. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • cites McGowan et al., 2005 source
  • Premisecitation

    An Aβ 12-28 synthetic peptide, which contains the apoE-binding site, reduced cerebral Aβ accumulation in animal models of Aβ amyloidosis.

    “an Aβ 12–28 synthetic peptide, which contains the apoE-binding site, reduced cerebral Aβ accumulation in animal models of Aβ amyloidosis (Kuszczyk et al., 2013; Pankiewicz et al., 2014; Sadowski et al., 2004; 2006).”
    Quote in the paperSubstantial claim2 of 3 sources checked
    • cites Kuszczyk et al., 2013 source
    • cites Pankiewicz et al., 2014 source
    • cites Sadowski et al., 2004; 2006

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

  • Premisecitation

    Most studies have demonstrated that apoE3 isoform promotes neurite outgrowth in primary embryonic and adult cortical neurons, as well as neuronal cell lines.

    “Most studies have demonstrated that apoE3 isoform promotes neurite outgrowth in primary embryonic and adult cortical neurons, as well as neuronal cell lines (Nathan et al., 1994; 2002; Sun et al., 1998).”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites Nathan et al., 1994; 2002

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

    • cites Sun et al., 1998 source

      The Results report greater neurite outgrowth in embryonic day 19 primary hippocampal neurons exposed to apoE3-expressing astrocytes, and summarize previous findings in neuronal cell lines. The paper does not establish the claimed effect in primary embryonic or adult cortical neurons; its own primary-neuron experiments used embryonic hippocampal neurons. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
  • Premisecitation

    Lipid transports may be critical to maintaining neuronal activity.

    “Therefore, lipid transports may be critical to maintaining neuronal activity (Dietschy and Turley, 2004).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Dietschy and Turley, 2004 source
    • Rests on an assumption: Mature neurons do not produce sufficient cholesterol for membrane synthesis and repair.
  • Classified as probably not a substantial claim. 8
  • May combine two claims. 25

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

    Premisecitation

    Two neuropathological hallmarks of AD are extracellular Aβ aggregation and intraneuronal neurofibrillary tangles, mainly composed of hyperphosphorylated tau.

    “Two neuropathological hallmarks of AD are extracellular Aβ aggregation and intraneuronal neurofibrillary tangles, mainly composed of hyperphosphorylated tau (Golde et al., 2010).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Golde et al., 2010 source

      The Introduction identifies plaques and neurofibrillary tangles as the two hallmark lesions of AD and Aβ and tau as their principal components, respectively. “Targeting Tau. Have we identified tractable therapeutic targets?” describes hyperphosphorylated tau within tangles as an intracellular hallmark. Our copy does not explicitly locate Aβ aggregation extracellularly, so that qualifier is not verified. (LLM, conf=0.82)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Neuronal injuries are known to induce apoE expression and such increase in apoE level may help to repair the nervous system by delivering cholesterols and lipids to neurons.

    “Neuronal injuries are known to induce apoE expression and such increase in apoE level may help to repair the nervous system by delivering cholesterols and lipids to neurons (Mahley and Huang, 2012).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Mahley and Huang, 2012 source

  • May combine two claims.

    Premisecitation

    The differences of one or two amino acids among isoforms significantly alter the apoE's folding structure and change its ability to bind lipid and receptor.

    “The differences of one or two amino acids among isoforms significantly alter the apoE’s folding structure and change its ability to bind lipid and receptor (Mahley and Huang, 2012).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites Mahley and Huang, 2012 source

      The Introduction’s “Structural Differences among the Isoforms” section says single-amino-acid interchanges alter apoE stability and domain interaction, and that the apoE2 substitution causes defective lipoprotein-receptor binding. The copy does not establish that these isoform differences change apoE’s ability to bind lipids; its discussion of lipid capture does not compare isoforms. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Some studies reported that apoE4 had detrimental effects on neurite outgrowth, others found no effects or even stimulating effects.

    “While some studies reported that apoE4 had detrimental effects on neurite outgrowth (Teter et al., 2002), others found no effects (DeMattos et al., 1998) or even stimulating effects (Puttfarcken et al., 1997).”
    Quote in the paperNot a substantial claim1 of 3 sources checked
    • cites Teter et al., 2002 source
    • cites DeMattos et al., 1998 source
    • cites Puttfarcken et al., 1997 source

  • May combine two claims.

    Premisecitation

    ApoE mimetic peptide affected APP trafficking and inhibited Aβ production.

    “apoE mimetic peptide affected APP trafficking and inhibited Aβ production (Minami et al., 2010).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites Minami et al., 2010 source

  • May combine two claims.

    Premisecitation

    Activation of apoE receptor family member, LRP8/ApoER2, inhibits the function of n-cofilin and this subsequently leads to stabilization of actin filaments.

    “one study demonstrated that activation of apoE receptor family member, LRP8/ApoER2, inhibits the function of n-cofilin and this subsequently leads to stabilization of actin filaments (Chai et al., 2009) (Fig. 2).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites Chai et al., 2009 source

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

    Premisecitation

    Dynamic rearrangements of actin are regulated by Rho-like small GTPases, Rho-guanine-nucleotide exchange factors (GEFs) and Rho-GTPase activating proteins (GAPs).

    “Dynamic rearrangements of actin are regulated by Rho-like small GTPases, Rho-guanine-nucleotide exchange factors (GEFs) and Rho-GTPase activating proteins (GAPs) (Cingolani and Goda, 2008; Penzes and Jones, 2008).”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites Cingolani and Goda, 2008 source
    • cites Penzes and Jones, 2008 source

  • May combine two claims.

    Premisecitation

    A patient with no detectable apoE level due to a frameshift mutation in APOE gene had high levels of cholesterol and triglycerides in plasma, leading to familial dysbetalipoproteinemia.

    “The authors identified a patient with no detectable apoE level due to a frameshift mutation in APOE gene. As expected from apoE’s role in lipid transport, this patient had high levels of cholesterol and triglycerides in plasma, leading to familial dysbetalipoproteinemia.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites Mak et al., 2014 source

  • May combine two claims.

    Premisecitation

    The levels of Aβ42, total tau, and phospho-tau in the patient's cerebrospinal fluid were normal.

    “In addition, the levels of Aβ42, total tau, and phospho-tau in his cerebrospinal fluid were normal.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites Mak et al., 2014 source

  • May combine two claims.

    Premisecitation

    The patient with no detectable apoE did not have any severe abnormality in his cognition and other neurological function.

    “However, he did not have any severe abnormality in his cognition and other neurological function.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites Mak et al., 2014 source

  • May combine two claims.

    Premisecitation

    A particular fragment of apoE (1-272 amino acids) can translocate to cytosol and interact with cytoskeletal proteins.

    “Limited data suggest that a particular fragment of apoE (1–272 amino acids) can translocate to cytosol and interacts with cytoskeletal proteins (Chang et al., 2005).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Chang et al., 2005 source

  • May combine two claims.

    Premisecitation

    The addition of apoE2 caused a strong decrease in phosphorylation of GSK3β and tau, with apoE4 causing the least decrease.

    “For example, the addition of apoE2 caused the strong decrease in phosphorylation of GSK 3β and tau, apoE4 the least (Hoe et al., 2006).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites Hoe et al., 2006 source

  • May combine two claims.

    Premisenone given

    Aggregation of Aβ and hyperphosphorylated tau leads to synaptic deficits and neurodegeneration, thereby to memory loss.

    “Mounting evidence suggests that aggregation of amyloid-β (Aβ) and hyperphosphorylated tau leads to synaptic deficits and neurodegeneration, thereby to memory loss.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    ApoE4 leads to synaptic deficits and impairment in long-term potentiation, memory and cognition.

    “several lines of studies demonstrated that apoE4 leads to synaptic deficits and impairment in long-term potentiation, memory and cognition.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Dendritic spine loss in the hippocampus of young APP transgenic mice was ameliorated by apoE2 over-expression with a transferrin promoter, although an age-dependent reduction in spine density was not prevented by apoE2 expression.

    “In one study, dendritic spine loss in the hippocampus of young APP transgenic mice was ameliorated by apoE2 over-expression with a transferrin promoter, although an age-dependent reduction in spine density was not prevented by apoE2 expression (Lanz et al., 2003).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Lanz et al., 2003 source

  • May combine two claims.

    Premisecitation

    ApoE4, found in 65-80% of cases of sporadic and familial Alzheimer's disease, increases the occurrence of AD by ∼12 fold in two ɛ4 allele carriers, compared with those with no ɛ4 allele.

    “ApoE4, found in 65–80% of cases of sporadic and familial Alzheimer's disease, increases the occurrence of AD by ∼12 fold in two ɛ4 allele carriers, compared with those with no ɛ4 allele (Farrer et al., 1997).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Farrer et al., 1997 source

  • May combine two claims.

    Premisecitation

    ApoE gene deletion in APP transgenic mice leads to dramatically decreased amyloid plaques without affecting Aβ production.

    “ApoE gene deletion in APP transgenic mice leads to dramatically decreased amyloid plaques without affecting Aβ production (Bales et al., 1997).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Bales et al., 1997 source

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

    Premisecitation

    There are three major isoforms (apoE2, apoE3, and apoE4) in humans, whereas mice express only one type of apoE protein.

    “There are three major isoforms (apoE2, apoE3, and apoE4) in humans, whereas mice express only one type of apoE protein (Kim et al., 2009a).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Kim et al., 2009a

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

  • May combine two claims.

    Premisecitation

    Both negative effects and minor beneficial effects on neurites and synaptic functions have been associated with apoE4.

    “Both negative effects and minor beneficial effects on neurites and synaptic functions have been associated with apoE4 (Cambon et al., 2000; Masliah et al., 1997; Veinbergs et al., 1999).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Cambon et al., 2000 source
    • cites Masliah et al., 1997 source
    • cites Veinbergs et al., 1999 source

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationreasoning

    Binding of apoE to syndecan may induce conformational changes in syndecan, leading to recruitment of kinases, PDZ-domain proteins or cytoskeletal proteins.

    “Binding of apoE to syndecan may induce conformational changes in syndecan, leading to recruitment of kinases, PDZ-domain proteins or cytoskeletal proteins.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    Currently, there is no strong evidence that directly links apoE with the modulation of actin dynamics.

    “Currently, there is no strong evidence that directly links apoE with the modulation of actin dynamics.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationreasoning

    Other apoE receptors could also mediate apoE isoform-specific effect on neurite outgrowth by its differential biding affinity to each apoE isoform.

    “Other apoE receptors could also mediate apoE isoform-specific effect on neurite outgrowth by its differential biding affinity to each apoE isoform.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    LTP in apoE2 knock-in mice was significantly less than apoE3 mice and comparable with apoE4 mice.

    “Surprisingly, LTP in apoE2 knock-in mice was significantly less than apoE3 mice and comparable with apoE4 mice (Trommer et al., 2004).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Trommer et al., 2004 source

  • May combine two claims.

    Premisecitation

    N-syndecan (syndecan-3) acts as a receptor for heparin-binding growth-associated molecule (HB-GAM) and promotes neurite outgrowth.

    “N-syndecan (syndecan-3) acts as a receptor for heparin-binding growth-associated molecule (HB-GAM) and promotes neurite outgrowth (Kinnunen et al., 1996).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Kinnunen et al., 1996 source

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationreasoning

    Stabilization of the actin cytoskeleton by the reelin-ApoER2 signaling pathway might occur at the dendritic spine as well.

    “Stabilization of the actin cytoskeleton by the reelin-ApoER2 signaling pathway might occur at the dendritic spine as well.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Dendritic spine dysfunction and degeneration are thought to be one of the earliest pathogenic events in AD and correlate well with cognitive deficits in AD patients.

    “Dendritic spine dysfunction and degeneration are thought to be one of the earliest pathogenic events in AD and correlate well with cognitive deficits in AD patients (Selkoe, 2002).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Selkoe, 2002 source

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

    Premisecitation

    Mushroom spines are considered as relatively more stable connections, while thin spines are dynamic and can respond to synaptic activity.

    “Mushroom spines are considered as relatively more stable connections, while thin spines are dynamic and can respond to synaptic activity (Bourne and Harris, 2008).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Bourne and Harris, 2008 source

  • May combine two claims.

    Premisecitation

    ApoE3 binds avidly to tau through the direct interaction between the N-terminal domain of apoE and the microtubule-binding repeat regions of tau, whereas apoE4 does not interact strongly with tau.

    “Interestingly, apoE3 binds avidly to tau through the direct interaction between the N-terminal domain of apoE and the microtubule-binding repeat regions of tau, whereas apoE4 does not interact strongly with tau (Strittmatter et al., 1994).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Strittmatter et al., 1994 source

  • May combine two claims.

    Premisecitation

    Neuronal microtubules are dynamic and can transiently move from the dendritic shaft to dendritic spines.

    “However, emerging data suggests that neuronal microtubules are dynamic and can transiently move from the dendritic shaft to dendritic spines (Gu et al., 2008; Hu et al., 2008).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Gu et al., 2008

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

    • cites Hu et al., 2008

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

  • May combine two claims.

    Interpretationnone given

    ApoE modulates not only Aβ clearance but also other neuropathological changes observed in AD, such as cerebral energy metabolism, neuroinflammation, neurovascular function, neurogenesis, and synaptic plasticity.

    “However, apoE modulates not only Aβ clearance but also other neuropathological changes observed in AD, such as cerebral energy metabolism, neuroinflammation, neurovascular function, neurogenesis, and synaptic plasticity.”
    Quote in the paperNot a substantial claim
30 of 30

  • The authors state this as an assumption.

    Matching apoE protein levels between isoform mice will circumvent any potential artifacts due to the difference in apoE expression levels.

    “It has been generally assumed that matching apoE protein levels between isoform mice will circumvent any potential artifacts due to the difference in apoE expression levels.”

  • The paper relies on this without support.

    Mature neurons do not produce sufficient cholesterol for membrane synthesis and repair.

    “However, mature neurons appear not to produce sufficient cholesterol for membrane synthesis and repair.”

  • The paper relies on this without support.

    Tau is a microtubule-stabilizing protein and a major component of neurofibrillary tangles.

    “Given the fact that tau, the major component of neurofibrillary tangle, is a microtubule stabilizing protein, there have been several studies aimed to investigate the functional link among apoE, tau, and microtubules.”

  • The paper relies on this without support.

    In vivo studies providing more definitive mechanisms behind the apoE isoform-dependent effects on tau are lacking.

    “Although in vitro studies have provided some insights, in vivo studies providing more definitive mechanisms behind the apoE isoform-dependent effects on tau are still lacking.”

  • The paper relies on this without support.

    The underlying mechanism for the increased risk of AD by apoE4 is unclear.

    “Although there have been numerous reports demonstrating differential roles of apoE isoforms in various aspects of AD pathogenesis, the underlying mechanism for the increased risk of AD by apoE4 is unclear yet.”

  • The paper relies on this without support.

    There are significant conflicting findings in isoform-dependent roles of apoE in synaptic plasticity.

    “However, there are a significant amount of conflicting findings in isoform-dependent roles of apoE in synaptic plasticity.”

  • The paper relies on this without support.

    The presence of the APOE ε4 allele does not necessarily cause AD.

    “Although the presence of APOE ɛ4 allele does not necessarily cause AD, apoE may cooperate with Aβ to accelerate AD development and progression in an isoform-dependent manner.”
7 of 7

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?

  • APOE4 genotype is the strongest genetic risk factor for AD.

    “APOE4 genotype is the strongest genetic risk factor for AD”

    From MicroRNAs in brain cholesterol metabolism and their implications for Alzheimer's disease (2016) · cites this paper as [52]

    The ALZHEIMER’S DISEASE section identifies the APOE ε4 allele as the strongest genetic risk factor for late-onset Alzheimer’s disease (LOAD). The citing sentence says AD without that qualification, extending the statement beyond the population specified in the paper’s body text. No page number is available in our copy. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • ApoE may affect Alzheimer's disease pathogenesis through amyloid β-independent pathways.

    “In addition, ApoE may directly affect neuroinflammation, cerebral vascular integrity, metabolism, synaptic plasticity, and transcription through amyloid β-independent mechanisms [23,35,50].”

    From Apolipoprotein E metabolism and functions in brain and its role in Alzheimer's disease (2017) · cites this paper as [50]

  • Previous studies demonstrated that ApoE isoforms differentially affect synaptic function.

    “Previous studies demonstrated that ApoE isoforms differentially affect synaptic function [50].”

    From Apolipoprotein E metabolism and functions in brain and its role in Alzheimer's disease (2017) · cites this paper as [50]

  • ApoE has been implicated as a vital factor for synaptic plasticity, neuronal activity, and injury repair.

    “ApoE, a critical cholesterol transport protein, has been implicated as a vital factor for synaptic plasticity, neuronal activity, and injury repair124142.”

    From Neuronally-directed effects of RXR activation in a mouse model of Alzheimer’s disease (2017) · cites this paper as [41]

Cites

Flagged first, then by citations

3 of the 100 references couldn’t be matched to a known paper.

Cited by

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Related

Authors
Kim, J., Yoon, H., Basak, J., & Kim, J.
Affiliations
Mayo Clinic (US)
ORCID
Venue
Molecules and Cells
Publisher
Elsevier BV
Published
2014-11
Volume
37
Issue
11
Pages
767-776
ISSN
  • 0219-1032 (ISSN-L)
  • 1016-8478
DOI
10.14348/molcells.2014.0248
PMC
PMC4255096
OpenAlex
W2040546047
Semantic Scholar
b4fa5a3aea55b78a43bafaceb46a53a6b0b2042e
Cited by
141
References
100
Citations by year
2026: 8 · 2025: 11 · 2024: 8 · 2023: 6 · 2022: 13 · 2021: 14 · 2020: 11 · 2019: 11 · 2018: 15 · 2017: 19 · 2016: 19 · 2015: 6
FWCI
8.55
Type
journal article
Language
en
Open access
Licence
Locations
  • Molecules and Cells (publishedVersion, cc-by-nc-sa)
  • PubMed (publishedVersion)
  • PubMed Central (submittedVersion, cc-by-nc-sa)
Funders
  • Alzheimer's Association
  • BrightFocus Foundation
  • GHR Foundation
  • National Institutes of Health (AG016574, 5p50ag016574-20)
  • National Institute on Aging (P50‐AG016574, NIH AG016574)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
apolipoprotein E, APOE ε4, Alzheimer's disease, synaptic plasticity, amyloid-beta aggregation, amyloid-beta clearance, tau hyperphosphorylation, synaptic dysfunction, long-term potentiation, memory loss, APOE isoforms, LRP1, syndecans, neuroinflammation, neurovascular function, neurogenesis, brain energy metabolism, cholesterol
MeSH terms
Alzheimer Disease, Animals, Apolipoproteins E, Brain, Humans, Neuronal Plasticity, Synapses, Amyloid beta-Peptides

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