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Cited by 191Alzheimer's disease research and treatmentsNeuroinflammation and Neurodegeneration MechanismsDementia and Cognitive Impairment Research

Apolipoprotein E metabolism and functions in brain and its role in Alzheimer's disease

Open access
Liao, Fan, Yoon, Hyejin, Kim, Jungsu·2017·Current Opinion in Lipidology
DOI 10.1097/mol.0000000000000383PMC PMC5213812
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Abstract

Purpose of review: APOE4 genotype is the strongest genetic risk factor for Alzheimer's disease. Prevailing evidence suggests that amyloid β plays a critical role in Alzheimer's disease. The objective of this article is to review the recent findings about the metabolism of apolipoprotein E (ApoE) and amyloid β and other possible mechanisms by which ApoE contributes to the pathogenesis of Alzheimer's disease. Recent findings: ApoE isoforms have differential effects on amyloid β metabolism. Recent studies demonstrated that ApoE-interacting proteins, such as ATP-binding cassette A1 (ABCA1) and LDL receptor, may be promising therapeutic targets for Alzheimer's disease treatment. Activation of liver X receptor and retinoid X receptor pathway induces ABCA1 and other genes, leading to amyloid β clearance. Inhibition of the negative regulators of ABCA1, such as microRNA-33, also induces ABCA1 and decreases the levels of ApoE and amyloid β. In addition, genetic inactivation of an E3 ubiquitin ligase, myosin regulatory light chain interacting protein, increases LDL receptor levels and inhibits amyloid accumulation. Although amyloid β-dependent pathways have been extensively investigated, there have been several recent studies linking ApoE with vascular function, neuroinflammation, metabolism, synaptic plasticity, and transcriptional regulation. For example, ApoE was identified as a ligand for a microglial receptor, TREM2, and studies suggested that ApoE may affect the TREM2-mediated microglial phagocytosis. Summary: Emerging data suggest that ApoE affects several amyloid β-independent pathways. These underexplored pathways may provide new insights into Alzheimer's disease pathogenesis. However, it will be important to determine to what extent each mechanism contributes to the pathogenesis of Alzheimer's disease.

AI snapshot

Written from the paper’s full text.

TL;DR

This review summarizes how apolipoprotein E (ApoE) metabolism and ApoE-interacting proteins influence Alzheimer’s disease through amyloid β-dependent and emerging amyloid β-independent pathways. It highlights ABCA1, LDLR/LRP1, TREM2, and ApoE effects on vascular function, neuroinflammation, metabolism, synaptic plasticity, and transcription.

Key findings

  • APOE4 is the strongest genetic risk factor for Alzheimer’s disease, with ε4 risk-increasing and ε2 protective; brain amyloid β accumulation follows ApoE4 > ApoE3 > ApoE2.
  • In >92,000 individuals, the ABCA1 loss-of-function variant N1800H occurred at 0.2% frequency and increased Alzheimer’s disease hazard ratio to 4.13, while APOE ε4/4 versus ε3/3 had a hazard ratio of 7.70; CSF from mild cognitive impairment and Alzheimer’s disease patients showed 30% less ABCA1-mediated cholesterol efflux than cognitively normal participants.
  • Rare TREM2 missense variants are associated with approximately two-fold to four-fold increased Alzheimer’s disease risk; ApoE binds TREM2 and facilitates TREM2-mediated microglial phagocytosis, and TREM2 disease variants reduce ApoE–TREM2 affinity, though TREM2 binding affinity does not differ among ApoE isoforms.
  • ApoE also affects amyloid β-independent pathways: ApoE4 binds promoter regions of ∼1700 genes in human glioblastoma cells, ApoE4 led to lower TREM2 expression than ApoE3 in primary microglia, and ApoE2 enhanced synaptosome–astrocyte binding and astrocyte phagocytic capacity in ApoE knock-in mice.

Methods

  • Narrative review article synthesizing recent findings on ApoE metabolism and Alzheimer’s disease, focusing on ABCA1, ApoE receptors, ApoE proteases, and ApoE roles in cerebral vascular function, neuroinflammation, lipid/glucose metabolism, synaptic plasticity, and transcriptional regulation.
  • Evidence is drawn from cited human studies, APP/ApoE mouse models, ApoE knock-in mice, and cell-based or in vitro experiments; no primary data collection or systematic quantitative analysis is described.

Limitations

  • The paper states that it will be important to determine to what extent each mechanism contributes to Alzheimer’s disease pathogenesis; the exact in vivo ApoE protease remains elusive, and most previous studies used recombinant ApoE with no or little lipidation under in vitro conditions, so further physiological investigations are warranted.
  • The paper notes that the physical TREM2–ApoE interaction may not explain differential ApoE isoform effects, that it is unknown whether ApoE actively transports amyloid β from parenchyma to blood vessels or cotranslocates to preformed aggregates, and that whether ApoE4 disrupts blood-brain barrier integrity independent of amyloid β is still debated.
  • Evident from the text: as a narrative review, it lacks a systematic search strategy, explicit inclusion criteria, and quantitative synthesis, so conclusions depend on selected cited studies.

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

Integrity signals

Registry

Crossref · 10.1097/mol.0000000000000383

Cites

54 of 55 references verified0 citation errors · 1 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

52 of 85 cited sources checked · 35 supported · 0 flagged · accuracy not yet measured

  • Premisecitation

    ABCA1 indirectly facilitates amyloid β clearance through ApoE lipidation in brain.

    “In addition to its role in lipid transport, ABCA1 also indirectly facilitates amyloid β clearance through ApoE lipidation in brain [6].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [6] Koldamova R Fitz NF Lefterov I ATP-binding cassette transporter A1: from metabolism to neurodegeneration. Neurobiol Dis 2014; 72: 13– 21. 24844148 PMC4302328 source

      The Introduction says ABCA1 affects apoE lipidation and that apoE is implicated in Aβ clearance. In “ABCA1 and AD model mice,” the authors propose that ABCA1-generated apoE-containing particles facilitate clearance in the brain, but present that specific mechanism as a hypothesis rather than an established fact. Page numbers are unavailable in our copy. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
  • Premisecitation

    There is no or very low correlation between plasma and CSF ApoE levels.

    “there is no or very low correlation between plasma and CSF ApoE levels [10,11].”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [10] Martinez-Morillo E Hansson O Atagi Y Total apolipoprotein E levels and specific isoform composition in cerebrospinal fluid and plasma from Alzheimer's disease patients and controls. Acta Neuropathol 2014; 127: 633– 643. 24633805 source
    • cites [11] Wildsmith KR Basak JM Patterson BW In vivo human apolipoprotein E isoform fractional turnover rates in the CNS. PLoS One 2012; 7: e38013. 22675504 PMC3366983 source
  • Premisecitation

    Peripheral ApoE cannot penetrate the blood-brain barrier.

    “Because peripheral ApoE cannot penetrate the blood-brain barrier (BBB) [9]”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [9] Yoon H Flores LF Kim J MicroRNAs in brain cholesterol metabolism and their implications for Alzheimer's disease. Biochim Biophys Acta 2016; 1861: 2139– 2147. 27155217 PMC5097035 source
  • Interpretationcitation

    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].”
    Quote in the paperNot a substantial claim3 of 3 sources checked
    • cites [23] Tai LM Thomas R Marottoli FM The role of APOE in cerebrovascular dysfunction. Acta Neuropathol 2016; 131: 709– 723. 26884068 PMC4837016 source
    • cites [35] Tai LM Ghura S Koster KP APOE-modulated Abeta-induced neuroinflammation in Alzheimer's disease: current landscape, novel data, and future perspective. J Neurochem 2015; 133: 465– 488. 25689586 PMC4400246 source

      The section “APOE modulation of Aβ-independent neuroinflammation” describes apoE effects on neuroinflammation and blood–brain barrier function without Aβ. The Introduction also lists metabolism and neuronal plasticity as functions modulated by neuroinflammation, but does not establish that apoE directly affects those functions or transcription through Aβ-independent mechanisms. The source supports the claim’s general possibility, not every pathway in the citing sentence. (LLM, conf=0.82)

      Experimental — accuracy not yet measured
    • cites [50] Kim J Yoon H Basak JM Kim J Apolipoprotein E in synaptic plasticity and Alzheimer's disease: potential cellular and molecular mechanisms. Mol Cells 2014; 37: 767– 776. 25358504 PMC4255096 source
  • Premisecitation

    There is an isoform-specific difference in amyloid β clearance and accumulation.

    “multiple lines of human and animal data clearly demonstrate that there is an isoform-specific difference in amyloid β clearance and accumulation [4,5].”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [4] Kim J Basak JM Holtzman DM The role of apolipoprotein E in Alzheimer's disease. Neuron 2009; 63: 287– 303. 19679070 PMC3044446 source

      The Human studies and In vivo animal data sections report apoE isoform-related differences in Aβ burden and deposition. The Aβ Clearance section reports faster clearance of Aβ bound to apoE2 or apoE3 than to apoE4 in one mouse study, but also cites a mouse study finding no difference and says isoform-specific clearance effects need further study. Thus, the claim that human and animal data clearly demonstrate differences in both clearance and accumulation overstates the clearance evidence. Page numbers were not supplied. (LLM, conf=0.87)

      Experimental — accuracy not yet measured
    • cites [5] Castellano JM Kim J Stewart FR Human apoE isoforms differentially regulate brain amyloid-β peptide clearance. Sci Transl Med 2011; 3: 89ra57. PMC3192364 21715678 source

      The Results report apoE isoform-dependent Aβ clearance in two mouse models, and the Introduction describes isoform-dependent amyloid deposition in humans and mice. But the Discussion says APOE genotype was not assessed in the cited human clearance study and calls for further investigation, so this paper does not establish isoform-specific Aβ clearance in humans. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
  • May combine two claims. 23
  • Classified as probably not a substantial claim. 4

  • May combine two claims.

    Premisecitation

    Deletion of ABCA1 gene increases amyloid β accumulation, whereas its overexpression prevents amyloid β aggregation in amyloid mouse models.

    “Deletion of ABCA1 gene increases amyloid β accumulation, whereas its overexpression prevents amyloid β aggregation in amyloid mouse models [6].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [6] Koldamova R Fitz NF Lefterov I ATP-binding cassette transporter A1: from metabolism to neurodegeneration. Neurobiol Dis 2014; 72: 13– 21. 24844148 PMC4302328 source

      The “ABCA1 and AD model mice” section reports that ABCA1 deficiency increases amyloid plaques and that mice overexpressing ABCA1 in the brain have fewer plaques. It proposes decreased Aβ aggregation as a hypothesis, but does not establish that overexpression prevents aggregation. Page numbers were not provided. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Agonists of nuclear receptors LXR, RXR, and PPAR increased the levels of ABCA1 and decreased amyloid β accumulation in APP mouse models.

    “Agonists of these nuclear receptors increased the levels of ABCA1 and decreased amyloid β accumulation in APP mouse models [6].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [6] Koldamova R Fitz NF Lefterov I ATP-binding cassette transporter A1: from metabolism to neurodegeneration. Neurobiol Dis 2014; 72: 13– 21. 24844148 PMC4302328 source

      The “ABCA1 and Alzheimer’s disease” section reports that LXR and RXR ligands increase Abca1 expression in mice and ameliorate amyloid pathology; “Therapeutic implications” discusses these effects in APP mice. The paper says PPARs regulate ABCA1 transcription, but does not report that PPAR agonists both increased ABCA1 and decreased amyloid accumulation in APP mice. It also notes that follow-up studies did not confirm the reported plaque reduction with the RXR agonist bexarotene. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Pharmacological and genetic inhibition of miR-33 significantly increased ABCA1 level and decreased amyloid β levels in the brain.

    “pharmacological and genetic inhibition of miR-33 significantly increased ABCA1 level and decreased amyloid β levels in the brain [16].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [16] Kim J Yoon H Horie T microRNA-33 regulates ApoE lipidation and amyloid-beta metabolism in the brain. J Neurosci 2015; 35: 14717– 14726. 26538644 PMC4635126 source

  • May combine two claims.

    Premisecitation

    Deletion of an E3 ubiquitin ligase increased LDLR and decreased ApoE and amyloid β in the brain.

    “Deletion of an E3 ubiquitin ligase increased LDLR and decreased ApoE and amyloid β in the brain.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [19] Choi J Gao J Kim J The E3 ubiquitin ligase Idol controls brain LDL receptor expression, ApoE clearance, and Abeta amyloidosis. Sci Transl Med 2015; 7: 314ra184. PMC7153735 26582899 source

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

    Premisecitation

    More than 30 proteins are known to bind LRP1.

    “more than 30 proteins are known to bind LRP1 [4].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [4] Kim J Basak JM Holtzman DM The role of apolipoprotein E in Alzheimer's disease. Neuron 2009; 63: 287– 303. 19679070 PMC3044446 source

      The “Lipoprotein receptor-related protein 1 (LRP1)” section identifies several protein ligands of LRP1. It does not state that more than 30 proteins bind LRP1, so the numerical claim is unsupported by our copy. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Higher CSF ApoE levels were associated with higher CSF tau levels and cognitive decline in human.

    “higher CSF ApoE levels were associated with higher CSF tau levels and cognitive decline in human [12].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [12] Toledo JB Da X Weiner MW CSF Apo-E levels associate with cognitive decline and MRI changes. Acta Neuropathol 2014; 127: 621– 632. 24385135 PMC3988233 source

      The Abstract reports that higher CSF Apo-E levels were associated with higher total and phosphorylated CSF tau levels. But the Results section on cognitive decline reports that *low*, not high, CSF Apo-E levels were associated with greater longitudinal cognitive decline. The claim is therefore supported for tau but misleading about the direction of the cognitive association. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    ApoE binds amyloid β and attenuates the uptake of amyloid β by cultured microglia.

    “The same group also reported that ApoE binds amyloid β and attenuates the uptake of amyloid β by cultured microglia [36].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [36] Chakrabarty P Li A Ceballos-Diaz C IL-10 alters immunoproteostasis in APP mice, increasing plaque burden and worsening cognitive behavior. Neuron 2015; 85: 519– 533. 25619653 PMC4320003 source

  • May combine two claims.

    Premisecitation

    In 5XFAD mice expressing one copy of murine ApoE and one copy of ApoE4, ApoE4 colocalized more with CAA while murine ApoE colocalized more with plaques.

    “In 5XFAD mice that express one copy of murine ApoE and one copy of ApoE4, ApoE4 colocalized more with CAA while murine ApoE colocalized more with plaques [34].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [34] Liao F Zhang TJ Jiang H Murine versus human apolipoprotein E4: differential facilitation of and co-localization in cerebral amyloid angiopathy and amyloid plaques in APP transgenic mouse models. Acta Neuropathol Commun 2015; 3: 70. 26556230 PMC4641345 source

      The Results section reports that, in 5XFAD mice with one murine apoE and one apoE4 copy, plaques contained more murine apoE and parenchymal CAA contained more apoE4. The claim omits the parenchymal qualifier: the same section reports more murine apoE than apoE4 in leptomeningeal CAA. (LLM, conf=0.87)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    ApoE affects cerebral vasculature by affecting cerebral blood flow, neuronal-vascular coupling, and BBB integrity.

    “ApoE affects cerebral vasculature by affecting cerebral blood flow, neuronal-vascular coupling, and BBB integrity [23].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [23] Tai LM Thomas R Marottoli FM The role of APOE in cerebrovascular dysfunction. Acta Neuropathol 2016; 131: 709– 723. 26884068 PMC4837016 source

  • May combine two claims.

    Premisecitation

    Some studies have shown that ApoE4 disrupts BBB integrity in non-APP mice, but non-APP ApoE4 knock-in mice do not have any widespread BBB disruption.

    “Although some studies have shown that ApoE4 disrupts BBB integrity in non-APP mice, it was recently reported that non-APP ApoE4 knock-in mice do not have any widespread BBB disruption [27].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [27] Bien-Ly N Boswell CA Jeet S Lack of widespread BBB disruption in Alzheimer's disease models: focus on therapeutic antibodies. Neuron 2015; 88: 289– 297. 26494278 source

  • May combine two claims.

    Premisecitation

    In APP transgenic mouse models, murine ApoE is associated with increased amyloid β plaques while ApoE4 is associated with increased CAA.

    “In APP transgenic mouse models, murine ApoE is associated with increased amyloid β plaques while ApoE4 is associated with increased CAA [32,33].”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [32] Fryer JD Simmons K Parsadanian M Human apolipoprotein E4 alters the amyloid-beta 40:42 ratio and promotes the formation of cerebral amyloid angiopathy in an amyloid precursor protein transgenic model. J Neurosci 2005; 25: 2803– 2810. 15772340 PMC6725147 source
    • cites [33] Oddo S Caccamo A Cheng D LaFerla FM Genetically altering Abeta distribution from the brain to the vasculature ameliorates tau pathology. Brain Pathol 2009; 19: 421– 430. 18657136 PMC4072242 source

  • May combine two claims.

    Premisecitation

    Some amyloid β antibodies triggered amyloid-related imaging abnormalities (ARIAs) in clinical trials and ARIAs tend to be more frequent in APOE4 carriers.

    “Some amyloid β antibodies triggered amyloid-related imaging abnormalities (ARIAs) in clinical trials and ARIAs tend to be more frequent in APOE4 carriers [28].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [28] Sperling R Salloway S Brooks DJ Amyloid-related imaging abnormalities in patients with Alzheimer's disease treated with bapineuzumab: a retrospective analysis. Lancet Neurol 2012; 11: 241– 249. 22305802 PMC4063417 source

  • May combine two claims.

    Premisecitation

    In plasma, ApoE4 associates preferentially with large, triglyceride-rich VLDL particles while ApoE2 and ApoE3 have a preference for small, phospholipid-rich HDL.

    “In the plasma, ApoE4 associates preferentially with large, triglyceride-rich VLDL particles while ApoE2 and ApoE3 have a preference for small, phospholipid-rich HDL [3].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [3] Huang Y Mahley RW Apolipoprotein E: structure and function in lipid metabolism, neurobiology, and Alzheimer's diseases. Neurobiol Dis 2014; 72: 3– 12. 25173806 PMC4253862 source

  • May combine two claims.

    Premisecitation

    In the periphery, ApoE has important implications in atherosclerosis and hyperlipoproteinemia, which also affect cerebral vasculature.

    “In the periphery, ApoE has important implications in atherosclerosis and hyperlipoproteinemia [3,23], which also affect cerebral vasculature.”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [3] Huang Y Mahley RW Apolipoprotein E: structure and function in lipid metabolism, neurobiology, and Alzheimer's diseases. Neurobiol Dis 2014; 72: 3– 12. 25173806 PMC4253862 source

      The Introduction and Receptor and Heparan Sulfate Proteoglycan Binding Activity section describe ApoE’s role in plasma lipoprotein clearance and link ApoE variants to type III hyperlipoproteinemia. The paper does not substantiate the cited clause’s claim about atherosclerosis; its discussion of blood–brain barrier integrity does not link either peripheral condition to effects on cerebral vasculature. No page numbers are available in our copy. (LLM, conf=0.82)

      Experimental — accuracy not yet measured
    • cites [23] Tai LM Thomas R Marottoli FM The role of APOE in cerebrovascular dysfunction. Acta Neuropathol 2016; 131: 709– 723. 26884068 PMC4837016 source

  • May combine two claims.

    Premisecitation

    ApoE modulates neuroinflammation through several pathways, including alteration of cytokine levels in response to various stimulus, microglial migration, or microglia-mediated amyloid β phagocytosis.

    “ApoE modulates neuroinflammation through several pathways, including the alteration of cytokine levels in response to various stimulus, microglial migration, or microglia-mediated amyloid β phagocytosis [35].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [35] Tai LM Ghura S Koster KP APOE-modulated Abeta-induced neuroinflammation in Alzheimer's disease: current landscape, novel data, and future perspective. J Neurochem 2015; 133: 465– 488. 25689586 PMC4400246 source

      The section on Aβ-independent neuroinflammation reports APOE-dependent cytokine responses to LPS and differences in a chemokine that may affect microglial migration. The sections on Aβ-dependent neuroinflammation and neuroinflammatory receptors discuss Aβ phagocytosis, but do not establish that apoE modulates microglia-mediated Aβ phagocytosis. No page numbers are available in our copy. (LLM, conf=0.85)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    The absence of LDLR or ApoE elevated serum cholesterol dramatically while having very subtle effects on fatty acids or lipid metabolism in the brain.

    “The absence of LDLR or ApoE elevated the serum cholesterol dramatically while having very subtle effects on the fatty acids or lipids metabolism in the brain [45].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [45] Lee J Choi J Wong GW Wolfgang MJ Neurometabolic roles of ApoE and Ldl-R in mouse brain. J Bioenerg Biomembr 2016; 48: 13– 21. 26686234 PMC4733629 source

  • May combine two claims.

    Premisecitation

    ApoE can translocate to the nucleus, bind DNA, and function as a transcription factor in human glioblastoma cells.

    “Recently, it was shown that ApoE can translocate to nucleus, bind DNA, and function as a transcription factor in human glioblastoma cells [53].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [53] Theendakara V Peters-Libeu CA Spilman P Direct transcriptional effects of apolipoprotein E. J Neurosci 2016; 36: 685– 700. 26791201 PMC4719010 source

  • May combine two claims.

    Premisecitation

    ApoE4 enhanced amyloid β-induced impairment of insulin signaling and accelerated hippocampal-dependent cognitive deficits compared with ApoE3 in an APP mouse model expressing human ApoE isoforms.

    “ApoE4 enhanced the amyloid β-induced impairment of insulin signaling and accelerated the hippocampal-dependent cognitive deficits, as compared with ApoE3 [49].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [49] Chan ES Shetty MS Sajikumar S ApoE4 expression accelerates hippocampus-dependent cognitive deficits by enhancing Abeta impairment of insulin signaling in an Alzheimer's disease mouse model. Sci Rep 2016; 6: 26119. 27189808 PMC4870502 source
    • Rests on an assumption: Type 2 diabetes is associated with Alzheimer's disease.

  • May combine two claims.

    Premisecitation

    Anti-amyloid β antibody treatment dramatically decreased amyloid β accumulation and slowed cognitive decline in a clinical trial.

    “Although it is still a preliminary finding, anti-amyloid β antibody treatment dramatically decreased amyloid β accumulation and slowed cognitive decline in a clinical trial [2].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [2] Sevigny J Chiao P Bussière T The antibody aducanumab reduces Aβ plaques in Alzheimer's disease. Nature 2016; 537: 50– 56. 27582220 source

  • May combine two claims.

    Premisecitation

    Overexpression of LRP minireceptor increased toxic amyloid β levels and caused deficits in learning and memory, whereas LDLR overexpression decreased amyloid β accumulation.

    “Overexpression of LRP minireceptor increased toxic amyloid β levels and caused the deficits in learning and memory, whereas LDLR overexpression decreased amyloid β accumulation [18].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [18] Han SH Park JC Mook-Jung I Amyloid beta-interacting partners in Alzheimer's disease: from accomplices to possible therapeutic targets. Prog Neurobiol 2016; 137: 17– 38. 26721621 source

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

    Premisecitation

    An increase in the production of CSF may be yet another mechanism that mediates the beneficial effects of nuclear receptors.

    “An increase in the production of CSF may be yet another mechanism that mediates the beneficial effects of nuclear receptors [15].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [15] Dai YB Wu WF Huang B Liver X receptors regulate cerebrospinal fluid production. Mol Psychiatry 2016; 21: 844– 856. 26324101 source

  • May combine two claims.

    Premisecitation

    The N1800H variant was observed at 0.2% frequency and significantly increased the hazard ratio to 4.13.

    “The N1800H variant was observed at 0.2% frequency and significantly increased the hazard ratio to 4.13.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [8]

      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).

    Premisenone given

    ApoE4 may inhibit HtrA1-mediated tau degradation in vitro.

    “Preliminary data suggest that ApoE4 may inhibit HtrA1-mediated tau degradation in vitro.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    TREM2 disease variants reduced the affinity between ApoE and TREM2, which led to an impairment of phagocytosis.

    “The TREM2 disease variants reduced the affinity between ApoE and TREM2, which led to an impairment of phagocytosis.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [40▪▪–42▪▪]

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

  • May combine two claims.

    Premisecitation

    In several studies using APP mice, TREM2 deficiency consistently decreased the number of plaque-associated microglia and inflammatory cytokines.

    “In several studies using APP mice, TREM2 deficiency consistently decreased the number of plaque-associated microglia and inflammatory cytokines.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [37] Ulrich JD Holtzman DM TREM2 function in Alzheimer's disease and neurodegeneration. ACS Chem Neurosci 2016; 7: 420– 427. 26854967 source

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    Lower affinity between ApoE and TREM2 disease variants may decrease the uptake of amyloid β-ApoE complex.

    “It was proposed that the lower affinity between ApoE and TREM2 disease variants may decrease the uptake of amyloid β-ApoE complex [40▪▪–42▪▪].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [40▪▪–42▪▪]

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

  • May combine two claims.

    Premisenone given

    TREM2 is a novel risk factor for Alzheimer's disease and directly interacts with ApoE.

    “The most exciting finding comes from the discovery of TREM2 as a novel risk factor for Alzheimer's disease and its direct interaction with ApoE.”
    Quote in the paperNot a substantial claim
27 of 27

  • The paper relies on this without support.

    APOE4 genotype is the strongest genetic risk factor for Alzheimer's disease.

    “APOE4 genotype is the strongest genetic risk factor for Alzheimer's disease.”

  • The paper relies on this without support.

    In the brain, apoE is produced predominantly by astrocytes and to some extent microglia.

    “In the brain, apoE is produced predominantly by astrocytes and to some extent microglia.”

  • The paper relies on this without support.

    ApoE2 has only 1–2% of binding affinity to LDL receptor (LDLR), compared with ApoE3 and ApoE4.

    “For example, ApoE2 has only 1–2% of binding affinity to LDL receptor (LDLR), compared with ApoE3 and ApoE4.”

  • The paper relies on this without support.

    Neuroinflammation contributes to Alzheimer's disease pathogenesis.

    “Neuroinflammation is believed to contribute to Alzheimer's disease pathogenesis, although the exact mechanism is complex and not fully understood.”

  • The paper relies on this without support.

    Rare missense variants in TREM2 are associated with an approximately two-fold to four-fold increase in risk of Alzheimer's disease.

    “Rare missense variants in TREM2 are associated with an approximately two-fold to four-fold increase in risk of Alzheimer's disease.”

  • The paper relies on this without support.

    In brain, the only lipoprotein particle is HDL-like in size.

    “In brain, the only lipoprotein particle is HDL-like in size.”

  • The paper relies on this without support.

    Type 2 diabetes is associated with Alzheimer's disease.

    “Type 2 diabetes is associated with Alzheimer's disease, although it is still not clear whether it is a cause or consequence of Alzheimer's disease.”
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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?

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.

  • ABCA1 variant is identified with conflicting amino acids

    Minor

    "Asp1800His" identifies the original amino acid as aspartate, whereas "N1800H" and the subsequent description identify it as asparagine. The paper gives two different identities for the amino acid replaced by histidine.

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Authors
Liao, F., Yoon, H., & Kim, J.
Affiliations
  • Washington University in St. Louis (US)
  • Mayo Clinic (US)
Corresponding author
Kim, Jungsu
ORCID
Venue
Current Opinion in Lipidology
Publisher
Ovid Technologies (Wolters Kluwer Health)
Published
2017-02
Volume
28
Issue
1
Pages
60-67
ISSN
  • 0957-9672 (ISSN-L)
  • 1473-6535
DOI
10.1097/mol.0000000000000383
PMC
PMC5213812
OpenAlex
W2559764604
Semantic Scholar
3d7b3b7fc89401daec1c6db2515f4640011229e7
Cited by
191
References
54
Citations by year
2026: 14 · 2025: 24 · 2024: 24 · 2023: 22 · 2022: 23 · 2021: 22 · 2020: 26 · 2019: 25 · 2018: 7 · 2017: 4
FWCI
8.21
Type
journal article
Language
en
Open access
Licence
Locations
  • Current Opinion in Lipidology (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (submittedVersion, cc-by-nc-nd)
  • PubMed Central (submittedVersion, cc-by-nc-nd)
Funders
National Institute on Aging (R01AG054102, R01 AG053500, R01AG053242, R21 AG050804)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Keywords
apolipoprotein E, APOE ε4, Alzheimer's disease, amyloid-beta metabolism, ABCA1, LDL receptor, liver X receptor, retinoid X receptor, microRNA-33, TREM2, microglial phagocytosis, neuroinflammation, synaptic plasticity, vascular function, transcriptional regulation
MeSH terms
Alzheimer Disease, Animals, Apolipoproteins E, Brain, Gene Expression Regulation, Humans, Neuronal Plasticity, Transcription, Genetic

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-17.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-17.

Cited sources are checked by gpt-6-sol.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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