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Cited by 595Neuroinflammation and Neurodegeneration MechanismsAlzheimer's disease research and treatmentsInflammasome and immune disorders

Interplay between innate immunity and Alzheimer disease: APOE and TREM2 in the spotlight

Open access
Shi, Yang, Holtzman, David M.·2018·Nature Reviews Immunology
DOI 10.1038/s41577-018-0051-1PMC PMC6425488
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Abstract

Alzheimer disease is more than a pure proteopathy. Chronic neuroinflammation stands out during the pathogenesis of the disease and in turn modulates disease progression. The central nervous system (CNS) is separated from the blood circulation by the blood-brain barrier. In Alzheimer disease, neuroinflammation heavily relies on innate immune responses that are primarily mediated by CNS-resident microglia. APOE (which encodes apolipoprotein E) is the strongest genetic risk factor for Alzheimer disease, and APOE was recently shown to affect the disease in part through its immunomodulatory function. This function of APOE is likely linked to triggering receptor expressed on myeloid cells 2 (TREM2), which is expressed by microglia in the CNS. Here, we review the rapidly growing literature on the role of disease-associated microglia, TREM2 and APOE in the pathogenesis of Alzheimer disease and present an integrated view of innate immune function in Alzheimer disease.

AI snapshot

Written from the paper’s full text.

TL;DR

This review argues that Alzheimer’s disease is not only a proteopathy but also a disease of innate immune dysfunction, with microglia, TREM2, and ApoE forming a central disease-stage-dependent axis. It proposes that ApoE and TREM2 jointly regulate microglial activation, plaque seeding/compaction, tau pathology, and neurodegeneration.

Key findings

  • More than 30 Alzheimer’s disease-risk loci have been identified; over 50% of gene variants validated by functional genomics are implicated in microglial and innate immune cell function, including the top two risk genes, *APOE* and *TREM2*.
  • Microglial effects are disease-stage dependent: activated microglia may promote amyloid-β plaque seeding early, restrain plaque growth and plaque-associated neuronal damage during plaque deposition, and exacerbate tau pathology and neurodegeneration late. TREM2 deficiency causes a mild reduction of plaque deposition in early-stage disease but enhanced amyloid-β pathology in advanced stages.
  • TREM2 is essential for microglial association with plaques; TREM2 haplodeficiency, ablation, or the TREM2R47H mutation reduces plaque-associated microglia and leads to enlarged, less compact plaques with greater neuritic dystrophy.
  • *APOE* is the strongest genetic risk factor for late-onset Alzheimer’s disease; ε4 carriers show earlier onset, heavier amyloid-β plaque load, greater brain atrophy, and accelerated progression. ApoE deficiency attenuates inflammation and disease severity in tauopathy, synucleinopathy, and EAE models, while ApoE is required for the microglial neurodegenerative phenotype and plaque response, supporting an ApoE–TREM2 axis.

Methods

  • Narrative review synthesizing genetic, functional, and mechanistic literature on innate immunity, microglia, TREM2, and ApoE in Alzheimer’s disease.
  • No primary experimental data are reported; the paper discusses mouse models, human genetic and biomarker evidence, postmortem brain studies, and in vitro work.
  • Main analysis is an integrated conceptual synthesis, including proposed disease-stage model and ApoE–TREM2–microglia axis.

Limitations

  • The paper states that more research is needed to verify microglial promotion of amyloid-β seeding and to exclude artefacts from specific animal models or off-target drug properties.
  • The paper states that TREM2 overexpression gene signatures need verification in isolated microglia and confirmation in a murine TREM2−/− background.
  • Evident from the text: this is a narrative review without systematic search or meta-analysis, and many mechanistic conclusions rely heavily on mouse models, with human evidence more limited.

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

Integrity signals

Registry

Crossref · 10.1038/s41577-018-0051-1

Cites

158 of 158 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 179 cited sources checked · 0 supported · 0 flagged

  • Findingcitation

    Alzheimer's disease GWAS loci are preferentially enriched in enhancer sequences implicated in innate immune processes.

    “epigenomic analysis has shown that Alzheimer’s disease GWAS loci are preferentially enriched in enhancer sequences implicated in innate immune processes7”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [7] Gjoneska, E. et al. Conserved epigenomic signals in mice and humans reveal immune basis of Alzheimer’s disease. Nature 518, 365–369 (2015). source

      Not checked in the free run.

  • Findingcitation

    Of the Alzheimer's disease risk loci, over 50% of gene variants validated by functional genomics are implicated in microglial and innate immune cell function, including the top two risk genes, APOE and TREM2.

    “Of these risk loci, over 50% of gene variants validated by functional genomics are implicated in microglial and innate immune cell function, including the top two risk genes, APOE and TREM2.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [6] Pimenova, A. A., Raj, T. & Goate, A. M. Untangling genetic risk for Alzheimer’s disease. Biol. Psychiatry 83, 300–310 (2017). source

      Not checked in the free run.

  • Findingcitation

    The common disease-associated microglial cell signature, defined as the MGnD or DAM phenotype, is characterized by suppression of microglial homeostatic genes and induction of pro-inflammatory genes as well as genes involved in microglial phagocytotic function targeting degenerated/injured neurons and amyloid plaques.

    “This signature is characterized by a suppression of microglial homeostatic genes, and an induction of pro-inflammatory genes as well as genes involved in microglial phagocytotic function targeting degenerated/injured neurons and amyloid plaques27,28.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [27] Keren-Shaul, H. et al. A Unique microglia type associated with restricting development of Alzheimer’s disease. Cell 169, 1276–1290 (2017). source

      Not checked in the free run.

    • cites [28] Krasemann, S. et al. The TREM2-APOE pathway drives the transcriptional phenotype of dysfunctional microglia in neurodegenerative diseases. Immunity 47, 566–581 (2017). This work and reference 27 raise the concept of a neurodegenerative microglial phenotype. They define the molecular signatures of the phenotype and demonstrate the requirement of TREM2 and APOE for its activation. source

      Not checked in the free run.

  • Findingcitation

    Recent single-cell RNA-seq data identified a two-stage microglial cell activation process during disease progression in an amyloid-β-depositing mouse model, where the transition from the first to the second stage is determined by TREM2.

    “Recent single-cell RNA-seq data identified a two-stage microglial cell activation process that occurs during disease progression in an amyloid-β-depositing mouse model, where the transition from the first to the second stage is determined by TREM227.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [27] Keren-Shaul, H. et al. A Unique microglia type associated with restricting development of Alzheimer’s disease. Cell 169, 1276–1290 (2017). source

      Not checked in the free run.

  • Findingcitation

    End-stage activated microglia display a conserved core-expression profile harbouring certain degrees of diversity across individual disease phenotypes.

    “The end-stage activated microglia appear to display a conserved core-expression profile harbouring certain degrees of diversity across individual disease phenotypes27,28.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [27] Keren-Shaul, H. et al. A Unique microglia type associated with restricting development of Alzheimer’s disease. Cell 169, 1276–1290 (2017). source

      Not checked in the free run.

    • cites [28] Krasemann, S. et al. The TREM2-APOE pathway drives the transcriptional phenotype of dysfunctional microglia in neurodegenerative diseases. Immunity 47, 566–581 (2017). This work and reference 27 raise the concept of a neurodegenerative microglial phenotype. They define the molecular signatures of the phenotype and demonstrate the requirement of TREM2 and APOE for its activation. source

      Not checked in the free run.

  • May combine two claims. 49
  • Classified as probably not a substantial claim. 13

  • May combine two claims.

    Findingcitation

    In the brains of patients with Alzheimer's disease and amyloid-β depositing mice, the NLRP3 inflammasome is activated and ASC specs are present in the core of amyloid plaques.

    “In the brains of patients with Alzheimer’s disease and amyloid-β depositing mice, the NLRP3 inflammasome is activated and ASC specs are found to present in the core of amyloid plaques41”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [41] Venegas, C. et al. Microglia-derived ASC specks cross-seed amyloid-β in Alzheimer’s disease. Nature 552, 355–361 (2017). This work shows that activated microglia promote amyloid-β seeding via secreting adaptor protein ASC specks that cross-seed amyloid-β. This study together with reference 39 suggests that microglia participate in the initiation stage of plaque formation by affecting amyloid-β seeding. source

      Not checked in the free run.

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

    Findingcitation

    Other studies have suggested that inhibition of inflammation attenuates amyloid-β pathology.

    “However, other studies have suggested that inhibition of inflammation attenuates amyloid-β pathology35–37.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [35] Vom Berg, J. et al. Inhibition of IL-12/IL-23 signaling reduces Alzheimer’s disease-like pathology and cognitive decline. Nat. Med. 18, 1812–1819 (2012). source

      Not checked in the free run.

    • cites [36] Kiyota, T. et al. CNS expression of anti-inflammatory cytokine interleukin-4 attenuates Alzheimer’s disease-like pathogenesis in APP+PS1 bigenic mice. FASEB J. 24, 3093–3102 (2010). source

      Not checked in the free run.

    • cites [37] Qiao, X., Cummins, D. J. & Paul, S. M. Neuroinflammation-induced acceleration of amyloid deposition in the APPV717F transgenic mouse. Eur. J. Neurosci. 14, 474–482 (2001). source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    ASC-deficient APPSwePSEN1dE9 mice have significantly reduced cerebral plaque loads, and show little seeding and spreading of amyloid-β pathology when receiving cerebral injection of brain homogenates containing amyloid-β seeds.

    “ASC-deficient APPSwePSEN1dE9 mice [G] have significantly reduced cerebral plaque loads, and show little seeding and spreading of amyloid-β pathology when receiving cerebral injection of brain homogenates containing amyloid-β seeds41.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [41] Venegas, C. et al. Microglia-derived ASC specks cross-seed amyloid-β in Alzheimer’s disease. Nature 552, 355–361 (2017). This work shows that activated microglia promote amyloid-β seeding via secreting adaptor protein ASC specks that cross-seed amyloid-β. This study together with reference 39 suggests that microglia participate in the initiation stage of plaque formation by affecting amyloid-β seeding. source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    Several studies have found that activating pro-inflammatory pathways, for example by overexpressing TNF, IFNγ or IL-6, or by inhibiting anti-inflammatory cytokines such as IL-10, reduces plaque deposition, and vice versa.

    “Several studies have found that activating pro-inflammatory pathways — for example, by overexpressing TNF29, IFNγ30 or IL-631, or by inhibiting anti-inflammatory cytokines such as IL-1032 — reduces plaque deposition, and vice versa33,34.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [29] Chakrabarty, P., Herring, A., Ceballos-Diaz, C., Das, P. & Golde, T. E. Hippocampal expression of murine TNFα results in attenuation of amyloid deposition in vivo. Mol. Neurodegener. 6, 16 (2011). source

      Not checked in the free run.

    • cites [30] Chakrabarty, P. et al. IFN-gamma promotes complement expression and attenuates amyloid plaque deposition in amyloid β precursor protein transgenic mice. J. Immunol. 184, 5333–5343 (2010). source

      Not checked in the free run.

    • cites [31] Chakrabarty, P. et al. Massive gliosis induced by interleukin-6 suppresses Aβ deposition in vivo: evidence against inflammation as a driving force for amyloid deposition. FASEB J. 24, 548–559 (2010). source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    Patients with Alzheimer's disease who carry the TREM2R47H mutation show patterns of plaque morphology and neurite dystrophy that resemble the plaques observed in TREM2-deficient amyloid-β depositing mice, indicating that this mutation causes a loss of function.

    “Patients with Alzheimer’s disease who carry the TREM2R47H mutation show patterns of plaque morphology and neurite dystrophy that resemble the plaques observed in TREM2-deficient amyloid-β depositing mice49, indicating that this mutation causes a loss of function.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [49] Yuan, P. et al. TREM2 haplodeficiency in mice and humans impairs the microglia barrier function leading to decreased amyloid compaction and severe axonal dystrophy. Neuron 90, 724–739 (2016). References 48 and 49 demonstrate a major TREM2-dependent function of plaque-associated microglia to trim and compact plaques and to serve as a barrier to reduce neuritic dystrophy. source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    Overall, TREM2 deficiency leads to a mild reduction of plaque deposition in early-stage disease, but causes enhanced amyloid-β pathology in advanced stages of the disease.

    “Overall, TREM2 deficiency leads to a mild reduction of plaque deposition in early-stage disease, but causes enhanced amyloid-β pathology in advanced stages of the disease45–47.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [45] Jay, T. R. et al. TREM2 deficiency eliminates TREM2+ inflammatory macrophages and ameliorates pathology in Alzheimer’s disease mouse models. J. Exp. Med. 212, 287–295 (2015). source

      Not checked in the free run.

    • cites [46] Wang, Y. et al. TREM2 lipid sensing sustains the microglial response in an Alzheimer’s disease model. Cell 160, 1061–1071 (2015). source

      Not checked in the free run.

    • cites [47] Jay, T. R. et al. Disease progression-dependent effects of TREM2 deficiency in a mouse model of Alzheimer’s disease. J. Neurosci. 37, 637–647 (2017). References 44–47 show that TREM2 promotes microglial clustering around amyloid-β plaques and demonstrate a disease stage-dependent effect of TREM2 deficiency on amyloid-β pathology. source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    Plaque-associated microglia drop in number with TREM2 overexpression and exhibit elongated and ramified processes with a sharp reduction of IBA1 signal, indicating an altered activation status, likely reflecting less activation.

    “Surprisingly, plaque-associated microglia drop in number with TREM2 overexpression and exhibit elongated and ramified processes with a sharp reduction of ionized calcium binding adaptor molecule 1 (IBA1) [G] signal, indicating an altered activation status, likely reflecting less activation52.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [52] Lee, C. Y. D. et al. Elevated TREM2 gene dosage reprograms microglia responsivity and ameliorates pathological phenotypes in Alzheimer’s disease models. Neuron 97, 1032–1048 (2018). source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    Chronic intraperitoneal administration of LPS to 3xTg-AD mice for 6 weeks induces marked microglial activation and promotes site-specific tau hyperphosphorylation.

    “chronic intraperitoneal administration of LPS to 3xTg-AD mice[G] for 6-weeks is shown to induce marked microglial activation and promote site-specific tau hyperphosphorylation59.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [59] Kitazawa, M., Oddo, S., Yamasaki, T. R., Green, K. N. & LaFerla, F. M. Lipopolysaccharide-induced inflammation exacerbates tau pathology by a cyclin-dependent kinase 5-mediated pathway in a transgenic model of Alzheimer’s disease. J. Neurosci. 25, 8843–8853 (2005). source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    TREM2−/− amyloid-β depositing mice consistently show downregulation of inflammatory genes, such as Tnf and Il1b, and also of key genes associated with the MGnD phenotype, such as Clec7a and Itgax.

    “TREM2−/− amyloid-β depositing mice consistently show downregulation of inflammatory genes, such as Tnf and Il1b45–47, and also of key genes associated with the MGnD phenotype, such as c-type lectin domain family 7 member A (Clec7a) and integrin subunit alpha X (Itgax)27,28”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [27] Keren-Shaul, H. et al. A Unique microglia type associated with restricting development of Alzheimer’s disease. Cell 169, 1276–1290 (2017). source

      Not checked in the free run.

    • cites [28] Krasemann, S. et al. The TREM2-APOE pathway drives the transcriptional phenotype of dysfunctional microglia in neurodegenerative diseases. Immunity 47, 566–581 (2017). This work and reference 27 raise the concept of a neurodegenerative microglial phenotype. They define the molecular signatures of the phenotype and demonstrate the requirement of TREM2 and APOE for its activation. source

      Not checked in the free run.

    • cites [45] Jay, T. R. et al. TREM2 deficiency eliminates TREM2+ inflammatory macrophages and ameliorates pathology in Alzheimer’s disease mouse models. J. Exp. Med. 212, 287–295 (2015). source

      Not checked in the free run.

    • cites [46] Wang, Y. et al. TREM2 lipid sensing sustains the microglial response in an Alzheimer’s disease model. Cell 160, 1061–1071 (2015). source

      Not checked in the free run.

    • cites [47] Jay, T. R. et al. Disease progression-dependent effects of TREM2 deficiency in a mouse model of Alzheimer’s disease. J. Neurosci. 37, 637–647 (2017). References 44–47 show that TREM2 promotes microglial clustering around amyloid-β plaques and demonstrate a disease stage-dependent effect of TREM2 deficiency on amyloid-β pathology. source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    Lack of TREM2 results in impaired plaque trimming, which leads to enlarged plaques with reduced compaction.

    “Lack of TREM2 results in impaired plaque trimming, which leads to enlarged plaques with reduced compaction48,49.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [48] Wang, Y. et al. TREM2-mediated early microglial response limits diffusion and toxicity of amyloid plaques. J. Exp. Med. 213, 667–675 (2016). source

      Not checked in the free run.

    • cites [49] Yuan, P. et al. TREM2 haplodeficiency in mice and humans impairs the microglia barrier function leading to decreased amyloid compaction and severe axonal dystrophy. Neuron 90, 724–739 (2016). References 48 and 49 demonstrate a major TREM2-dependent function of plaque-associated microglia to trim and compact plaques and to serve as a barrier to reduce neuritic dystrophy. source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    Expressing human TREM2 under the endogenous human regulatory elements on top of murine TREM2 in 5XFAD mice leads to reduced fibrillar amyloid-β deposition with denser cores, accompanied by ameliorated neuritic dystrophy.

    “a recent study showed that expressing human TREM2 under the endogenous human regulatory elements on top of murine TREM2 in 5XFAD mice leads to reduced fibrillar amyloid-β deposition with denser cores, accompanied by ameliorated neuritic dystrophy52.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [52] Lee, C. Y. D. et al. Elevated TREM2 gene dosage reprograms microglia responsivity and ameliorates pathological phenotypes in Alzheimer’s disease models. Neuron 97, 1032–1048 (2018). source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    A1 astrocytes demonstrate strong neurotoxicity by secreting toxic factors that can rapidly induce neuronal death, and by losing normal functions to support neuronal survival, growth or functionality and to maintain environmental homeostasis.

    “A1 astrocytes demonstrate strong neurotoxicity by secreting toxic factors that can rapidly induce neuronal death, and by losing normal functions to support neuronal survival, growth or functionality and to maintain environmental homeostasis9.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [9] Liddelow, S. A. et al. Neurotoxic reactive astrocytes are induced by activated microglia. Nature 541, 481–487 (2017). This study defines the roles of A1 astrocytes in neurodegenerative diseases and demonstrates an essential role of microglia–astrocytes crosstalk in A1 astrocytic activation. source

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    Findingcitation

    A1 astrocytes strongly upregulate genes involved in classical complement activation which are shown to be destructive to synapses, therefore are considered harmful; whereas A2 astrocytes upregulate neurotrophic genes that promote neuronal survival and growth, and are deemed protective.

    “A1 astrocytes strongly upregulate genes involved in classical complement activation which are shown to be destructive to synapses, therefore are considered harmful; whereas A2 astrocytes upregulate neurotrophic genes that promote neuronal survival and growth, and are deemed protective77.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [77] Zamanian, J. L. et al. Genomic analysis of reactive astrogliosis. J. Neurosci. 32, 6391–6410 (2012). source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    TREM2 deficiency enhances tau hyperphosphorylation at an early disease stage in htau mice and a mid-disease stage in P301S mice, but does not affect tau pathology at a late-disease stage in P301S mice.

    “TREM2 deficiency is reported to enhance tau hyperphosphorylation at an early disease stage in htau mice65 and a mid-disease stage in P301S mice [G]66, but does not affect tau pathology at a late-disease stage in P301S mice67”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [65] Bemiller, S. M. et al. TREM2 deficiency exacerbates tau pathology through dysregulated kinase signaling in a mouse model of tauopathy. Mol. Neurodegener. 12, 74 (2017). source

      Not checked in the free run.

    • cites [66] Jiang, T. et al. Silencing of TREM2 exacerbates tau pathology, neurodegenerative changes, and spatial learning deficits in P301S tau transgenic mice. Neurobiol. Aging 36, 3176–3186 (2015). source

      Not checked in the free run.

    • cites [67] Leyns, C. E. G. et al. TREM2 deficiency attenuates neuroinflammation and protects against neurodegeneration in a mouse model of tauopathy. Proc. Natl Acad. Sci. USA 114, 11524–11529 (2017). This work shows that dampening neurodegenerative microglial activation via TREM2 deletion reduces neurodegeneration at an advanced disease stage in a tauopathy mouse model, supporting a role of microglia in modulating neurodegeneration. source

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  • May combine two claims.

    Findingcitation

    ApoE4 significantly exacerbates neurodegeneration whereas ApoE ablation strongly attenuates the damage compared to the presence of ApoE regardless of ApoE isoforms.

    “ApoE4 significantly exacerbates neurodegeneration whereas ApoE ablation strongly attenuates the damage compared to the presence of ApoE regardless of ApoE isoforms69.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [69] Shi, Y. et al. ApoE4 markedly exacerbates tau-mediated neurodegeneration in a mouse model of tauopathy. Nature 549, 523–527 (2017). This study demonstrates an amyloid-β-independent role of APOE in regulating neurodegeneration and neuroinflammation in the setting of a tauopathy. The protective effect of APOE deficiency on neurodegeneration is in line with that of TREM2. source

      Not checked in the free run.

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    Premisecitation

    Amyloid-β aggregation is the earliest pathological event in Alzheimer's disease, followed at a later stage by tau aggregation extending beyond the limbic system to the neocortex, which correlates with brain atrophy and cognitive decline.

    “Extensive biomarker and imaging studies indicate that amyloid-β aggregation is the earliest pathological event in Alzheimer’s disease, followed at a later stage by pathological changes of tau aggregation extending beyond the limbic system to the neocortex, which correlates with brain atrophy and cognitive decline2,3.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [2] Jack, C. R. Jr. et al. Hypothetical model of dynamic biomarkers of the Alzheimer’s pathological cascade. Lancet Neurol. 9, 119–128 (2010). source

      Not checked in the free run.

    • cites [3] Bateman, R. J. et al. Clinical and biomarker changes in dominantly inherited Alzheimer’s disease. N. Engl. J. Med. 367, 795–804 (2012). source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    Marked neuroinflammation is observed in the brains of patients with Alzheimer's disease, alongside amyloid-β and tau pathology.

    “marked neuroinflammation is observed in the brains of patients with Alzheimer’s disease, alongside amyloid-β and tau pathology”
    Quote in the paperNot a substantial claim

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

    Premisenone given

    Apolipoprotein E (ApoE) is the strongest genetic risk factor for Alzheimer's disease.

    “Apolipoprotein E (ApoE) is the strongest genetic risk factor for Alzheimer’s disease”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationnone given

    The immunomodulatory function of ApoE is likely linked to TREM2, which is expressed by microglia in the CNS.

    “This function of ApoE is likely linked to triggering receptor expressed on myeloid cells 2 (TREM2), which is expressed by microglia in the CNS.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationnone given

    Chronic neuroinflammation is a prominent feature during Alzheimer's disease pathogenesis and modulates disease progression.

    “Chronic neuroinflammation stands out during the pathogenesis of the disease and in turn modulates disease progression.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    The core expression profile of end-stage activated microglia is likely induced by neuronal cell death or damage, whereas distinct pathologies may contribute to the diversity.

    “The core expression profile is likely induced by neuronal cell death or damage, whereas distinct pathologies may contribute to the diversity.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    In the adult brain, highly dynamic microglia processes constantly survey the local environment in a speed estimated to cover the entire parenchyma within a few hours.

    “In the adult brain, highly dynamic microglia processes constantly survey the local environment19,20 in a speed estimated to cover the entire parenchyma within a few hours20.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [19] Davalos, D. et al. ATP mediates rapid microglial response to local brain injury in vivo. Nat. Neurosci. 8, 752–758 (2005). source

      Not checked in the free run.

    • cites [20] Nimmerjahn, A., Kirchhoff, F. & Helmchen, F. Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science 308, 1314–1318 (2005). source

      Not checked in the free run.

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

    Premisenone given

    Activation of the complement system promotes membrane attack complex formation, creating pores on cell membranes to induce cell lysis.

    “activation of the complement system promotes membrane attack complexes (MAC) formation, creating pores on cell membranes to induce cell lysis”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Innate immunity is an indispensable component in Alzheimer's disease pathogenesis and may constitute a driving force for disease progression.

    “Therefore, innate immunity is an indispensable component in Alzheimer’s disease pathogenesis and may constitute a driving force for disease progression.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Microglia have the capacity to monitor neuronal activity and modulate synaptic plasticity.

    “This grants microglia the capacity to monitor neuronal activity and modulate synaptic plasticity22.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [22] Wu, Y., Dissing-Olesen, L., MacVicar, B. A. & Stevens, B. Microglia: dynamic mediators of synapse development and plasticity. Trends Immunol. 36, 605–613 (2015). source

      Not checked in the free run.

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    Premisecitation

    Microglia are derived from embryonic yolk sac precursors and maintain their CNS population via local self-renewal, with little contribution from bone marrow-derived monocytes.

    “They are derived from embryonic yolk sac (YS) precursors and maintain their CNS population via local self-renewal, with little contribution from bone marrow-derived monocytes12,13.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [12] Ginhoux, F. et al. Fate mapping analysis reveals that adult microglia derive from primitive macrophages. Science 330, 841–845 (2010). source

      Not checked in the free run.

    • cites [13] Ajami, B., Bennett, J. L., Krieger, C., Tetzlaff, W. & Rossi, F. M. Local self-renewal can sustain CNS microglia maintenance and function throughout adult life. Nat. Neurosci. 10, 1538–1543 (2007). source

      Not checked in the free run.

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    Interpretationcitation

    The M1/M2 nomenclature for activated microglia is now deemed inaccurate as accumulating evidence has revealed a broad diversity of macrophage activation statuses and remarkable plasticity to change phenotypes in response to environmental cues.

    “However, this nomenclature is now deemed inaccurate as accumulating evidence has revealed a broad diversity of macrophage activation statuses and shown that macrophages show remarkable plasticity to change phenotypes in response to environmental cues25,26.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [25] Mosser, D. M. & Edwards, J. P. Exploring the full spectrum of macrophage activation. Nat. Rev. Immunol. 8, 958–969 (2008). source

      Not checked in the free run.

    • cites [26] Murray, P. J. et al. Macrophage activation and polarization: nomenclature and experimental guidelines. Immunity 41, 14–20 (2014). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Innate immunity affects amyloid-β and tau pathology buildup, which in turn can influence neurodegeneration.

    “In addition to a direct effect on neuronal viability, innate immunity also affects amyloid-β and tau pathology buildup, which in turn can influence neurodegeneration.”
    Quote in the paperSubstantial claim

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

    Interpretationreasoning

    These effects have been proposed to mainly result from enhanced phagocytotic activity of microglia induced by potent inflammation, leading to greater amyloid-β clearance, whereas APP synthesis or processing is not affected.

    “These effects have been proposed to mainly result from enhanced phagocytotic activity of microglia induced by potent inflammation, leading to greater amyloid-β clearance, whereas APP synthesis or processing is not affected.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Plaque-associated microglia perform plaque trimming and compacting functions that help to restrict plaque growth, and these cells serve as a barrier to limit plaque-induced neuronal toxicity.

    “indicating that plaque-associated microglia perform plaque trimming and compacting functions that help to restrict plaque growth, and that these cells serve as a barrier to limit plaque-induced neuronal toxicity.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Tau is primarily an intracellular neuronal protein, but is normally secreted into the interstitial fluid and is believed to transmit tau pathology in a prion-like manner.

    “In the brain, tau is primarily an intracellular neuronal protein, but is normally secreted into the interstitial fluid (ISF)53 and is believed to transmit tau pathology in a prion-like manner54.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [53] Yamada, K. et al. In vivo microdialysis reveals age-dependent decrease of brain interstitial fluid tau levels in P301S human tau transgenic mice. J. Neurosci. 31, 13110–13117 (2011). source

      Not checked in the free run.

    • cites [54] Clavaguera, F., Hench, J., Goedert, M. & Tolnay, M. Invited review: Prion-like transmission and spreading of tau pathology. Neuropathol. Appl. Neurobiol. 41, 47–58 (2015). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    During the advanced disease stage, plaques are already formed, hence seeding efficiency is no longer a determining factor; instead, microglial plaque-trimming function becomes a dominating factor influencing plaque growth.

    “By contrast, during the advanced disease stage plaques are already formed, hence seeding efficiency is no longer a determining factor. Instead, microglial plaque-trimming function becomes a dominating factor influencing plaque growth.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    These effects are interpreted to derive from enhanced microglial phagocytotic capacity induced by TREM2 overexpression which requires less microglial activation to trim plaques.

    “These effects are interpreted to derive from enhanced microglial phagocytotic capacity induced by TREM2 overexpression which requires less microglial activation to trim plaques.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationnone given

    Activated microglia may generate ROS and NO and induce A1 astrocytes to aggravate neuronal loss.

    “Meanwhile, they may generate ROS and NO and induce A1 astrocytes to aggravate neuronal loss.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    End-stage MGnD microglia that harbour high phagocytotic and inflammatory capacity may directly kill stressed neurons, such as tau-loaded neurons, via phagoptosis; or damage and kill healthy neurons by secreting neurotoxic substances, independent of their effects on Alzheimer's disease pathology.

    “end-stage MGnD microglia that harbour high phagocytotic and inflammatory capacity may directly kill stressed neurons, such as tau-loaded neurons, via phagoptosis; or damage and kill healthy neurons by secreting neurotoxic substances, independent of their effects on Alzheimer’s disease pathology.”
    Quote in the paperSubstantial claim

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

    Interpretationreasoning

    The late stage may be similar in all neurodegenerative diseases, and detrimental neuroinflammation during this stage may constitute a major mechanism for neurodegeneration across different diseases.

    “This stage may be similar in all neurodegenerative diseases, and detrimental neuroinflammation during this stage may constitute a major mechanism for neurodegeneration across different diseases.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationnone given

    The mid-stage is characterized by plaque accumulation, during which activated microglia target growing plaques to restrict their expansion and toxicity to neighboring neurons, hence playing a protective role.

    “The mid-stage (FIG. 1b) is characterized by plaque accumulation, during which time activated microglia target growing plaques to restrict their expansion and toxicity to neighboring neurons, hence playing a protective role.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Astrocytes are immune-competent; they respond to a wide range of brain insults and are activated in a wide range of neurodegenerative diseases including Alzheimer's disease.

    “However, astrocytes are immune-competent. They respond to a wide range of brain insults and are activated in a wide range of neurodegenerative diseases including Alzheimer’s disease9,69–71.”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [9] Liddelow, S. A. et al. Neurotoxic reactive astrocytes are induced by activated microglia. Nature 541, 481–487 (2017). This study defines the roles of A1 astrocytes in neurodegenerative diseases and demonstrates an essential role of microglia–astrocytes crosstalk in A1 astrocytic activation. source

      Not checked in the free run.

    • cites [69] Shi, Y. et al. ApoE4 markedly exacerbates tau-mediated neurodegeneration in a mouse model of tauopathy. Nature 549, 523–527 (2017). This study demonstrates an amyloid-β-independent role of APOE in regulating neurodegeneration and neuroinflammation in the setting of a tauopathy. The protective effect of APOE deficiency on neurodegeneration is in line with that of TREM2. source

      Not checked in the free run.

    • cites [70] Kraft, A. W. et al. Attenuating astrocyte activation accelerates plaque pathogenesis in APP/PS1 mice. FASEB J. 27, 187–198 (2013). source

      Not checked in the free run.

    • cites [71] Liddelow, S. A. & Barres, B. A. Reactive astrocytes: production, function, and therapeutic potential. Immunity 46, 957–967 (2017). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    APOE ε4 carriers show earlier disease onset, heavier amyloid-β plaque load, greater brain atrophy, and accelerated disease progression compared to non-carriers.

    “The ε4 allele is significantly enriched in patients with Alzheimer’s disease, and ε4-carrying patients show earlier disease onset92, heavier amyloid-β plaque load in the brain93, greater brain atrophy94, and accelerated disease progression69 compared to patients who do not carry this allele.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [92] Corder, E. H. et al. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science 261, 921–923 (1993). source

      Not checked in the free run.

    • cites [93] Schmechel, D. E. et al. Increased amyloid β-peptide deposition in cerebral cortex as a consequence of apolipoprotein E genotype in late-onset Alzheimer disease. Proc. Natl Acad. Sci. USA 90, 9649–9653 (1993). source

      Not checked in the free run.

    • cites [94] Agosta, F. et al. Apolipoprotein E ε4 is associated with disease-specific effects on brain atrophy in Alzheimer’s disease and frontotemporal dementia. Proc. Natl Acad. Sci. USA 106, 2018–2022 (2009). source

      Not checked in the free run.

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

    Interpretationnone given

    There appear to be three major disease stages during the course of Alzheimer's disease.

    “There appear to be three major disease stages during the course of Alzheimer’s disease (FIG. 1).”
    Quote in the paperNot a substantial claim

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

    Interpretationnone given

    The late stage is represented by accumulating tau pathology with plateaued amyloid-β pathology.

    “The late stage (FIG. 1c) is represented by accumulating tau pathology with plateaued amyloid-β pathology.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationnone given

    During the late stage, cell death increases and MGnD microglia are primarily involved in removal of dead neurons and targeting stressed-but-viable neurons injured by tau pathology for phagoptosis.

    “During this time, cell death increases and MGnD microglia are primarily involved in removal of dead neurons and targeting stressed-but-viable neurons injured by tau pathology for phagoptosis.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    In a tauopathy mouse model, genetic ablation of ApoE markedly reduces activation of microglia and astrocytes and ameliorates brain atrophy.

    “In a tauopathy mouse model, genetic ablation of ApoE markedly reduces activation of microglia and astrocytes activation and ameliorates brain atrophy69.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [69] Shi, Y. et al. ApoE4 markedly exacerbates tau-mediated neurodegeneration in a mouse model of tauopathy. Nature 549, 523–527 (2017). This study demonstrates an amyloid-β-independent role of APOE in regulating neurodegeneration and neuroinflammation in the setting of a tauopathy. The protective effect of APOE deficiency on neurodegeneration is in line with that of TREM2. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Despite higher excitability of microglia in the absence of ApoE, their impaired neurodegenerative functionality may hinder their capacity to kill and damage neurons via phagoptosis or inflammatory mechanisms, which may underlie the protective effect of ApoE deficiency in various neurodegenerative settings.

    “Hence, despite higher excitability of microglia in the absence of ApoE, their impaired neurodegenerative functionality may hinder their capacity to kill and damage neurons via phagoptosis or inflammatory mechanisms, which may underlie the protective effect of ApoE deficiency in various neurodegenerative settings.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    A greater immune response associated with the ε4 allele is also observed in human APOE-TR mice and in cultured microglia/macrophages upon LPS stimulation.

    “A greater immune response associated with the ε4 allele is also observed in human ApoE-targeted replacement (APOE-TR) mice [G] and in cultured microglia/macrophages upon LPS stimulation108–110.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [108] Gale, S. C. et al. APOE4 is associated with enhanced in vivo innate immune responses in human subjects. J. Allergy Clin. Immunol. 134, 127–134 (2014). source

      Not checked in the free run.

    • cites [109] Vitek, M. P., Brown, C. M. & Colton, C. A. APOE genotype-specific differences in the innate immune response. Neurobiol. Aging 30, 1350–1360 (2009). source

      Not checked in the free run.

    • cites [110] Zhu, Y. et al. APOE genotype alters glial activation and loss of synaptic markers in mice. Glia 60, 559–569 (2012). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    TREM2 deletion in APPPS1-21 or SOD1 mice results in ApoE downregulation and a similar suppression of core inflammatory MGnD genes and restoration of homeostatic genes.

    “TREM2 deletion in APPPS1–21 [G] or superoxide dismutase 1 (SOD1) mice [G] results in ApoE downregulation and a similar suppression of core inflammatory MGnD genes and restoration of homeostatic genes28.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [28] Krasemann, S. et al. The TREM2-APOE pathway drives the transcriptional phenotype of dysfunctional microglia in neurodegenerative diseases. Immunity 47, 566–581 (2017). This work and reference 27 raise the concept of a neurodegenerative microglial phenotype. They define the molecular signatures of the phenotype and demonstrate the requirement of TREM2 and APOE for its activation. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    ApoE ablation in EAE mice reduces inflammation and disease severity.

    “ApoE ablation in EAE mice also reduces inflammation and disease severity107.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [107] Shin, S. et al. Apolipoprotein E mediation of neuro-inflammation in a murine model of multiple sclerosis. J. Neuroimmunol. 271, 8–17 (2014). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    ApoE binding to cell surface is significantly enhanced in apoptotic N2a cells compared to healthy cells, and cultured microglia phagocytose significantly more apoptotic N2a cells with increased levels of ApoE in the medium.

    “Supporting this hypothesis, ApoE binding to cell surface was shown to be significantly enhanced in apoptotic N2a cells, a murine neuroblastoma cell line, compared to healthy cells, and cultured microglia phagocytose significantly more apoptotic N2a cells with increased levels of ApoE in the medium116.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [116] Bailey, C. C., DeVaux, L. B. & Farzan, M. The triggering receptor expressed on myeloid cells 2 binds apolipoprotein E. J. Biol. Chem. 290, 26033–26042 (2015). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In a mouse model of Parkinson's disease featuring synucleinopathy, ApoE deletion significantly attenuates loss of spinal cord motor neurons, delays disease onset, and improves survival.

    “In a mouse model of Parkinson’s disease featuring synucleinopathy, ApoE deletion significantly attenuates the loss of spinal cord motor neurons, delays disease onset, and improves survival106.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [106] Gallardo, G., Schluter, O. M. & Sudhof, T. C. A molecular pathway of neurodegeneration linking α-synuclein to ApoE and Aβ peptides. Nat. Neurosci. 11, 301–308 (2008). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    ApoE may accumulate on the surfaces of damaged and dead neurons as a result of impaired neuronal uptake function, and serve as an opsonin to promote neuronal phagocytosis by microglia.

    “we propose that ApoE may accumulate on the surfaces of damaged and dead neurons as a result of impaired neuronal uptake function, and serve as an opsonin to promote neuronal phagocytosis by microglia.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    ApoE4 is less effective than ApoE3 in inducing cholesterol efflux from macrophages, causing cholesterol accumulation on cell membranes.

    “ApoE4 is reported to be less effective than ApoE3 in inducing cholesterol efflux from macrophages114, which causes cholesterol accumulation on cell membranes108,114.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [114] Okoro, E. U. et al. Apolipoprotein E4 is deficient in inducing macrophage ABCA1 expression and stimulating the Sp1 signaling pathway. PLoS ONE 7, e44430 (2012). source

      Not checked in the free run.

    • cites [108] Gale, S. C. et al. APOE4 is associated with enhanced in vivo innate immune responses in human subjects. J. Allergy Clin. Immunol. 134, 127–134 (2014). source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    This mechanism explains the higher immune reactivity associated with ApoE4.

    “This mechanism has been proposed to explain the higher immune reactivity associated with ApoE4.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Targeting TREM2 signaling in the facial nerve axotomy model ameliorates neuronal loss, and ablation of TREM2 in tauopathy mice attenuates neuroinflammation and neurodegeneration, similar to the effect of ApoE deletion.

    “Targeting TREM2 signaling in the facial nerve axotomy model ameliorates neuronal loss28, and ablation of TREM2 in tauopathy mice attenuates neuroinflammation and neurodegeneration67, similar to the effect of ApoE deletion.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [28] Krasemann, S. et al. The TREM2-APOE pathway drives the transcriptional phenotype of dysfunctional microglia in neurodegenerative diseases. Immunity 47, 566–581 (2017). This work and reference 27 raise the concept of a neurodegenerative microglial phenotype. They define the molecular signatures of the phenotype and demonstrate the requirement of TREM2 and APOE for its activation. source

      Not checked in the free run.

    • cites [67] Leyns, C. E. G. et al. TREM2 deficiency attenuates neuroinflammation and protects against neurodegeneration in a mouse model of tauopathy. Proc. Natl Acad. Sci. USA 114, 11524–11529 (2017). This work shows that dampening neurodegenerative microglial activation via TREM2 deletion reduces neurodegeneration at an advanced disease stage in a tauopathy mouse model, supporting a role of microglia in modulating neurodegeneration. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    ApoE deletion prevents full acquisition of the microglial neurodegenerative phenotype with suppression of key MGnD genes.

    “ApoE deletion prevents full acquisition of the microglial neurodegenerative phenotype with suppression of key MGnD genes28”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [28] Krasemann, S. et al. The TREM2-APOE pathway drives the transcriptional phenotype of dysfunctional microglia in neurodegenerative diseases. Immunity 47, 566–581 (2017). This work and reference 27 raise the concept of a neurodegenerative microglial phenotype. They define the molecular signatures of the phenotype and demonstrate the requirement of TREM2 and APOE for its activation. source

      Not checked in the free run.

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

    Interpretationnone given

    Substantial genetic and functional evidence point to a central role of innate immunity in neurodegenerative diseases.

    “Substantial genetic and functional evidence point to a central role of innate immunity in neurodegenerative diseases.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    ApoE deletion leads to impaired microglial cell response to plaques, the same phenotype observed with TREM2 deficiency.

    “Corresponding to loose and enlarged plaques, ApoE deletion leads to impaired microglial cell response to plaques120, the same phenotype observed with TREM2 deficiency44,46.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [120] Huynh, T. V. et al. Age-dependent effects of apoE reduction using antisense oligonucleotides in a model of β-amyloidosis. Neuron 96, 1013–1023 (2017). source

      Not checked in the free run.

    • cites [44] Ulrich, J. D. et al. Altered microglial response to Aβ plaques in APPPS1-21 mice heterozygous for TREM2. Mol. Neurodegener. 9, 20 (2014). source

      Not checked in the free run.

    • cites [46] Wang, Y. et al. TREM2 lipid sensing sustains the microglial response in an Alzheimer’s disease model. Cell 160, 1061–1071 (2015). source

      Not checked in the free run.

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

    Interpretationreasoning

    The shared features between ApoE and TREM2 suggest an ApoE-TREM2 axis linking ApoE to microglial function.

    “The shared features between ApoE and TREM2 suggest an ApoE-TREM2 axis linking ApoE to microglial function.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Interpretationnone given

    ApoE affects Alzheimer's disease risk in large part due to its effects on amyloid-β seeding and clearance; it is also a core immune regulator that may influence Alzheimer's disease through its immunomodulatory functions.

    “ApoE affects Alzheimer’s disease risk in large part due to its effects on amyloid-β seeding and clearance; it is also a core immune regulator that may influences Alzheimer’s disease through its immunomodulatory functions.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    ApoE binds to apoptotic neuronal cell surface.

    “This work demonstrates that ApoE is a receptor for TREM2, and shows that ApoE binds to apoptotic neuronal cell surface and increases TREM2-mediated phagocytosis by microglia in vitro, supporting the ApoE oponization hypothesis.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [116] Bailey, C. C., DeVaux, L. B. & Farzan, M. The triggering receptor expressed on myeloid cells 2 binds apolipoprotein E. J. Biol. Chem. 290, 26033–26042 (2015). source

      Not checked in the free run.

59 of 59

  • The paper relies on this without support.

    Findings from mouse models of neurodegenerative diseases can be extrapolated to human Alzheimer’s disease.

    “In a tauopathy mouse model, genetic ablation of ApoE markedly reduces activation of microglia and astrocytes activation and ameliorates brain atrophy69.”

  • The paper relies on this without support.

    The ApoE-TREM2 axis is conserved between mice and humans.

    “The shared features between ApoE and TREM2 suggest an ApoE-TREM2 axis linking ApoE to microglial function.”
2 of 2

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?

  • TREM2, expressed by DAM/MGnD, exerts protective function in AD via ligation of ApoE or Aβ oligomers.

    “TREM2, a receptor expressed by DAM/MGnD, which exerts its protective function in AD via ligation of ApoE (apolipoprotein E), which binds to loose Aβ aggregates, or direct ligation of Aβ oligomers [286, 295, 338, 357, 366]”

    From Microglia and monocytes in inflammatory CNS disease: integrating phenotype and function (2022) · cites this paper as [286]

    In “TREM2 and amyloid-β pathology” (page unavailable), the review says TREM2 is upregulated in plaque-associated microglia, promotes a DAM signature, and binds amyloid-β oligomers more strongly than monomers. “Immune functions of ApoE in neurodegeneration” identifies TREM2 as an ApoE receptor, while “ApoE and amyloid-β pathology” proposes that ApoE may help microglia target plaques. The review does not establish that ApoE binds loose Aβ aggregates or that either ligation is the definitive mechanism of TREM2’s protective effect in AD. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • APOE is involved in the regulation of DAMs and the microglial response to amyloid.

    “APOE is involved in the regulation of DAMs and the microglial response to amyloid [57, 64–66].”

    From APOE Christchurch enhances a disease-associated microglial response to plaque but suppresses response to tau pathology (2025) · cites this paper as [64]

  • APOE and TREM2 act in the same axis in regulating many aspects of microglial functions.

    “APOE and TREM2 act in the same axis in regulating many aspects of microglial functions (Shi and Holtzman, 2018).”

    From Overexpressing low‐density lipoprotein receptor reduces tau‐associated neurodegeneration in relation to apoE‐linked mechanisms (2021) · cites this paper as Shi and Holtzman, 2018

  • ApoE has modulatory effects on tau pathology and tau-related neurodegeneration.

    “ApoE also has modulatory effects on tau pathology and tau-related neurodegeneration”

    From Alzheimer Disease: An Update on Pathobiology and Treatment Strategies (2019) · cites this paper as Shi and Holtzman, 2018

  • Cellular origin plays a crucial role in apoE's biophysical properties and pathological effects.

    “Cellular origin plays a crucial role in apoE’s biophysical properties and pathological effects.”

    From Apolipoprotein E4, inhibitory network dysfunction, and Alzheimer’s disease (2019) · cites this paper as [27]

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.

  • ApoE and TREM2 receptor roles are reversed in a reference note

    Minor

    The main text identifies TREM2 as an ApoE receptor, whereas the note for reference 116 calls ApoE a receptor for TREM2. The reference title instead identifies ApoE as a ligand for TREM2.

  • Citation 51 attributes a finding to the wrong authors

    Minor

    The text attributes the finding to Keren-Shaul et al. and cites reference 51, but reference 51 is a paper by Zhang et al. Keren-Shaul et al. are listed as reference 27.

2 of 2

Cites

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Related

Authors
Shi, Y., & Holtzman, D. M.
Affiliations
Washington University in St. Louis (US)
Corresponding author
Holtzman, David M.
ORCID
Venue
Nature Reviews Immunology
Publisher
Springer Science and Business Media LLC
Published
2018-08-23
Volume
18
Issue
12
Pages
759-772
ISSN
  • 1474-1733 (ISSN-L)
  • 1474-1741
DOI
10.1038/s41577-018-0051-1
PMC
PMC6425488
OpenAlex
W2888662179
Cited by
595
References
158
Citations by year
2026: 38 · 2025: 67 · 2024: 80 · 2023: 101 · 2022: 98 · 2021: 81 · 2020: 72 · 2019: 51 · 2018: 6 · 2012: 1
FWCI
4.99
Type
journal article
Language
en
Open access
Licence
www.springer.com/tdm (tdm)
Locations
  • Nature reviews. Immunology (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institute on Aging (R01AG047644, RF1AG047644)
  • National Institute of Neurological Disorders and Stroke (R01NS034467, R01NS090934, RF1NS090934)
Topics
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
Keywords
Alzheimer's disease, innate immunity, neuroinflammation, apolipoprotein E, TREM2, microglia, disease-associated microglia, blood-brain barrier, immunomodulation, genetic risk factors, pathogenesis
MeSH terms
Alzheimer Disease, Apolipoproteins E, Humans, Immunity, Innate, Membrane Glycoproteins, Receptors, Immunologic, Microglia

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 2026-10-09.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-09.

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.

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