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Cited by 125Lipoproteins and Cardiovascular HealthAlzheimer's disease research and treatmentsDementia and Cognitive Impairment Research

Plasma levels of apolipoprotein E, APOE genotype and risk of dementia and ischemic heart disease: A review

Open access
Rasmussen, Katrine Laura·2016·Atherosclerosis
DOI 10.1016/j.atherosclerosis.2016.10.037
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Abstract

Dementia is one of the major causes of disability in later life, and ischemic heart disease is a leading cause of morbidity and mortality. Apolipoprotein E (apoE) plays a pivotal role in lipoprotein metabolism in the brain and in the periphery, and is implicated in both dementia and ischemic heart disease. Peripherally, liver-derived apoE is the main source of plasma apoE. Approximately half of plasma apoE is associated with triglyceride-rich lipoproteins, where apoE serves as the main ligand for the low density lipoprotein (LDL) receptor and the LDL receptor Related Protein (LRP). In the brain, apoE is produced mainly by astrocytes. Astrocyte-derived apoE is pivotal for cerebral cholesterol metabolism and clearance of β-amyloid, a major pathological hallmark of Alzheimer disease. Plasma levels of apoE and other lipids and lipoproteins are under strong genetic influence by the APOE polymorphism, and the ε4 allele is a strong genetic risk factor for Alzheimer disease. The characteristics of the APOE polymorphism thus suggest the qualitative importance of apoE, whereas studies of familial absolute apoE deficiency suggest a quantitative importance of plasma apoE levels in lipid metabolism. Whether plasma levels of apoE are associated with increased risk of dementia and ischemic heart disease, and whether these associations are independent of the APOE polymorphism and of lipids and lipoproteins has only recently been established. The aim of this review is to summarize and discuss the current epidemiological and biological evidence for an association of plasma levels of apoE with risk of dementia and ischemic heart disease.

AI snapshot

Written from the paper’s full text.

TL;DR

This review summarizes evidence that plasma apolipoprotein E (apoE) levels and APOE genotype are linked to dementia and ischemic heart disease, with low apoE associated with future dementia and high apoE with ischemic heart disease. It argues for the qualitative importance of the APOE polymorphism and an emerging quantitative importance of plasma apoE, though associations differ by disease and are partly mediated by lipids and triglyceride-rich lipoproteins.

Key findings

  • Plasma apoE levels are strongly influenced by APOE genotype, with stepwise decreases from ε22 to ε32 to ε42 to ε33 to ε43 to ε44; the APOE polymorphism accounts for roughly 15–25% of variability in plasma apoE. In the Copenhagen General Population Study and Copenhagen City Heart Study, genotype frequencies were 0.7%, 12.4%, 2.9%, 55.8%, 25.4%, and 2.9% for ε22, ε32, ε42, ε33, ε43, and ε44, respectively.
  • The ε4 allele is a major genetic risk factor for late-onset Alzheimer disease: one copy is associated with a two- to three-times increased risk, and two copies with roughly an eight- to ten-times increased risk; ε2 is associated with decreased risk. Low plasma apoE levels were epidemiologically associated with increased risk of future dementia in the general population, independent of APOE genotype.
  • For ischemic heart disease, high plasma apoE was associated with increased risk in men but not women in a prospective general population cohort of ~91,000 participants; the association was not attenuated by adjustment for APOE genotype but was attenuated after adjustment for triglycerides. In a population-based study of 546 elderly individuals, high plasma apoE was associated with increased cardiovascular mortality in both genders, independently of APOE genotype and plasma triglycerides, LDL cholesterol, and HDL cholesterol.
  • Mechanistically, liver-derived apoE is the main source of plasma apoE, and approximately half of plasma apoE is associated with triglyceride-rich lipoproteins, where it serves as the main ligand for the LDL receptor and LRP. In the brain, astrocyte-derived apoE is pivotal for cerebral cholesterol metabolism and amyloid-β clearance, and both decreased apoE levels and APOE genotype may contribute to dementia via impaired amyloid-β clearance.

Methods

  • Narrative review summarizing epidemiological and biological evidence on plasma apoE levels, APOE genotype, and risk of dementia and ischemic heart disease.
  • Draws on population studies including the Copenhagen General Population Study and Copenhagen City Heart Study, the ApoEurope project, the Rotterdam Study, and a prospective general population cohort of ~91,000 participants, as well as animal and in vitro studies.
  • No new primary data collection or meta-analysis is reported; the paper synthesizes prior findings and presents combined CGPS/CCHS data in figures.

Limitations

  • Stated: word and reference limits required prioritization of the literature; human studies of plasma or cerebrospinal fluid apoE in Alzheimer disease are conflicting, possibly reflecting different disease stages; immunoassay results may be biased by isoform-dependent epitope masking and lipid complexation; animal model results differ and complicate translation to humans.
  • Stated: whether blood apoE levels reflect cerebral apoE levels has been debated, although cerebrospinal fluid apoE shows a genotype-dependent pattern similar to plasma.
  • Evident from the text: this is a narrative rather than systematic review, so literature selection and synthesis may be selective; observational associations cannot establish causality; and the contrasting directions of apoE associations with dementia versus ischemic heart disease indicate different disease mechanisms that remain incompletely understood.

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

Integrity signals

Registry

Crossref · 10.1016/j.atherosclerosis.2016.10.037

Cites

129 of 129 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

50 of 139 cited sources checked · 26 supported · 3 flagged · accuracy not yet measured

  • Premisecitation

    Rasmussen et al. showed that adjustment for C-reactive protein did not have any impact on the risk between plasma levels of apoE and ischemic heart disease.

    “The importance of high C-reactive protein levels has been investigated by some studies, however Rasmussen et al. showed that adjustment for C-reactive protein did not have any impact on the risk between plasma levels of apoE and ischemic heart disease [44,116,121,122].”
    Quote in the paperNot a substantial claim3 of 4 sources checked
    • cites [44] Mooijaart, 2006, ApoE plasma levels and risk of cardiovascular mortality in old age, PLoS Med. source

      The Results section (page unavailable) reports that cardiovascular mortality risk associated with high apoE depended on CRP level: it was highest at low CRP levels and absent at high levels. The paper studies cardiovascular mortality, not ischemic heart disease, and does not report the claimed finding about adjustment for CRP. (LLM, conf=0.82)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured
    • cites [116] Rasmussen, 2016, Plasma levels of apolipoprotein E and risk of ischemic heart disease in the general population, Atherosclerosis source
    • cites [121] Corsetti, 2012, Apolipoprotein E predicts incident cardiovascular disease risk in women but not in men with concurrently high levels of high-density lipoprotein cholesterol and C-reactive protein, Metabolism source

      The Discussion (section 4; page not given) says apoE-associated risk was absent in women with high HDL-C and low CRP, while the Results (section 3.3; page not given) report risk in the high-CRP subgroup. That is contrary to the claim that CRP had no impact on the association. The paper also does not report a Rasmussen analysis of CRP adjustment. (LLM, conf=0.76)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured
    • cites [122] Corsetti, 2012, Apolipoprotein A-II influences apolipoprotein E-linked cardiovascular disease risk in women with high levels of HDL cholesterol and C-reactive protein, PLoS One source

      The Study Populations section (page unavailable) reports that apoE predicted cardiovascular disease risk in women with high CRP. The Statistical Analyses section lists CRP among potential adjustment variables, but neither passage says CRP adjustment left the apoE risk association unchanged. The cited paper also does not establish the claim about Rasmussen et al. or specifically ischemic heart disease. (LLM, conf=0.82)

      Experimental — accuracy not yet measured
  • Premisecitation

    Hypertriglyceridemic patients have higher plasma levels of apoE compared with normal control subjects.

    “Hypertriglyceridemic patients have higher plasma levels of apoE compared with normal control subjects; this could probably be explained by the finding, that increased levels of apoE stimulate VLDL triglyceride production in the liver and impairs lipoprotein lipase-mediated lipolysis, thus leading to hypertriglyceridemia [56,65].”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [56] Rifai, 1987, A simple immunotechnique for the determination of serum concentration of apolipoprotein E, Clin. Chim. Acta source
    • cites [65] Huang, 1998, Overexpression and accumulation of apolipoprotein E as a cause of hypertriglyceridemia, J. Biol. Chem. source
  • Premisecitation

    Recent in vitro studies found that apoE4 expressed in neurons, but not in astrocytes, reduces mitochondrial function.

    “Recent in vitro studies have found that apoE4 expressed in neurons -but not in astrocytes - reduces the mitochondrial function [41].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [41] Chen, 2011, Apolipoprotein E4 domain interaction mediates detrimental effects on mitochondria and is a potential therapeutic target for Alzheimer disease, J. Biol. Chem. source
  • Premisecitation

    The ε4 allele increased brain amyloid burden in a dose-dependent manner in normal elderly individuals and in mild cognitive impairment patients.

    “The ε4 allele increased brain amyloid burden in a dose-dependent manner in normal elderly individuals and in mild cognitive impairment patients [93,94].”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [93] Reiman, 2009, Fibrillar amyloid-beta burden in cognitively normal people at 3 levels of genetic risk for Alzheimer's disease, Proc. Natl. Acad. Sci. U. S. A. source

      The Results report that fibrillar amyloid-β burden increased with APOE ε4 gene dose among 28 cognitively normal participants. The paper includes only one participant with mild cognitive impairment, whose burden was high; it does not establish a dose-dependent relationship in MCI patients. (LLM, conf=0.90)

      Experimental — accuracy not yet measured
    • cites [94] Villemagne, 2011, Longitudinal assessment of Abeta and cognition in aging and Alzheimer disease, Ann. Neurol. source

      The PiB Baseline Results report higher amyloid burden in ε4 carriers than noncarriers in both healthy controls and MCI patients. The Follow-up PiB Studies report a dose-dependent relationship only when clinical groups were combined, with no significant differences when each group was examined separately. The copy therefore does not support a dose-dependent finding in each of the two populations named. (LLM, conf=0.90)

      Experimental — accuracy not yet measured
  • Premisecitation

    Two copies of the ε4 allele are associated with roughly an eight to ten times increased risk for Alzheimer disease.

    “One copy of the ε4 allele is associated with a two to three times increased risk for Alzheimer disease, and two copies of the ε4 allele is associated with roughly an eight to ten times increased risk [23,100].”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [23] Rasmussen, 2015, Plasma levels of apolipoprotein E and risk of dementia in the general population, Ann. Neurol. source
    • cites [100] Verghese, 2011, Apolipoprotein E in Alzheimer's disease and other neurological disorders, Lancet Neurol. source

      The *APOE* and Alzheimer’s disease section says that two copies of ε4 increase late-onset Alzheimer’s disease risk approximately 12-fold. It supports the increased-risk association, but not the cited estimate of roughly eight to ten times. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
  • May combine two claims. 47
  • Classified as probably not a substantial claim. 18

  • May combine two claims.

    Premisecitation

    At the level of an individual, the effect of the APOE polymorphism on plasma lipid levels is moderate, but because the polymorphism is common, it contributes substantially to total phenotypic variability in plasma lipid levels in the general population.

    “At the level of an individual the effect of the APOE polymorphism on plasma lipid levels is moderate, however since the APOE polymorphism is common, it contributes substantially to the total phenotypic variability in plasma lipid levels in the general population [21,24,58].”
    Quote in the paperNot a substantial claim1 of 3 sources checked
    • cites [21] Smit, 1988, Apolipoprotein E polymorphism in The Netherlands and its effect on plasma lipid and apolipoprotein levels, Hum. Genet. source
    • cites [24] Davignon, 1988, Apolipoprotein E polymorphism and atherosclerosis, Arteriosclerosis source
    • cites [58] Haddy, 2002, The importance of plasma apolipoprotein E concentration in addition to its common polymorphism on inter-individual variation in lipid levels: results from Apo Europe, Eur. J. Hum. Genet. source

      Split into 2 atoms — 0 confirmed, 1 partially supported, 1 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    The characteristics of the APOE polymorphism suggest a qualitative importance of apoE, whereas studies of familial absolute apoE deficiency suggest a quantitative importance of plasma apoE levels in lipid metabolism.

    “The characteristics of the APOE polymorphism thus suggest a qualitative importance of apoE, whereas studies of familial absolute apoE deficiency suggest a quantitative importance of plasma apoE levels in lipid metabolism [26,27].”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [26] Schaefer, 1986, Familial apolipoprotein E deficiency, J. Clin. Investig. source
    • cites [27] Mak, 2014, Effects of the absence of apolipoprotein e on lipoproteins, neurocognitive function, and retinal function, JAMA Neurol. source

  • May combine two claims.

    Premisecitation

    ApoE4 exhibits a near-normal and slightly changed affinity to the LDL receptor, whereas apoE4 has a slightly more compact structure compared with apoE3.

    “ApoE4 exhibits a near-normal and slightly changed affinity to the LDL receptor, whereas apoE4 has a slightly more compact structure compared with apoE3 [33].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [33] Mahley, 2009, Apolipoprotein E: structure determines function, from atherosclerosis to Alzheimer's disease to AIDS, J. Lipid Res. source

      The section on apoE2 and LDL-receptor binding says that apoE3 and apoE4 both bind avidly to LDL receptors, supporting the near-normal binding characterization, but it does not establish a slight difference in their affinity. The apoE4 section explicitly says apoE4 has a more compact conformation than apoE3. Page numbers are unavailable in our copy. (LLM, conf=0.84)

      Experimental — accuracy not yet measured

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

    Premisecitation

    In the brain, apoE is produced mainly by astrocytes, although microglia and neurons can synthesize apoE under various physiological and pathological conditions.

    “In the brain, apoE is mainly produced by astrocytes, although microglia and neurons can synthesize apoE under various physiological and pathological conditions [66,67].”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [66] Huang, 2004, Apolipoprotein E: diversity of cellular origins, structural and biophysical properties, and effects in Alzheimer's disease, J. Mol. Neurosci. source
    • cites [67] Kim, 2009, The role of apolipoprotein E in Alzheimer's disease, Neuron source

  • May combine two claims.

    Premisecitation

    ApoE3 shows preference for HDL particles, whereas apoE4 shows preference for VLDL particles.

    “Despite near-normal receptor affinity of apoE4 the amino acid change leads to differences in distribution in lipoprotein classes: apoE3 shows preference for high density lipoprotein (HDL) particles, whereas apoE4 shows preference for very low density lipoprotein (VLDL) particles [38].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [38] Gregg, 1986, Abnormal in vivo metabolism of apolipoprotein E4 in humans, J. Clin. Investig. source

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

    Premisecitation

    Lipid-free apoE consists of two domains connected by a hinge region: the amino-terminal domain (amino acids 1 to 191) contains the receptor-binding function, and the carboxyl-terminal domain (~amino acids 225 to 299) contains the lipid-binding function.

    “Lipid-free apoE consists of two domains connected by a “hinge region”: the amino-terminal domain (amino acids 1 to 191) contains the receptor-binding function and the carboxyl-terminal domain (~amino acids 225 to 299) contains the lipid-binding function [28,33].”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [28] Weisgraber, 1994, Apolipoprotein E: structure-function relationships, Adv. Protein Chem. source
    • cites [33] Mahley, 2009, Apolipoprotein E: structure determines function, from atherosclerosis to Alzheimer's disease to AIDS, J. Lipid Res. source

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

    Premisecitation

    Additional common variation includes promoter SNPs in the 5' region of APOE: -491A>T (rs449647), -427T>C (rs769446), and -219G>T (rs405509).

    “Additional common variation includes promoter SNPs located in the 5 0 region of the APOE gene: À491A>T (rs449647), À427T>C (rs769446), and À219G>T (rs405509) [31,32].”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [31] Artiga, 1998, Allelic polymorphisms in the transcriptional regulatory region of apolipoprotein E gene, FEBS Lett. source

      The Results and discussion identifies promoter polymorphisms at −491 A/T, −427 T/C, and −219 T/G, and reports measuring their frequencies in 215 individuals. The paper does not give the three rs identifiers, so our copy cannot verify the claimed mappings; G/T at −219 describes the same allele pair in reverse order. (LLM, conf=0.82)

      Experimental — accuracy not yet measured
    • cites [32] Frikke-Schmidt, 2004, Gender- and age-specific contributions of additional DNA sequence variation in the 5' regulatory region of the APOE gene to prediction of measures of lipid metabolism, Hum. Genet. source

  • May combine two claims.

    Premisecitation

    Insufficient levels of apoE also lead to hypertriglyceridemia, because less apoE protein is present to serve as ligands for the LDL receptor and LRP, as clinically illustrated by familial apoE deficiency.

    “Interestingly, insufficient levels of apoE also lead to hypertriglyceridemia, because less apoE protein is present to serve as ligands for the LDL receptor and LRP, clinically illustrated by familial apoE deficiency [9,26,27].”
    Quote in the paperNot a substantial claim2 of 3 sources checked
    • cites [9] Mahley, 2001, Type III hyperlipoproteinemia (dysbetalipoproteinemia): the role of apolipoprotein E in normal and abnormal lipoprotein metabolism

      Not checked in the free run.

    • cites [26] Schaefer, 1986, Familial apolipoprotein E deficiency, J. Clin. Investig. source

      The Lipoprotein analysis section reports increased VLDL and IDL triglycerides in homozygotes with familial apoE deficiency. The paper also suggests that apoE is essential for receptor-mediated clearance of triglyceride-rich remnants, but the passages do not identify both the LDL receptor and LRP as the receptors responsible. Its finding is specific to homozygous deficiency; heterozygotes generally had normal plasma lipids. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
    • cites [27] Mak, 2014, Effects of the absence of apolipoprotein e on lipoproteins, neurocognitive function, and retinal function, JAMA Neurol. source

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

    Premisecitation

    In the brain, apoE is mainly produced by astrocytes, although microglia and neurons can synthesize apoE under various physiological and pathological conditions.

    “In the brain, apoE is mainly produced by astrocytes, although microglia and neurons can synthesize apoE under various physiological and pathological conditions [66,67].”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [66] Huang, 2004, Apolipoprotein E: diversity of cellular origins, structural and biophysical properties, and effects in Alzheimer's disease, J. Mol. Neurosci. source
    • cites [67] Kim, 2009, The role of apolipoprotein E in Alzheimer's disease, Neuron source

  • May combine two claims.

    Premisecitation

    ApoE is the major cholesterol carrier in the central nervous system; in the brain, lipids are transported on HDL-like particles where apoE is the primary apolipoprotein, unlike in the circulation where apoA1 is primary and apoE is present at lower levels.

    “ApoE is the major cholesterol carrier in the central nervous system: in the brain, lipids are transported on lipoproteins that resemble HDL particles, but while apolipoprotein A1 (apoA1) is the primary apolipoprotein and apoE is present in lower levels in HDL in the circulation, in contrast apoE is the primary apolipoprotein on these HDL-like particles found in the brain [67,73,75].”
    Quote in the paperNot a substantial claim2 of 3 sources checked
    • cites [67] Kim, 2009, The role of apolipoprotein E in Alzheimer's disease, Neuron source
    • cites [73] Hirsch-Reinshagen, 2009, Why lipids are important for Alzheimer disease?, Mol. Cell Biochem. source
    • cites [75] Mahley, 2016, Central nervous system lipoproteins: ApoE and regulation of cholesterol metabolism, Arterioscler. Thromb. Vasc. Biol. source

  • May combine two claims.

    Premisecitation

    In men, levels of apoE leveled off after age 45 years, whereas they continued to increase in women.

    “In men, the levels of apoE leveled off after the age of 45 years, whereas they continued to increase in women [58].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [58] Haddy, 2002, The importance of plasma apolipoprotein E concentration in addition to its common polymorphism on inter-individual variation in lipid levels: results from Apo Europe, Eur. J. Hum. Genet. source

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

    Premisecitation

    Type III hyperlipoproteinemia is characterized by elevations of both plasma cholesterol and triglycerides due to an increase in chylomicron remnants, VLDL, and IDL.

    “Type III hyperlipoproteinemia is characterized by elevations of both plasma cholesterol and triglycerides due to an increase in chylomicron remnants, VLDL and IDL [9,26,52].”
    Quote in the paperNot a substantial claim1 of 3 sources checked
    • cites [9] Mahley, 2001, Type III hyperlipoproteinemia (dysbetalipoproteinemia): the role of apolipoprotein E in normal and abnormal lipoprotein metabolism

      Not checked in the free run.

    • cites [26] Schaefer, 1986, Familial apolipoprotein E deficiency, J. Clin. Investig. source
    • cites [52] Brewer, 1983, NIH conference. Type III hyperlipoproteinemia: diagnosis, molecular defects, pathology, and treatment, Ann. Intern Med. source

  • May combine two claims.

    Premisecitation

    Pericyte inflammation leads to neuronal uptake of neurotoxic proteins from the blood, microvascular and cerebral blood flow reductions, and subsequently impaired clearance of amyloid-b.

    “Pericyte inflammation leads to neuronal uptake of neurotoxic proteins from the blood, and microvascular and cerebral blood flow reductions, which altogether subsequently lead to impaired clearance of amyloid-b [86,87].”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [86] Zlokovic, 2011, Neurovascular pathways to neurodegeneration in Alzheimer's disease and other disorders, Nat. Rev. Neurosci. source

      In “Blood–brain barrier breakdown” (page not provided), the review links pericyte deficiency to BBB leakage and microvascular degeneration, and describes blood-derived molecules entering the brain and suppressing capillary flow. In “Alzheimer’s disease” (page not provided), it links BBB dysfunction to impaired amyloid-β clearance. It does not identify pericyte inflammation as the initiating cause or say that neurons take up the leaked proteins; nor does it establish the claimed sequence in which all these effects lead to impaired clearance. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [87] Bell, 2012, Apolipoprotein E controls cerebrovascular integrity via cyclophilin A, Nature source

      The paper reports that activation of a proinflammatory pathway in pericytes of APOE4-expressing and Apoe-deficient mice leads to neuronal uptake of blood-derived neurotoxic proteins and reductions in microvasculature and cerebral blood flow (opening summary, page unavailable). It does not say that these changes subsequently impair amyloid-β clearance; clearance appears in the titles of works in its References, not as a finding establishing that sequence. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Convincing evidence suggests the APOE polymorphism is involved in development of Alzheimer disease, cerebral amyloid angiopathy, and traumatic brain injury.

    “Whereas there is convincing evidence to suggest that the APOE polymorphism is involved in development of Alzheimer disease, cerebral amyloid angiopathy as well as traumatic brain injury, the role of APOE has not been quite as clear for other subtypes of dementia or for other neurological diseases [100].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [100] Verghese, 2011, Apolipoprotein E in Alzheimer's disease and other neurological disorders, Lancet Neurol. source

      The Summary and Introduction support a strong association of APOE genotype with Alzheimer disease and cerebral amyloid angiopathy risk, and say associations with other neurological diseases are less clear. For traumatic brain injury, however, the Summary and Table 1 link APOE to outcome after injury, not to the development of the injury. (LLM, conf=0.90)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Studies of familial apoE deficiency describe persons examined in their 40s without neurological defects, although peripheral lipid metabolism was affected.

    “Finally, studies of familial apoE deficiency describe persons examined in their 40s without neurological defects, although the peripheral lipid metabolism was affected [27,97].”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [27] Mak, 2014, Effects of the absence of apolipoprotein e on lipoproteins, neurocognitive function, and retinal function, JAMA Neurol. source
    • cites [97] Lohse, 1992, Familial apolipoprotein E deficiency and type III hyperlipoproteinemia due to a premature stop codon in the apolipoprotein E gene, J. Lipid Res. source

  • May combine two claims.

    Premisecitation

    The APOE polymorphism affects risk of Alzheimer disease in a dose-dependent manner; the ε4 allele is associated with increased risk and the ε2 allele with decreased risk.

    “The APOE polymorphism affects risk of Alzheimer disease in a dose-dependent manner; the ε4 allele is associated with an increased risk and the ε2 allele is associated with a decreased risk [100].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [100] Verghese, 2011, Apolipoprotein E in Alzheimer's disease and other neurological disorders, Lancet Neurol. source

  • May combine two claims.

    Premisecitation

    Induction of murine Apoe expression improves amyloid-b clearance and cognition.

    “Additionally, induction of murine Apoe expression improves amyloid-b clearance and cognition; this finding also underlines the importance of the level of apoE [89].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [89] Cramer, 2012, ApoE-directed therapeutics rapidly clear beta-amyloid and reverse deficits in AD mouse models, Science source

  • May combine two claims.

    Premisecitation

    In vitro studies have shown that the apoA-II and apoE heterodimeric complex on HDL cholesterol modulates receptor affinity for the LDL receptor, and that LDL receptor affinity is dependent on available apoE, probably dependent on apoE isoform.

    “Previously, in vitro studies have shown that the apoA-II and apoE heterodimeric complex on HDL cholesterol modulates the receptor affinity for the LDL receptor, and that the LDL receptor affinity is dependent on available apoE, an affinity probably dependent on apoE isoform [124,125].”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [124] Weisgraber, 1978, Apoprotein (E–A-II) complex of human plasma lipoproteins. I. Characterization of this mixed disulfide and its identification in a high density lipoprotein subfraction, J. Biol. Chem. source

      Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured
    • cites [125] Innerarity, 1978, Apoprotein (E–A-II) complex of human plasma lipoproteins. II. Receptor binding activity of a high density lipoprotein subfraction modulated by the apo(E–A-II) complex, J. Biol. Chem. source

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

    Findingcitation

    In the CGPS and CCHS, APOE genotype frequencies were 0.7%, 12.4%, 2.9%, 55.8%, 25.4%, and 2.9% for ε22, ε32, ε42, ε33, ε43, and ε44, respectively.

    “In the Copenhagen General Population Study (CGPS) and the Copenhagen City Heart Study (CCHS), the APOE genotype frequencies were 0.7%, 12.4%, 2.9%, 55.8%, 25.4%, and 2.9% for ε22, ε32, ε42, ε33, ε43, and ε44, respectively [23].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [23] Rasmussen, 2015, Plasma levels of apolipoprotein E and risk of dementia in the general population, Ann. Neurol. source

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

    Premisecitation

    The mature apoE protein consists of 299 amino acids, and an 18-amino acid signal peptide is removed post-translationally.

    “The mature apoE protein consists of 299 amino acids and an 18amino acid signal peptide is removed post-translationally [17,28].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [17] Rall, 1982, Human apolipoprotein E. The complete amino acid sequence, J. Biol. Chem. source
    • cites [28] Weisgraber, 1994, Apolipoprotein E: structure-function relationships, Adv. Protein Chem. source

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

    Premisecitation

    The LDL receptor binding region is situated in helix four between amino acids 136 and 150.

    “The low density lipoprotein (LDL) receptor binding region is situated in helix four between amino acids 136 and 150 [17,28].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [17] Rall, 1982, Human apolipoprotein E. The complete amino acid sequence, J. Biol. Chem. source
    • cites [28] Weisgraber, 1994, Apolipoprotein E: structure-function relationships, Adv. Protein Chem. source

  • May combine two claims.

    Premisecitation

    Plasma levels of apoE and other lipids and lipoproteins are under strong genetic influence by the APOE polymorphism, and the ε4 allele is a strong genetic risk factor for Alzheimer disease.

    “Plasma levels of apoE and other lipids and lipoproteins are under strong genetic influence by the APOE polymorphism defining the three apoE isoforms, and the ε4 allele is a strong genetic risk factor for Alzheimer disease [18e25].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [18e25]

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

  • May combine two claims.

    Premisecitation

    Approximately half of plasma apoE is associated with triglyceride-rich lipoproteins, where apoE serves as the main ligand for the LDL receptor and LRP.

    “Approximately half of plasma apoE is associated with triglyceriderich lipoproteins, and apoE serves as the main ligand for the LDL receptor and LDL receptor Related Protein (LRP) [9,60,61].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [9] Mahley, 2001, Type III hyperlipoproteinemia (dysbetalipoproteinemia): the role of apolipoprotein E in normal and abnormal lipoprotein metabolism

      Not checked in the free run.

    • cites [60] Bersot, 1976, Interaction of swine lipoproteins with the low density lipoprotein receptor in human fibroblasts, J. Biol. Chem. source
    • cites [61] Havel, 2001, Introduction: structure and metabolism of plasma lipoproteins

      Not checked in the free run.

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

    Premisecitation

    The two APOE SNPs combine into six common APOE genotypes, ε22, ε32, ε42, ε33, ε43, and ε44, corresponding to six plasma apoE phenotypes.

    “The two genotypes combine into six common APOE genotypes, ε22, ε32, ε42, ε33, ε43 and ε44, corresponding to six plasma apoE phenotypes: apoE22, apoE32, apoE42, apoE33, apoE43 and apoE44 [14].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [14] Zannis, 1982, Proposed nomenclature of apoE isoproteins, apoE genotypes, and phenotypes, J. Lipid Res. source

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

    Premisecitation

    The APOE gene is located on chromosome 19 and consists of four exons.

    “The APOE gene is located on chromosome 19 and consists of four exons [28].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [28] Weisgraber, 1994, Apolipoprotein E: structure-function relationships, Adv. Protein Chem. source

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

    Premisecitation

    Human apoE has three isoforms, apoE2, apoE3, and apoE4, corresponding to three common alleles, ε2, ε3, and ε4, defined by two exonic SNPs, rs429358/ε4 and rs7412/ε2, in APOE.

    “Human apoE has three isoforms: apoE2, apoE3, and apoE4.Genetically, these isoforms correspond to three common alleles, ε2, ε3, and ε4, defined by two exonic single nucleotide polymorphisms (SNPs; rs429358/ε4, rs7412/ε2) in APOE [13,29].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [13] Zannis, 1981, Human apolipoprotein E isoprotein subclasses are genetically determined, Am. J. Hum. Genet.
    • cites [29] Zannis, 1981, Human very low density lipoprotein apolipoprotein E isoprotein polymorphism is explained by genetic variation and posttranslational modification, Biochemistry source

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

    Premisenone given

    Apolipoprotein E plays a pivotal role in lipoprotein metabolism in the brain and in the periphery and is implicated in both dementia and ischemic heart disease.

    “Apolipoprotein E (apoE) plays a pivotal role in lipoprotein metabolism in the brain and in the periphery, and is implicated both in dementia and ischemic heart disease.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    One percent of the inter-individual variation in plasma apoE levels was attributable to variation of age and sex in a sample of 563 blood-bank donors.

    “Boerwinkle and Utermann found that 1% of the inter-individual variation in plasma apoE levels was attributable to variation of age and sex in a sample of 563 blood-bank donors [20].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [20] Boerwinkle, 1988, Simultaneous effects of the apolipoprotein E polymorphism on apolipoprotein E, apolipoprotein B, and cholesterol metabolism, Am. J. Hum. Genet.

  • May combine two claims.

    Premisecitation

    The three common promoter SNPs as well as rare variation in APOE affect plasma levels of apoE.

    “Further, the mentioned three common promoter SNPs as well as rare variation in APOE affect plasma levels of apoE [23,51e53].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [23,51e53]

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

  • May combine two claims.

    Premisecitation

    Utermann et al. found that genotypes with the ε2 allele had the highest and those with the ε4 allele had the lowest average serum apoE levels.

    “Utermann et al. studied the association between levels of apoE in serum and the common APOE genotypes, and found that genotypes with the ε2 allele had highest and those with the ε4 allele had lowest average levels [20,43].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [20] Boerwinkle, 1988, Simultaneous effects of the apolipoprotein E polymorphism on apolipoprotein E, apolipoprotein B, and cholesterol metabolism, Am. J. Hum. Genet.
    • cites [43] Utermann, 1985, Apolipoprotein E mutants, hyperlipidemia and arteriosclerosis, Adv. Exp. Med. Biol. source

  • May combine two claims.

    Premisecitation

    Plasma levels of apoE are under strong genetic influence by the three common APOE alleles, ε2, ε3, and ε4, with stepwise decreases from ε22 to ε32 to ε42 to ε33 to ε43 to ε44 genotype.

    “Subsequently, it has been shown repeatedly that plasma levels of apoE are under strong genetic influence by the three common APOE alleles, ε2, ε3, and ε4 with stepwise decreases from ε22 to ε32 to ε42 to ε33 to ε43 to ε44 genotype [23,44e50].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [23,44e50]

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

  • May combine two claims.

    Premisecitation

    The ε2 allele is associated with lower levels of plasma cholesterol and LDL cholesterol and higher levels of triglycerides compared with the ε3 allele, whereas the ε4 allele is associated with higher levels of total cholesterol, LDL cholesterol, and triglycerides.

    “The ε2 allele is associated with lower levels of plasma cholesterol and LDL cholesterol and higher levels of triglycerides compared with the ε3 allele, whereas the ε4 allele is associated with higher levels of total cholesterol, LDL cholesterol and triglycerides [18,19].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [18] Bennet, 2007, Association of apolipoprotein E genotypes with lipid levels and coronary risk, JAMA source
    • cites [19] Sing, 1985, Role of the apolipoprotein E polymorphism in determining normal plasma lipid and lipoprotein variation, Am. J. Hum. Genet.

      Not checked in the free run.

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

    Premisecitation

    Plasma levels of apoE vary only slightly between the fasting and non-fasting state.

    “Plasma levels of apoE vary only slightly between the fasting and non-fasting state [64].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [64] Annuzzi, 1989, Concentrations of apolipoproteins B, C-I, C-II, C-III, E and lipids in serum and serum lipoproteins of normal subjects during alimentary lipaemia, Scand. J. Clin. Lab. Investig. source

  • May combine two claims.

    Premisecitation

    VLDL and IDL are cleared mainly by apoE interaction with the LDL receptor and LRP, whereas LDL is cleared via the LDL receptor by interaction with apoB100.

    “VLDL and IDL are cleared mainly by apoE interaction with the LDL receptor and LRP, whereas LDL is cleared via the LDL receptor by interaction with apoB100 [61].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [61] Havel, 2001, Introduction: structure and metabolism of plasma lipoproteins

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    ABCA1 regulates apoE levels and lipidation in the brain; in mice, ABCA1 deficiency leads to loss of apoE with residual apoE being poorly lipidated, whereas overexpression promotes apoE lipidation and reduces amyloid plaque formation.

    “ABCA1 regulates apoE levels and lipidation of apoE in the brain; in mice, deficiency of ABCA1 leads to loss of apoE with residual apoE being poorly lipidated; in contrast, overexpression of ABCA1 promotes apoE lipidation and reduces formation of amyloid plaques [73].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [73] Hirsch-Reinshagen, 2009, Why lipids are important for Alzheimer disease?, Mol. Cell Biochem. source

  • May combine two claims.

    Interpretationreasoning

    Increased content of apoE in apoB-containing lipoproteins has the potential to increase deposition in the arterial wall, resulting in increased atherosclerosis.

    “Therefore, increased content of apoE in apoB containing lipoproteins have the potential to increase the deposition in the arterial wall, resulting in increased atherosclerosis.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    Less than one in 20 individuals with the ε22 genotype will have overt type III hyperlipoproteinemia.

    “It is estimated that less than one in 20 individuals with the ε22 genotype will have overt type III hyperlipoproteinemia [24].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [24] Davignon, 1988, Apolipoprotein E polymorphism and atherosclerosis, Arteriosclerosis source

  • May combine two claims.

    Premisecitation

    In the general population, a loss-of-function mutation in ABCA1 is associated with low levels of apoE and increased risk of Alzheimer disease.

    “In the general population, a loss-of-function mutation in ABCA1 has been shown to be associated with low levels of apoE and increased risk of Alzheimer disease [79].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [79] Nordestgaard, 2015, Loss-of-function mutation in ABCA1 and risk of Alzheimer's disease and cerebrovascular disease, Alzheimers Dement. source

  • May combine two claims.

    Premisecitation

    The pattern of associations between the six common APOE genotypes and plasma lipid levels is similar across populations, although the magnitude differs between populations and subgroups, suggesting both context-dependent and invariant associations.

    “The pattern of associations between the six common APOE genotypes and plasma lipid levels is similar across populations, although the magnitude of the associations differs between populations and subgroups within populations; thus both context-dependent and invariant associations could be suggested [9,24,30].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [9] Mahley, 2001, Type III hyperlipoproteinemia (dysbetalipoproteinemia): the role of apolipoprotein E in normal and abnormal lipoprotein metabolism

      Not checked in the free run.

    • cites [24] Davignon, 1988, Apolipoprotein E polymorphism and atherosclerosis, Arteriosclerosis source
    • cites [30] Frikke-Schmidt, 2000, Context-dependent and invariant associations between APOE genotype and levels of lipoproteins and risk of ischemic heart disease: a review, Scand. J. Clin. Lab. Investig. Suppl.

  • May combine two claims.

    Premisecitation

    APOE ε22 homozygotes have a propensity to develop type III hyperlipoproteinemia, which can be triggered by secondary factors such as age, diabetes, hypothyroidism, and obesity.

    “APOE ε22 homozygotes have the propensity to develop type III hyperlipoproteinemia, which can be triggered by secondary factors such as age, diabetes, hypothyroidism and obesity [9,52].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [9] Mahley, 2001, Type III hyperlipoproteinemia (dysbetalipoproteinemia): the role of apolipoprotein E in normal and abnormal lipoprotein metabolism

      Not checked in the free run.

    • cites [52] Brewer, 1983, NIH conference. Type III hyperlipoproteinemia: diagnosis, molecular defects, pathology, and treatment, Ann. Intern Med. source

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

    Premisecitation

    Pericytes are important for the maintenance of the blood-brain barrier.

    “Pericytes are important for the maintenance of the bloodebrain barrier [96].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [96] Armulik, 2010, Pericytes regulate the blood-brain barrier, Nature source

  • May combine two claims.

    Premisecitation

    ApoE is involved in amyloid precursor protein processing and amyloid-beta production and deposition.

    “ApoE is involved in amyloid precursor protein processing and amyloid-b production and the deposition of amyloid-b [80e82].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [80e82]

      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). May combine two claims.

    Premisecitation

    The brain is the most cholesterol-rich organ in the body, containing ~25% of total body cholesterol.

    “The brain is the most cholesterol-rich organ in the body, containing ~25% of total body cholesterol [73].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [73] Hirsch-Reinshagen, 2009, Why lipids are important for Alzheimer disease?, Mol. Cell Biochem. source

  • May combine two claims.

    Premisecitation

    Triglyceride-rich lipoproteins are causally associated with risk of ischemic heart disease, and apoE plays a central role in their plasma clearance via receptor-mediated uptake by the liver.

    “Triglyceride-rich lipoproteins are causally associated with risk of ischemic heart disease and apoE plays a central role in their plasma clearance via receptor mediated uptake by the liver [9,59].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [9] Mahley, 2001, Type III hyperlipoproteinemia (dysbetalipoproteinemia): the role of apolipoprotein E in normal and abnormal lipoprotein metabolism

      Not checked in the free run.

    • cites [59] Nordestgaard, 2014, Triglycerides and cardiovascular disease, Lancet source

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

    Interpretationreasoning

    Deficiency of apoE in the preclinical state may affect neuronal regeneration and plasticity through decreased cholesterol and phospholipid cell supply.

    “Further, deficiency of apoE in the preclinical state may affect neuronal regeneration and plasticity through decreased cholesterol and phospholipid cell supply.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Some human studies of plasma or serum apoE found decreased levels in Alzheimer disease patients compared with controls, whereas other studies reported no differences.

    “Previously, some human studies of plasma or serum levels of apoE have found decreased levels in Alzheimer disease patients compared with control individuals, whereas other studies have reported that there was no differences [48e50, 103,104].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [48e50, 103,104]

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

  • May combine two claims.

    Interpretationreasoning

    Whether lack of murine Apoe is beneficial or detrimental for Alzheimer disease seems influenced by the mouse model studied, complicating interpretation from experimental animal models to the human situation.

    “Whether lack of murine Apoe is beneficial or detrimental for Alzheimer disease seems to be influenced by the mouse model studied, and this complicates the interpretation of results from experimental animal models to the human situation.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    In several meta-analyses, ε4 has been associated with a moderately increased risk of ischemic heart disease, whereas ε2 has been associated with reduced risk.

    “In several meta-analyses, ε4 has been associated with a moderately increased risk of ischemic heart disease, whereas ε2 has been associated with reduced risk [18,117e120].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [18,117e120]

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

  • May combine two claims.

    Interpretationreasoning

    Experimental and epidemiological data suggest that both decreased apoE levels and APOE genotype are involved in dementia, possibly via impaired amyloid-b clearance from the brain.

    “Taken together, experimental and epidemiological data suggest that both decreased apoE levels and APOE genotype are involved in dementia, possibly via impaired amyloid-b clearance from the brain.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Rare ε22 homozygotes have the propensity to develop type III hyperlipoproteinemia with an increased risk of atherosclerosis and premature cardiovascular disease.

    “Although the more frequent ε32 genotype is associated with a decreased risk of ischemic heart disease, rare ε22 homozygotes have the propensity to develop type III hyperlipoproteinemia with an increased risk of atherosclerosis and premature cardiovascular disease [9].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [9] Mahley, 2001, Type III hyperlipoproteinemia (dysbetalipoproteinemia): the role of apolipoprotein E in normal and abnormal lipoprotein metabolism

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    The characteristics of the APOE polymorphism suggest a qualitative importance of apoE both for risk of dementia and for risk of ischemic heart disease.

    “The characteristics of the APOE polymorphism suggest a qualitative importance of apoE both for risk of dementia and for risk of ischemic heart disease.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    The general population cohort of about 91,000 individuals covers ages from 20 to 100+ years and shows strong associations between all major lipids, lipoproteins and apolipoproteins and risk of ischemic heart disease.

    “In contrast, the general population cohort of ~91,000 individuals covers ages from 20 to 100þ years, and shows strong associations between all major lipids, lipoproteins and apolipoproteins and risk of ischemic heart disease [116].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [116] Rasmussen, 2016, Plasma levels of apolipoprotein E and risk of ischemic heart disease in the general population, Atherosclerosis source

  • May combine two claims.

    Interpretationreasoning

    The effects of plasma apoE on ischemic heart disease are more subtle than for dementia, and are possibly mediated by triglyceride-rich lipoproteins in accordance with the role of apoE in lipid metabolism.

    “The effects are, however, more subtle than for dementia, and are possibly mediated by triglyceride-rich lipoproteins in accordance with the role of apoE in lipid metabolism.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Both ε22 homozygosity and the ε4 allele are associated with ischemic heart disease, although the receptor affinity of these isoforms is very different.

    “Both ε22 homozygozity and the ε4 allele are associated with ischemic heart disease, although the receptor affinity of these isoforms is very different.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Low levels of apoE are associated with future risk of dementia, whereas high levels of apoE are associated with future risk of ischemic heart disease, indicating different mechanisms of disease.

    “Interestingly, low levels of apoE are associated with future risk of dementia, whereas high levels of apoE are associated with future risk of ischemic heart disease, indicating different mechanisms of disease.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    High plasma levels of apoE seem to be associated with increased risk of ischemic heart disease, an association possibly mediated by triglyceride-rich lipoproteins.

    “Taken together, high plasma levels of apoE seems to be associated with increased risk of ischemic heart disease, an association possibly mediated by triglyceride-rich lipoproteins [116].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [116] Rasmussen, 2016, Plasma levels of apolipoprotein E and risk of ischemic heart disease in the general population, Atherosclerosis source
56 of 56

  • The paper relies on this without support.

    Whether plasma levels of apoE are associated with increased risk of dementia and ischemic heart disease, and whether these associations are independent of the APOE polymorphism and of lipids and lipoproteins, has only recently been established.

    “Whether plasma levels of apoE are associated with increased risk of dementia and ischemic heart disease, and whether these associations are independent of the APOE polymorphism and of lipids and lipoproteins has only recently been established.”
1 of 1

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?

  • The ɛ4 allele has detrimental effects on production, deposition, and clearance of amyloid-β, phosphorylation of tau, neurotoxicity, mitochondrial dysfunction, and blood-brain barrier permeability.

    “The ɛ4 allele has detrimental effects on production, deposition, and clearance of amyloid-β, in phosphorylation of tau, in neurotoxicity, mitochondrial dysfunction, and in blood–brain barrier permeability.57,59,60”

    From Plasma levels of apolipoprotein E, <i>APOE</i> genotype, and all-cause and cause-specific mortality in 105 949 individuals from a white general population cohort (2019) · cites this paper as [60]

    Section 6 links apoE4 to tau phosphorylation, increased amyloid burden, direct toxicity, and blood–brain barrier breakdown. It also discusses amyloid-β production and clearance, neurotoxicity, and mitochondrial dysfunction, but attributes several of those effects to apoE generally rather than establishing a detrimental effect of the ε4 allele on each one. Page numbers are not provided in our copy. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • Both mass-spectrometry-based and immunoassay-based approaches have shown that plasma ApoE isoform quantification can discriminate ε4 carriers from non-carriers with high accuracy.

    “Both mass-spectrometry-based and immunoassay-based approaches have shown that plasma ApoE isoform quantification can discriminate ε4 carriers from non-carriers with high accuracy [16–18].”

    From Plasma ApoE proteotyping for ApoE ε4 stratification in the anti-amyloid therapies era (2026) · cites this paper as [18]

    The References section (page unavailable) lists a targeted mass-spectrometry assay for plasma ApoE4 and immunoassays for total ApoE concentration. Section 8 (page unavailable) discusses possible isoform-dependent bias in immunoassays. The review does not report that both approaches quantify plasma ApoE isoforms or distinguish ε4 carriers from non-carriers with high accuracy. (LLM, conf=0.78)

    Experimental — accuracy not yet measured

  • ApoE is a central apolipoprotein in cerebral cholesterol metabolism and is involved in brain amyloid metabolism, blood brain barrier integrity, and transport of various lipid species to neuronal cells.

    “apoE is a central apolipoprotein in cerebral cholesterol metabolism and is involved in brain amyloid metabolism, blood brain barrier integrity, and transport of various lipid species to neuronal cells [15][16][17][18][19].”

    From APOE and vascular disease: Sequencing and genotyping in general population cohorts (2023) · cites this paper as [19]

  • Plasma levels of apoE vary only slightly between the fasting and non-fasting state.

    “However, plasma levels of apoE vary only slightly between the fasting and non-fasting state.60,79”

    From Plasma levels of apolipoprotein E, <i>APOE</i> genotype, and all-cause and cause-specific mortality in 105 949 individuals from a white general population cohort (2019) · cites this paper as [60]

  • Earlier association studies of plasma ApoE level with Alzheimer's disease have reported inconsistent findings.

    “Earlier association studies of plasma ApoE level with AD have reported inconsistent findings [26–31]”

    From Genome-wide analysis identifies novel loci influencing plasma apolipoprotein E concentration and Alzheimer’s disease risk (2023) · cites this paper as [30]

Cites

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Authors
Rasmussen, K. L.
Affiliations
Herlev Hospital (DK)
Corresponding author
Rasmussen, Katrine Laura
ORCID
Rasmussen, Katrine Laura
Venue
Atherosclerosis
Publisher
Elsevier BV
Published
2016-12
Volume
255
Pages
145-155
ISSN
0021-9150 (ISSN-L)
DOI
10.1016/j.atherosclerosis.2016.10.037
OpenAlex
W2538539323
Semantic Scholar
e7c03178a5a28d575d81f22bf67525d67017350e
Cited by
125
References
129
Citations by year
2026: 14 · 2025: 17 · 2024: 9 · 2023: 14 · 2022: 17 · 2021: 21 · 2020: 11 · 2019: 13 · 2018: 7 · 2017: 2
FWCI
1.45
Type
journal article
Language
en
Open access
Licence
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations
  • Atherosclerosis (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Keywords
apolipoprotein E, APOE polymorphism, APOE ε4, dementia, ischemic heart disease, Alzheimer's disease, LDL receptor, LDL receptor-related protein, triglyceride-rich lipoproteins, lipoprotein metabolism, amyloid-beta clearance, genetic risk factors
MeSH terms
Adult, Aged, Aged, 80 and over, Animals, Apolipoproteins E, Brain, Dementia, Female, Humans, Liver, Male, Middle Aged, Phenotype, Polymorphism, Genetic, Protein Conformation, Risk Factors, Structure-Activity Relationship, Biomarkers, Myocardial Ischemia, Risk Assessment, Genetic Predisposition to Disease, Young Adult

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 2026-10-31.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-31.

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.

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