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Cited by 129Lipoproteins and Cardiovascular HealthParaoxonase enzyme and polymorphismsGenetic Associations and Epidemiology

ApoE Plasma Levels and Risk of Cardiovascular Mortality in Old Age

Open access
Mooijaart, Simon P, Berbée, Jimmy F. P, van Heemst, Diana, Havekes, Louis M, de Craen, Anton J. M, Slagboom, P. Eline, Rensen, Patrick C. N, Westendorp, Rudi G. J·2006·PLoS Medicine
DOI 10.1371/journal.pmed.0030176PMC PMC1457005
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Abstract

BACKGROUND: The epsilon2, epsilon3, and epsilon4 alleles of the apolipoprotein E gene (APOE) encode three isoforms, apoE2, E3, and E4, respectively. The apoE isoforms circulate in different plasma concentrations, but plasma concentrations of the same isoform also differ between individuals. Whereas the isoforms have been associated with cardiovascular disease, the relation between plasma apoE levels and cardiovascular disease is unknown. METHODS AND FINDINGS: We assessed APOE genotypes, plasma levels of apoE, cardiovascular risk factors, and mortality in a population-based sample of 546 individuals aged 85 y who participated in the Leiden 85-plus Study and were prospectively followed for specific causes of death for 5 y. Participants in the highest tertile of apoE levels suffered a twofold-increased risk of cardiovascular mortality (hazard ratio compared to lowest tertile, 2.08; 95% confidence interval [CI], 1.30 to 3.33). Among the 324 participants with the epsilon3epsilon3 genotype, the hazard from cardiovascular disease was threefold increased (highest versus lowest tertile 3.01; 95% CI 1.60 to 5.66), with similar estimates for men and women. Other causes of death were not increased significantly. Plasma levels of apoE in epsilon3epsilon3 participants were positively correlated with total cholesterol (p < 0.001), low-density lipoprotein cholesterol (p < 0.001) and triglycerides (p < 0.001) and negatively with high-density lipoprotein cholesterol levels (p = 0.010). Adjustment for plasma lipids did not change the hazard ratios, whereas interaction was absent. The risk associated with high levels of apoE, however, was strongest in participants from the lowest tertile of C-reactive protein (CRP) levels and absent in those from the highest tertile (p(interaction) < 0.001). Among participants from the lowest tertile of CRP levels, those with a high apoE levels had a significantly steeper increase in CRP than those with low apoE levels (p = 0.020). Similar cardiovascular mortality risks as in epsilon3epsilon3 participants were found in epsilon2 and epsilon4 carriers. CONCLUSIONS: In old age, high plasma apoE levels precede an increase of circulating CRP and strongly associates with cardiovascular mortality, independent of APOE genotype and plasma lipids.

AI snapshot

Written from the paper’s full text.

TL;DR

In a population-based cohort of 546 85-year-olds, high plasma apoE levels were associated with increased cardiovascular mortality, independent of APOE genotype and plasma lipids. High apoE also preceded rises in CRP, suggesting a proinflammatory pathway.

Key findings

  • In the total cohort, the highest apoE tertile had a 2.08-fold increased risk of cardiovascular mortality versus the lowest tertile (HR 2.08; 95% CI 1.30–3.33); intermediate levels had HR 1.74 (95% CI 1.09–2.79).
  • Among 324 participants with the ε3ε3 genotype, high apoE was associated with increased all-cause mortality (HR 2.05; 95% CI 1.39–3.02) and a threefold increased cardiovascular mortality risk (HR 3.01; 95% CI 1.60–5.66), with similar estimates in men (HR 2.89; 95% CI 1.13–7.36) and women (HR 2.96; 95% CI 1.27–6.90); other causes of death were not significantly increased.
  • In ε3ε3 participants, apoE levels correlated positively with total cholesterol, LDL cholesterol, and triglycerides (all p < 0.001) and negatively with HDL cholesterol (p = 0.010); adjustment for lipids did not change the mortality estimate (HR 3.09; 95% CI 1.55–6.15), and further adjustment for cardiovascular risk factors gave HR 3.20 (95% CI 1.56–6.59).
  • The cardiovascular mortality risk associated with high apoE was strongest in the lowest CRP tertile and absent in the highest tertile (p interaction < 0.001); in the lowest CRP stratum, high baseline apoE was associated with a steeper increase in CRP during follow-up (p = 0.020). Similar cardiovascular mortality risks were found in ε2 and ε4 carriers, and in the entire cohort with APOE genotype accounted for, high apoE had HR 3.45 (95% CI 1.98–6.02).

Methods

  • Prospective population-based follow-up within the Leiden 85-plus Study: 705 inhabitants reached age 85, 599 participated, 561 provided blood samples, and 546 were analyzed; there were no selection criteria on health or demographic characteristics. Follow-up was until 1 April 2004, mean 4.2 y, during which 274 of 546 participants died.
  • APOE genotypes were determined with TaqMan assays; plasma apoE was measured by a human apoE-specific sandwich ELISA in stored baseline samples; total cholesterol, HDL cholesterol, triglycerides, and CRP were measured on automated analyzers, with LDL cholesterol estimated by the Friedewald equation; causes of death were classified by ICD-10 codes.
  • Mortality risks were estimated with Cox proportional hazards models adjusted for gender; baseline comparisons used sex-adjusted linear regression or linear mixed models, and prospective CRP analysis used a linear mixed model adjusting for gender.

Limitations

  • Stated by the paper: blood samples were not fasting, which could add random error; CRP was not measured with high-sensitivity methods; few participants were on lipid-lowering medication because of Dutch prescribing policy at enrollment; findings cannot be directly extrapolated to nonfatal cardiovascular disease or beyond this age group; participants were survivors of their birth cohort; and stored plasma shifts apoE between lipoproteins, while many participants had died, preventing subclass fractionation.
  • Evident from the observational cohort design: causality cannot be established, although the paper interprets high apoE as a possible causal factor; residual confounding cannot be excluded despite adjustment for lipids and other cardiovascular risk factors.

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

Integrity signals

Registry

Crossref · 10.1371/journal.pmed.0030176

Cites

45 of 45 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

5 of 27 cited sources checked · 3 supported · 0 flagged · accuracy not yet measured

  • Premisecitation

    The APOE ɛ2/ɛ3/ɛ4 genotype is only a minor determinant of plasma apoE levels.

    “the APOE ɛ2/ɛ3/ɛ4 genotype is only a minor determinant of these levels [ 8, 40]”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [8] Neale, 2000, Genet Epidemiol source
    • cites [40] Beekman, 2004, Genet Epidemiol source

      The indexed Abstract reports that the APOE ε2/ε3/ε4 polymorphism was strongly associated with plasma apoE levels in two Dutch twin cohorts. It does not establish that the genotype is only a minor determinant of those levels; strength of association alone does not quantify its contribution to variation in levels. (LLM, conf=0.78)

      Experimental — accuracy not yet measured
  • Findingown data

    The effect of apoE on cardiovascular mortality is independent of lipid levels.

    “because we found in our analysis that the effect of apoE on cardiovascular mortality is independent of lipid levels”
    Quote in the paperSubstantial claim
  • Findingown data

    The association between high baseline apoE and higher increases in CRP during follow-up was absent in ɛ2 carriers (p = 0.76).

    “A similar association was observed in ɛ4 carriers ( p = 0.041), but was absent in ɛ2 carriers ( p = 0.76).”
    Quote in the paperNot a substantial claim
  • Findingown data

    The cardiovascular mortality risk associated with high levels of apoE was higher in participants who did not have a history of myocardial infarction compared to those who did.

    “As the cardiovascular mortality risk associated with high levels of apoE was even higher in participants who did not have a history of myocardial infarction compared to those who did”
    Quote in the paperSubstantial claim
  • Findingown data

    Triglyceride levels do not contribute to the association of apoE levels with cardiovascular disease mortality.

    “triglyceride levels do not contribute to the association of levels of apoE with cardiovascular disease mortality, as stratification and correction for triglyceride levels did not alter the effect of apoE levels on cardiovascular disease mortality.”
    Quote in the paperSubstantial claim
  • Classified as probably not a substantial claim. 21
  • May combine two claims. 29
  • The quote only partly states this claim. 2

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

    Premisecitation

    Irrespective of APOE genotype, plasma apoE levels are associated with cholesterol levels.

    “Irrespective of APOE genotype, plasma apoE levels are also associated with cholesterol levels [ 9, 10].”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [9] Boerwinkle, 1988, Am J Hum Genet

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

    • cites [10] Haddy, 2002, Eur J Hum Genet source

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

    Premisecitation

    ApoE was involved in the direct binding of lipopolysaccharide, thereby decreasing the inflammatory response to lipopolysaccharide.

    “apoE was involved in the direct binding of lipopolysaccharide, the main toxic component of gram-negative bacteria [ 36], thereby decreasing the inflammatory response to lipopolysaccharide [ 37].”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [36] Rensen, 1997, J Clin Invest source

      The Discussion (page unavailable) reports that apoE binds LPS and redirects it away from Kupffer cells in rats. The Introduction says lipoproteins reduced TNF and inhibited cytokine production, but the paper only suspects apoE is responsible for their protective effect; it does not directly demonstrate that apoE decreases the inflammatory response. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
    • cites [37] Van Oosten, 2001, J Biol Chem source

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

    Premisecitation

    ApoE4 binds to lipid particles with higher affinity than does apoE3 and shows preference for VLDL, whereas apoE2 and apoE3 mainly bind to HDL.

    “ApoE4 binds to lipid particles with higher affinity than does apoE3 and shows preference for VLDL, whereas apoE2 and apoE3 mainly bind to HDL [ 42].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [42] Saito, 2003, J Biol Chem source

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

    Premisecitation

    Plasma apoE levels are highly dependent on heritable factors.

    “Plasma apoE levels are highly dependent on heritable factors [ 3, 24, 25]”
    Quote in the paperNot a substantial claim1 of 3 sources checked
    • cites [3] Smit, 1988, Hum Genet source
    • cites [24] Beekman, 2002, Twin Res source
    • cites [25] Siest, 1995, Clin Chem source

  • May combine two claims.

    Findingown data

    At baseline, ɛ3ɛ3 participants with high apoE had significantly higher CRP levels than those with intermediate and low levels (p trend < 0.001), and adjustment for sex and lipids did not alter the association.

    “At baseline, ɛ3ɛ3 participants with high levels of apoE had significantly higher levels of CRP than those with intermediate and low levels ( p trend < 0.001), and adjustment for sex and lipids did not alter the association ( p trend < 0.001).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The risk of cardiovascular mortality associated with high apoE was similar in all tertiles of LDL cholesterol, HDL cholesterol, and triglycerides, with no significant interaction (all p interaction > 0.6).

    “We found that the risk associated with high level of apoE was similar in all tertiles of LDL and HDL cholesterol and triglycerides.”
    • Also stated in: § Association of Plasma ApoE Levels with Lipid Levels at Baseline and Relationship of Cardiovascular Mortality Risk Associated with Plasma ApoE and Lipid Levels · plain
      “Formal testing for interactions showed that there was no significant interaction between the risk of cardiovascular mortality associated with apoE and these lipids (all p interaction > 0.6).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    High baseline apoE levels correlate with higher increases in CRP during follow-up (p = 0.024), and adjusting for classical cardiovascular risk factors did not change the association (p = 0.020).

    “We found that high levels of apoE at baseline correlate with higher increases in levels of CRP during follow-up ( p = 0.024). Adjusting for classical cardiovascular risk factors did not change the observed association ( p = 0.020).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In the study population, ɛ4 carriers had lower plasma apoE levels and higher LDL and total cholesterol than non-carriers.

    “In brief, participants who were carriers of the ɛ2 allele had significantly higher plasma levels of apoE and lower levels of LDL cholesterol and total cholesterol, whereas carriers of the ɛ4 allele had lower levels of plasma apoE and higher levels of LDL and total cholesterol ( Table 2).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    In the study, the association of apoE levels with cardiovascular disease was strongest in participants with low levels of CRP, and in these persons high levels of apoE preceded an increase in CRP.

    “In our study, the association of apoE levels with cardiovascular disease was strongest in participants with low levels of CRP, and in these persons high levels of apoE preceded an increase in CRP.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In the study population, ɛ2 carriers had significantly higher plasma apoE levels and lower LDL cholesterol and total cholesterol than non-carriers.

    “In brief, participants who were carriers of the ɛ2 allele had significantly higher plasma levels of apoE and lower levels of LDL cholesterol and total cholesterol, whereas carriers of the ɛ4 allele had lower levels of plasma apoE and higher levels of LDL and total cholesterol ( Table 2).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Levels of HDL cholesterol, triglycerides, and circulating CRP did not differ between the various APOE genotypes.

    “Levels of HDL cholesterol, triglycerides, and circulating CRP did not differ between the various genotypes.”
    Quote in the paperNot a substantial claim

  • The quote only partly states this claim.

    Findingown data

    In ɛ3ɛ3 participants, after adjustment for LDL and HDL cholesterol and triglycerides, high apoE remained associated with cardiovascular mortality (HR 3.09; 95% CI 1.55-6.15).

    “Participants with high levels of apoE had mortality risks similar to those in the crude model (hazard ratio, 3.09; 95% CI, 1.55 to 6.15).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    High plasma apoE levels precede chronic inflammation and cardiovascular mortality risk.

    “we now show that high plasma apoE levels precede chronic inflammation (of which circulating levels of CRP are a marker [ 35]) and cardiovascular mortality risk.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The risk of cardiovascular mortality associated with high apoE was strongest in participants in the lowest tertile of CRP and absent in those in the highest tertile (p interaction < 0.001).

    “The risk associated with high levels of apoE, however, was strongest in participants from the lowest tertile of C-reactive protein (CRP) levels and absent in those from the highest tertile ( p interaction < 0.001).”
    • Also stated in: § Association of Plasma ApoE Level and Increase in CRP Level during Follow-Up · plain
      “The cardiovascular mortality risk associated with high levels of apoE was dependent on level of CRP ( Table 5), as it was highest in participants with low levels of CRP and absent in those with high levels of CRP ( p interaction < 0.001).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Compared to ɛ3ɛ3 participants, cardiovascular mortality was lower in ɛ2ɛ3 and ɛ2ɛ4 carriers and higher in ɛ2ɛ2, ɛ3ɛ4, and ɛ4ɛ4 carriers, but none of the differences were statistically significant.

    “Compared to ɛ3ɛ3 participants, cardiovascular mortality was lower in ɛ2ɛ3 and ɛ2ɛ4 carriers, and higher in ɛ2ɛ2, ɛ3ɛ4, and ɛ4ɛ4 carriers, although none of the differences are statistically significant, possibly due to small numbers.”
    Quote in the paperNot a substantial claim

  • The quote only partly states this claim.

    Findingown data

    In ɛ3ɛ3 participants, further adjustment for hypertension, diabetes, BMI, and smoking did not change the association between high apoE and cardiovascular mortality (HR 3.20; 95% CI 1.56-6.59).

    “Further adjustment for the cardiovascular risk factors hypertension, diabetes, BMI, and smoking did not change the estimate (hazard ratio, 3.20; 95% CI, 1.56 to 6.59).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Adjustment for plasma lipids did not change the hazard ratios for the association between high apoE and cardiovascular mortality, and no interaction was present.

    “Adjustment for plasma lipids did not change the hazard ratios, whereas interaction was absent.”
    • Also stated in: § Association of Plasma ApoE Levels with Lipid Levels at Baseline and Relationship of Cardiovascular Mortality Risk Associated with Plasma ApoE and Lipid Levels · plain
      “Participants with high levels of apoE had mortality risks similar to those in the crude model (hazard ratio, 3.09; 95% CI, 1.55 to 6.15).”
    Quote in the paperSubstantial claim

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

    Findingown data

    APOE genotypes associate with plasma levels of apoE.

    “We found, as in other (younger) study populations, that APOE genotypes associate with plasma levels of apoE.”
    Quote in the paperNot a substantial claim

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

    Findingnone given

    In the study population, apoE level associates with levels of total cholesterol, HDL cholesterol, LDL cholesterol, and triglycerides.

    “In our study population, as in other (younger) populations, apoE level associates with levels of total cholesterol, HDL cholesterol, LDL cholesterol, and triglycerides.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    In this age group, the number of participants with levels of CRP below the detection limit of the assay was relatively small (102 out of 563 participants), and the variation in CRP levels was considerable.

    “in this age group the number of participants with levels of CRP below the detection limit of the assay was relatively small (102 out of 563 participants), and the variation in CRP levels was considerable.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    In old age, high plasma apoE levels precede an increase of circulating CRP and strongly associate with cardiovascular mortality, independent of APOE genotype and plasma lipids.

    “In old age, high plasma apoE levels precede an increase of circulating CRP and strongly associates with cardiovascular mortality, independent of APOE genotype and plasma lipids.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    The APOE gene influences lipid metabolism and disease risk.

    “The apolipoprotein E (APOE) gene influences lipid metabolism and disease risk.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [1] Mahley, 1999, J Lipid Res source

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

    Premisecitation

    ApoE2 exhibits lower affinity for the LDL receptor, resulting in slower clearance of apoE and higher plasma apoE levels.

    “ApoE2 exhibits lower affinity for the LDL receptor, resulting in slower clearance of apoE and higher plasma apoE levels [ 3, 4].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [3] Smit, 1988, Hum Genet source
    • cites [4] Utermann, 1979, Clin Genet source

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

    Premisecitation

    ApoE4 is cleared more efficiently, resulting in lower apoE levels and higher cholesterol levels.

    “Conversely, apoE4 is cleared more efficiently, resulting in lower apoE levels and higher cholesterol levels [ 3, 4].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [3] Smit, 1988, Hum Genet source
    • cites [4] Utermann, 1979, Clin Genet source

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

    Premisecitation

    ApoE is the main ligand for clearance of VLDLs and chylomicron remnants, and affects circulating concentrations of lipoproteins and plasma levels of cholesterol and triglycerides.

    “ApoE is the main ligand for clearance of VLDLs and chylomicron remnants, and as such affects circulating concentrations of lipoproteins and plasma levels of cholesterol and triglycerides [ 1].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [1] Mahley, 1999, J Lipid Res source

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

    Premisecitation

    ApoE mediates the presentation of lipid antigens to the immune system and influences the inflammatory process.

    “Moreover, it was shown recently that apoE mediates the presentation of lipid antigens to the immune system and in this way influences the inflammatory process [ 11].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [11] van den Elzen, 2005, Nature source

  • May combine two claims.

    Premisecitation

    Plasma apoE levels are only partially explained by the ɛ2/ɛ3/ɛ4 polymorphism, and plasma apoE levels vary between individuals with the same APOE genotype.

    “Plasma apoE levels are only partially explained by the ɛ2/ɛ3/ɛ4 polymorphism [ 8], and plasma apoE levels vary between individuals with the same APOE genotype.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [8] Neale, 2000, Genet Epidemiol source

  • May combine two claims.

    Interpretationreasoning

    In old age, high plasma apoE levels associate better with a proinflammatory response and/or detrimental lipoprotein profile than with the antiatherosclerotic effect of apoE expression in macrophages.

    “we interpret these findings to suggest that, in old age, high plasma apoE levels associate better with a proinflammatory response and/or detrimental lipoprotein profile than with the antiatherosclerotic effect of apoE expression in macrophages.”
    Quote in the paperSubstantial claim
    • The authors state this as an assumption: High plasma levels of apoE in combination with increased lipid-antigen presentation lead to chronic inflammation and thus may contribute to atherosclerosis.

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

    Premisecitation

    ApoE2 has lower receptor binding affinity than apoE3 and apoE4.

    “ApoE2 has lower receptor binding affinity than apoE3 and apoE4 [ 41].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [41] Lund-Katz, 2001, J Lipid Res source

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

    Premisecitation

    LDL cholesterol is no longer a cardiovascular risk factor in old age.

    “For instance, LDL cholesterol is no longer a cardiovascular risk factor [ 38].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [38] Shepherd, 2002, Lancet source

  • May combine two claims.

    Study design and conductreasoning

    The finding cannot directly be extrapolated to the incidence of nonfatal cardiovascular disease, and not beyond this age group.

    “A limitation of our study is that this finding cannot directly be extrapolated to the incidence of nonfatal cardiovascular disease, and not beyond this age group.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductcitation

    The participants were survivors of their birth cohort, and biology in old age may be different from that in other age groups, which may prevent extrapolation of the results to the population at large.

    “The participants of this study were the survivors of their birth cohort, and earlier studies in people of over 70 y of age have shown that biology in old age may be different from that in other age groups, which may prevent extrapolation of the results to the population at large.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    High plasma apoE levels are an early and specific indicator of cardiovascular disease risk and drive a proinflammatory response.

    “We interpret these results to indicate that high plasma apoE levels are an early and specific indicator of cardiovascular disease risk and drive a proinflammatory response.”
    Quote in the paperSubstantial claim
    • The authors state this as an assumption: High plasma levels of apoE in combination with increased lipid-antigen presentation lead to chronic inflammation and thus may contribute to atherosclerosis.

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    The current study was performed in a population-based sample of 85-y-olds.

    “The current study was performed in a population-based sample of 85-y-olds.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Levels of apoE may indicate a detrimental lipoprotein profile and/or a proinflammatory response, which both contribute to cardiovascular mortality.

    “We conclude that levels of apoE may indicate a detrimental lipoprotein profile and/or a proinflammatory response, which both contribute to cardiovascular mortality.”
    Quote in the paperSubstantial claim
    • The authors state this as an assumption: High plasma levels of apoE in combination with increased lipid-antigen presentation lead to chronic inflammation and thus may contribute to atherosclerosis.

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

    Study design and conductnone given

    Blood samples were not drawn fasting, which could add to the random error of the measurement of triglycerides, apoE, and CRP.

    “Blood samples were not drawn fasting, which could add to the random error of the measurement of triglycerides, apoE, and CRP.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    In old age, only levels of HDL cholesterol, but not total cholesterol, LDL cholesterol, and triglycerides, affect cardiovascular disease risk.

    “In contrast, in old age, only levels of HDL cholesterol, but not of total cholesterol, LDL cholesterol, and triglycerides, affect cardiovascular disease risk [ 12, 32, 38, 39].”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [12] Weverling-Rijnsburger, 2003, Arch Intern Med source
    • cites [32] Weverling-Rijnsburger, 1997, Lancet source
    • cites [38] Shepherd, 2002, Lancet source
    • cites [39] Packard, 2005, Circulation source

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

    Premisecitation

    Lipid-lowering medication (pravastatin) protects individuals from coronary artery disease at least up to the age of 82.

    “The PROSPER study, in part carried out in the same region as the current study, showed that lipid-lowering medication (in this case pravastatin) protects individuals from coronary artery disease at least up to the age of 82 [ 38].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [38] Shepherd, 2002, Lancet source

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

    Premisecitation

    The ɛ4 allele has been associated with an increased risk of cardiovascular disease in a meta-analysis of studies up to 1996.

    “the ɛ4 allele has been associated with an increased risk of cardiovascular disease in a meta-analysis of studies up to 1996 [ 43].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [43] Wilson, 1996, Arterioscler Thromb Vasc Biol source

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

    Study design and conductnone given

    The data come from a population-based study without inclusion criteria based on health and demographic characteristics.

    “Moreover, the data come from a population-based study without inclusion criteria based on health and demographic characteristics.”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    CRP levels were not measured with high-sensitivity methods.

    “CRP levels were not measured with high-sensitivity methods.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing), S4 (based).

    Interpretationreasoning

    The pathways that neutralize endogenous and exogenous stimuli may be different.

    “However, the pathways that neutralize endogenous and exogenous stimuli may be different.”
    Quote in the paperNot a substantial claim
    • The authors state this as an assumption: ApoE has a pleiotropic effect, with different pathways neutralizing endogenous and exogenous stimuli.
42 of 42

  • The paper relies on this without support.

    The relation between plasma apoE levels and cardiovascular disease risk has not been reported.

    “Whereas the isoforms have been associated with cardiovascular disease, the relation between plasma apoE levels and cardiovascular disease is unknown.”
    “Both lipids and inflammation are involved in the pathogenesis of atherosclerosis, but the relation of plasma apoE levels and cardiovascular disease risk has not yet been reported.”

  • The authors state this as an assumption.

    High plasma levels of apoE in combination with increased lipid-antigen presentation lead to chronic inflammation and thus may contribute to atherosclerosis.

    “In this model, high plasma levels of apoE in combination with increased lipid-antigen presentation lead to chronic inflammation and thus may contribute to atherosclerosis.”

  • The authors state this as an assumption.

    ApoE has a pleiotropic effect, with different pathways neutralizing endogenous and exogenous stimuli.

    “It is logical to assume such a pleiotropic effect, since genes regulating the inflammatory host response are under balanced evolutionary selection pressure.”

  • The paper relies on this without support.

    The concomitant inflammatory response adequately eliminates the lipid antigen from the circulation.

    “The concomitant inflammatory response adequately eliminates the lipid antigen from the circulation.”
4 of 4

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?

  • 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].”

    From Plasma levels of apolipoprotein E, APOE genotype and risk of dementia and ischemic heart disease: A review (2016) · cites this paper as [44]

    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

  • A possible explanation for the independence of plasma lipids in the 546 elderly study may be that it only included individuals at age 85 at baseline, an age range shown not to reproduce the strong risk association between plasma lipids and cardiovascular disease.

    “A possible explanation for the independence of plasma lipids in the study of 546 elderly individuals may be that the study only included individuals at the age of 85 years at baseline, an age-range shown not to reproduce the well-known strong risk association between plasma lipids and”

    From Plasma levels of apolipoprotein E, APOE genotype and risk of dementia and ischemic heart disease: A review (2016) · cites this paper as [44]

    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

  • In a population-based study of 546 elderly individuals followed for 5 years, high plasma levels of apoE were associated with increased cardiovascular mortality in both genders, independently of APOE genotype and plasma levels of triglycerides, LDL cholesterol and HDL cholesterol.

    “In a population-based study of 546 elderly individuals, prospectively followed for specific causes of death for 5 years, high plasma levels of apoE were associated with increased cardiovascular mortality in both genders, independently of APOE genotype and plasma levels of triglycerides, LDL cholesterol and HDL cholesterol [44].”

    From Plasma levels of apolipoprotein E, APOE genotype and risk of dementia and ischemic heart disease: A review (2016) · cites this paper as [44]

  • A few studies have addressed the association between plasma apoE and cardiovascular mortality.

    “A few studies have addressed the association between plasma apoE and cardiovascular mortality.26,27”

    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 [26]

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.

  • Conflicting publication year for the PROSPER study

    Minor

    The discussion says the PROSPER results were published in 2003, but its cited reference lists the publication year as 2002.

1 of 1

Cites

Flagged first, then by citations

Research works printed but not linked: 3

  1. Boerwinkle, 1988, Am J Hum Genet, 42, 104
  2. Larkin, 2000, Int J Mol Med, 6, 253
  3. O'Brien, 1994, Am J Pathol, 144, 538

Cited by

Sorted by citations

Related

Authors
Mooijaart, S. P., Berbée, J. F. P., van Heemst, D., Havekes, L. M., de Craen, A. J. M., Slagboom, P. E., Rensen, P. C. N., & Westendorp, R. G. J.
Affiliations
  • Leiden University Medical Center (NL)
  • Netherlands Organisation for Applied Scientific Research (NL)
Corresponding author
Mooijaart, Simon P
ORCID
Venue
PLoS Medicine
Publisher
Public Library of Science (PLoS)
Published
2006-05-09
Volume
3
Issue
6
Pages
e176
ISSN
  • 1549-1277 (ISSN-L)
  • 1549-1676
DOI
10.1371/journal.pmed.0030176
PMC
PMC1457005
OpenAlex
W2100023507
Semantic Scholar
e38d2cf5153b44a1e1d83065e58f7cde32a54da8
Cited by
129
References
44
Citations by year
2026: 4 · 2025: 3 · 2024: 4 · 2023: 2 · 2022: 7 · 2021: 7 · 2020: 1 · 2019: 10 · 2018: 5 · 2017: 9 · 2016: 6 · 2015: 9 · 2014: 5 · 2013: 9 · 2012: 7
FWCI
8.16
Type
journal article
Language
en
Open access
Licence
Locations
  • PLoS Medicine (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • TNO Repository (submittedVersion)
  • Repository hosted by TU Delft Library (TU Delft) (submittedVersion)
  • Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
Funders
  • Universiteit Leiden
  • Nederlandse Organisatie voor Wetenschappelijk Onderzoek (917.36.351, 014-90-001)
  • Leids Universitair Medisch Centrum
Topics
  • Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Paraoxonase enzyme and polymorphisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
Keywords
apolipoprotein E, cardiovascular mortality, APOE genotype, APOE ε3, APOE ε4, APOE ε2, C-reactive protein, cardiovascular risk factors, plasma lipids, older adults, Leiden 85-plus Study, cardiovascular risk, genetic polymorphism, triglycerides, LDL cholesterol, HDL cholesterol
MeSH terms
Age Factors, Aged, 80 and over, Apolipoproteins E, C-Reactive Protein, Cardiovascular Diseases, Female, Follow-Up Studies, Genotype, Humans, Lipids, Male, Risk Factors, Survival Rate, Proportional Hazards Models, Protein Isoforms

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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