Plasma levels of apolipoprotein E, APOE genotype, and all-cause and cause-specific mortality in 105 949 individuals from a white general population cohort
Open accessAbstract
Aims: To determine whether plasma apoE levels and APOE genotype are associated with all-cause and cause-specific mortality. Methods and results: Using a prospective cohort design with 105 949 white individuals from the general population, we tested the association between plasma apoE at study enrolment and death during follow-up, and whether this was independent of APOE genotype. We confirmed the well-known association between APOE genotypes and mortality. For all-cause, cardiovascular, and cancer mortality, high levels of apoE were associated with increased risk, while for dementia-associated mortality low levels were associated with increased risk. For the highest vs. the fifth septile of plasma apoE, hazard ratios (HRs) were 1.20 (95% confidence interval 1.12–1.28) for all-cause mortality, 1.28 (1.13–1.44) for cardiovascular mortality, and 1.18 (1.05–1.32) for cancer mortality. Conversely, for the lowest vs. the fifth septile the HR was 1.44 (1.01–2.05) for dementia-associated mortality. Results were similar in analyses restricted to APOE ɛ33 carriers. Examining genetically determined plasma apoE, a 1 mg/dL increase conferred risk ratios of 0.97 (0.92–1.03) for cardiovascular mortality and 1.01 (0.95–1.06) for cancer mortality, while a 1 mg/dL decrease conferred a risk ratio of 1.70 (1.36–2.12) for dementia-associated mortality. Conclusion: High plasma levels of apoE were associated with increased all-cause, cardiovascular, and cancer mortality, however of a non-causal nature, while low levels were causally associated with increased dementia-associated mortality.
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Written from the paper’s full text.
TL;DR
In 105,949 white Danish general-population individuals, high plasma apoE levels were associated with increased all-cause, cardiovascular, and cancer mortality, but Mendelian randomization suggested these associations were non-causal. Low plasma apoE levels were causally associated with increased dementia-associated mortality.
Key findings
- APOE genotype was associated with mortality: median survival decreased from 86.9 years in ε32 carriers to 83.7 years in ε44 carriers; all-cause mortality HRs vs ε33 were 1.10 (1.06–1.14) for ε43 and 1.43 (1.29–1.58) for ε44.
- For the highest vs the fifth septile of plasma apoE, HRs were 1.20 (1.12–1.28) for all-cause mortality, 1.28 (1.13–1.44) for cardiovascular mortality, and 1.18 (1.05–1.32) for cancer mortality; patterns were similar in analyses restricted to APOE ε33 carriers.
- For the lowest vs the fifth septile of plasma apoE, the HR was 1.44 (1.01–2.05) for dementia-associated mortality.
- Genetically determined plasma apoE: a 1 mg/dL increase gave risk ratios of 0.97 (0.92–1.03) for cardiovascular mortality and 1.01 (0.95–1.06) for cancer mortality, while a 1 mg/dL decrease gave a risk ratio of 1.70 (1.36–2.12) for dementia-associated mortality.
Methods
- Prospective cohort study combining the Copenhagen General Population Study and Copenhagen City Heart Study: 105,949 white individuals of Danish descent, with 13,693 deaths during median 8.5 years of follow-up (range 0–25 years) and no losses to follow-up.
- Plasma apoE was measured in 104,153 individuals; all 105,949 were APOE genotyped, and three APOE promoter variants were genotyped in 74,560 individuals.
- Cox regression models adjusted for age, sex, BMI, smoking, hypertension, diabetes, lipid-lowering therapy, alcohol consumption, physical inactivity, education, postmenopausal status, hormonal replacement therapy, LDL cholesterol, HDL cholesterol, and triglycerides, with further adjustment for APOE genotype or restriction to ε33 carriers; restricted cubic splines and septiles were used, plus Mendelian randomization instrumental-variable analyses.
Limitations
- The paper states that diagnostic information availability/completeness is a potential limitation, although Danish registry dementia, myocardial infarction, and cancer diagnoses have high validity; unregistered contributing causes of death would bias toward the null.
- The paper states that blood samples were not drawn fasting, which could add random measurement error, and that generalizability is limited because only white individuals were studied.
- The paper also cautions that Mendelian randomization for peripheral apoE effects should be interpreted cautiously because APOE variants affect many lipid, lipoprotein, and apolipoprotein traits (vertical pleiotropy), though multivariable instrumental-variable and sensitivity analyses did not change conclusions. Evident from the text: 1,839 of 13,693 deaths could not be classified by cause because the Danish Causes of Death Registry lagged the Civil Registration System, so cause-specific follow-up was truncated.
Model-written summary. Check it against the paper before relying on it.
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Cites
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Claims the paper makes
26 of 63 cited sources checked · 13 supported · 2 flagged · accuracy not yet measured
- Premisecitation
In mice, overexpression of apoE leads to hypertriglyceridaemia.
“In mice, overexpression of apoE has been shown to lead to hypertriglyceridaemia”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [42] Huang, 1998, Overexpression and accumulation of apolipoprotein E as a cause of hypertriglyceridemia, J Biol Chem source
- Premisecitation
In vitro, increased apoE expression by hepatoma cells correlates with increased very low-density lipoprotein synthesis and/or secretion irrespective of apoE isoform.
“in vitro increase in apoE expression by hepatoma cells correlates with increased very low-density lipoprotein synthesis and/or secretion irrespective of apoE isoform.42”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [42] Huang, 1998, Overexpression and accumulation of apolipoprotein E as a cause of hypertriglyceridemia, J Biol Chem source
- Premisecitation
Hypertriglyceridaemic patients have higher plasma levels of apoE compared with normal control subjects.
“Hypertriglyceridaemic patients have higher plasma levels of apoE compared with normal control subjects”
Quote in the paperNot a substantial claim1 of 2 sources checked - Premisecitation
Human liver transplantation studies clearly showed that apoE in the peripheral circulation and in the central nervous system originates from two separate compartments.
“Human liver transplantation studies clearly showed that apoE in the peripheral circulation and in the central nervous system originates from two separate compartments.61”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [61] Linton, 1991, Phenotypes of apolipoprotein B and apolipoprotein E after liver transplantation, J Clin Invest source
- Premisecitation
ApoE in blood and brain are regulated independently.
“suggesting that apoE in blood and brain are regulated independently.61,63”
Quote in the paperSubstantial claim1 of 2 sources checked
- Premisecitation
In murine interstitial fluid, a similar genotype-dependent pattern as in cerebrospinal fluid was observed.
“and in murine interstitial fluid a similar genotype-dependent pattern as in cerebrospinal fluid was observed.65”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [65] Ulrich, 2013, In vivo measurement of apolipoprotein E from the brain interstitial fluid using microdialysis, Mol Neurodegener source
- Premisecitation
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”
Quote in the paperSubstantial claim1 of 2 sources checked- cites [60] Rasmussen, 2016, Plasma levels of apolipoprotein E, APOE genotype and risk of dementia and ischemic heart disease: a review, Atherosclerosis source
- cites [79] 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 Invest source
- Findingown data
Plasma apoE decreased from ε22 to ε32 to ε42 to ε33 to ε43 to ε44 (P for trend ≤ 2 × 10−76).
“For the six APOE genotypes, total cholesterol, LDL cholesterol, and apolipoprotein B increased from ɛ22 to ɛ32 to ɛ42 to ɛ33 to ɛ43 to ɛ44 (P for trends < 1 × 10−300), whereas plasma apoE, high-density lipoprotein (HDL) cholesterol, and apolipoprotein AI levels decreased from ɛ22 to ɛ32 to ɛ42 to ɛ33 to ɛ43 to ɛ44 (P for trends ≤ 2 × 10−76) (Figure 2).”
Quote in the paperNot a substantial claim - Findingown data
Genetically determined plasma apoE, a 1 mg/dL increase, conferred a risk ratio of 0.97 (0.92-1.03) for cardiovascular mortality.
“Examining genetically determined plasma apoE, a 1 mg/dL increase conferred risk ratios of 0.97 (0.92–1.03) for cardiovascular mortality and 1.01 (0.95–1.06) for cancer mortality, while a 1 mg/dL decrease conferred a risk ratio of 1.70 (1.36–2.12) for dementia-associated mortality.”
Quote in the paperSubstantial claim- Rests on an assumption: The APOE allele score is a valid instrumental variable for plasma apoE, affecting cause-specific mortality only through plasma apoE and not through pleiotropic pathways.
- Findingown data
All-cause mortality increased with increasing plasma apoE levels relative to the reference of 4.5 mg/dL.
“All-cause mortality increased with increasing levels of apoE relative to the reference of 4.5 mg/dL.”
Quote in the paperSubstantial claim - Findingown data
There was no sign of non-linearity for all-cause and cause-specific mortality (P ≥ 0.30).
“There was no sign of non-linearity for all-cause and cause-specific mortality (P ≥ 0.30).”
Quote in the paperNot a substantial claim - Findingown data
In this cohort, high plasma apoE levels (highest vs. fifth septile) were associated with increased cardiovascular mortality (HR 1.28, 95% CI 1.13-1.44).
“For the highest vs. the fifth septile of plasma apoE, hazard ratios (HRs) were 1.20 (95% confidence interval 1.12–1.28) for all-cause mortality, 1.28 (1.13–1.44) for cardiovascular mortality, and 1.18 (1.05–1.32) for cancer mortality.”
Quote in the paperSubstantial claim- Rests on an assumption: Cause-specific deaths in the Danish Causes of Death Registry are accurately classified.
- Findingown data
Apolipoprotein B increased from ε22 to ε32 to ε42 to ε33 to ε43 to ε44 (P for trend < 1 × 10−300).
“For the six APOE genotypes, total cholesterol, LDL cholesterol, and apolipoprotein B increased from ɛ22 to ɛ32 to ɛ42 to ɛ33 to ɛ43 to ɛ44 (P for trends < 1 × 10−300), whereas plasma apoE, high-density lipoprotein (HDL) cholesterol, and apolipoprotein AI levels decreased from ɛ22 to ɛ32 to ɛ42 to ɛ33 to ɛ43 to ɛ44 (P for trends ≤ 2 × 10−76) (Figure 2).”
Quote in the paperNot a substantial claim - Findingown data
LDL cholesterol increased from ε22 to ε32 to ε42 to ε33 to ε43 to ε44 (P for trend < 1 × 10−300).
“For the six APOE genotypes, total cholesterol, LDL cholesterol, and apolipoprotein B increased from ɛ22 to ɛ32 to ɛ42 to ɛ33 to ɛ43 to ɛ44 (P for trends < 1 × 10−300), whereas plasma apoE, high-density lipoprotein (HDL) cholesterol, and apolipoprotein AI levels decreased from ɛ22 to ɛ32 to ɛ42 to ɛ33 to ɛ43 to ɛ44 (P for trends ≤ 2 × 10−76) (Figure 2).”
Quote in the paperNot a substantial claim - Findingown data
Total cholesterol increased from ε22 to ε32 to ε42 to ε33 to ε43 to ε44 (P for trend < 1 × 10−300).
“For the six APOE genotypes, total cholesterol, LDL cholesterol, and apolipoprotein B increased from ɛ22 to ɛ32 to ɛ42 to ɛ33 to ɛ43 to ɛ44 (P for trends < 1 × 10−300), whereas plasma apoE, high-density lipoprotein (HDL) cholesterol, and apolipoprotein AI levels decreased from ɛ22 to ɛ32 to ɛ42 to ɛ33 to ɛ43 to ɛ44 (P for trends ≤ 2 × 10−76) (Figure 2).”
Quote in the paperNot a substantial claim - Findingown data
Median survival decreased from 86.9 years in ε32 carriers to 83.7 years in ε44 carriers.
“Median survival decreased from 86.9 years in ɛ32 carriers to 86.4 in ɛ33 carriers to 86.3 in ɛ22 carriers to 86.1 in ɛ42 carriers to 85.9 in ɛ43 carriers through to 83.7 years in ɛ44 carriers.”
Quote in the paperSubstantial claim - Findingown data
In this cohort, high plasma apoE levels (highest vs. fifth septile) were associated with increased all-cause mortality (HR 1.20, 95% CI 1.12-1.28).
“For the highest vs. the fifth septile of plasma apoE, hazard ratios (HRs) were 1.20 (95% confidence interval 1.12–1.28) for all-cause mortality, 1.28 (1.13–1.44) for cardiovascular mortality, and 1.18 (1.05–1.32) for cancer mortality.”
Quote in the paperSubstantial claim - Findingown data
The associations between plasma apoE and all-cause, cardiovascular, cancer, and dementia-associated mortality were similar in analyses restricted to APOE ε33 carriers.
“Results were similar in analyses restricted to APOE ɛ33 carriers.”
- Also stated in: § Plasma levels of apolipoprotein E and all-cause and cause-specific mortality · plain
“Analyses solely in ɛ33 carriers showed similar patterns (Figure 5, lower panels).”
Quote in the paperSubstantial claim - Also stated in: § Plasma levels of apolipoprotein E and all-cause and cause-specific mortality · plain
- Findingown data
Genetically determined plasma apoE, a 1 mg/dL decrease, conferred a risk ratio of 1.70 (1.36-2.12) for dementia-associated mortality.
“Examining genetically determined plasma apoE, a 1 mg/dL increase conferred risk ratios of 0.97 (0.92–1.03) for cardiovascular mortality and 1.01 (0.95–1.06) for cancer mortality, while a 1 mg/dL decrease conferred a risk ratio of 1.70 (1.36–2.12) for dementia-associated mortality.”
Quote in the paperSubstantial claim- Rests on an assumption: The APOE allele score is a valid instrumental variable for plasma apoE, affecting cause-specific mortality only through plasma apoE and not through pleiotropic pathways.
- Findingown data
In this cohort, high plasma apoE levels (highest vs. fifth septile) were associated with increased cancer mortality (HR 1.18, 95% CI 1.05-1.32).
“For the highest vs. the fifth septile of plasma apoE, hazard ratios (HRs) were 1.20 (95% confidence interval 1.12–1.28) for all-cause mortality, 1.28 (1.13–1.44) for cardiovascular mortality, and 1.18 (1.05–1.32) for cancer mortality.”
Quote in the paperSubstantial claim- Rests on an assumption: Cause-specific deaths in the Danish Causes of Death Registry are accurately classified.
- Findingown data
HDL cholesterol decreased from ε22 to ε32 to ε42 to ε33 to ε43 to ε44 (P for trend ≤ 2 × 10−76).
“For the six APOE genotypes, total cholesterol, LDL cholesterol, and apolipoprotein B increased from ɛ22 to ɛ32 to ɛ42 to ɛ33 to ɛ43 to ɛ44 (P for trends < 1 × 10−300), whereas plasma apoE, high-density lipoprotein (HDL) cholesterol, and apolipoprotein AI levels decreased from ɛ22 to ɛ32 to ɛ42 to ɛ33 to ɛ43 to ɛ44 (P for trends ≤ 2 × 10−76) (Figure 2).”
Quote in the paperNot a substantial claim - Findingown data
APOE genotype is associated with mortality.
“We confirmed the well-known association between APOE genotypes and mortality.”
Quote in the paperSubstantial claim - Findingown data
Genetically determined plasma apoE, a 1 mg/dL increase, conferred a risk ratio of 1.01 (0.95-1.06) for cancer mortality.
“Examining genetically determined plasma apoE, a 1 mg/dL increase conferred risk ratios of 0.97 (0.92–1.03) for cardiovascular mortality and 1.01 (0.95–1.06) for cancer mortality, while a 1 mg/dL decrease conferred a risk ratio of 1.70 (1.36–2.12) for dementia-associated mortality.”
Quote in the paperSubstantial claim- Rests on an assumption: The APOE allele score is a valid instrumental variable for plasma apoE, affecting cause-specific mortality only through plasma apoE and not through pleiotropic pathways.
- Findingown data
In this cohort, low plasma apoE levels (lowest vs. fifth septile) were associated with increased dementia-associated mortality (HR 1.44, 95% CI 1.01-2.05).
“Conversely, for the lowest vs. the fifth septile the HR was 1.44 (1.01–2.05) for dementia-associated mortality.”
Quote in the paperSubstantial claim- Rests on an assumption: Cause-specific deaths in the Danish Causes of Death Registry are accurately classified.
- Findingown data
Apolipoprotein AI decreased from ε22 to ε32 to ε42 to ε33 to ε43 to ε44 (P for trend ≤ 2 × 10−76).
“For the six APOE genotypes, total cholesterol, LDL cholesterol, and apolipoprotein B increased from ɛ22 to ɛ32 to ɛ42 to ɛ33 to ɛ43 to ɛ44 (P for trends < 1 × 10−300), whereas plasma apoE, high-density lipoprotein (HDL) cholesterol, and apolipoprotein AI levels decreased from ɛ22 to ɛ32 to ɛ42 to ɛ33 to ɛ43 to ɛ44 (P for trends ≤ 2 × 10−76) (Figure 2).”
Quote in the paperNot a substantial claim - Findingown data
The associations between high plasma apoE and all-cause, cardiovascular, and cancer mortality appeared augmented in men.
“The associations between high levels of apoE and all-cause, cardiovascular, and cancer mortality appeared augmented in men (Supplementary material online, Figures S5–S7); otherwise largely similar patterns were observed in women and men, although overall with attenuation in women compared with in men.”
Quote in the paperNot a substantial claim - Findingown data
LDL cholesterol increased across apoE decreasing weighted and simple allele score groups.
“Plasma levels of apoE and HDL cholesterol decreased, while LDL cholesterol increased across apoE decreasing weighted and simple allele score groups (Supplementary material online, Figure S8).”
Quote in the paperNot a substantial claim - Findingown data
There was interaction between seven groups of plasma apoE and sex on cardiovascular mortality (P for interaction = 0.006).
“We found interaction between seven groups of plasma apoE and sex on all-cause and cardiovascular mortality (P for interaction = 0.02 and 0.006), but no interaction for seven groups of plasma apoE and sex on dementia-associated and cancer mortality (P for interaction = 0.10 and 0.12).”
Quote in the paperSubstantial claim - Findingown data
HDL cholesterol decreased across apoE decreasing weighted and simple allele score groups.
“Plasma levels of apoE and HDL cholesterol decreased, while LDL cholesterol increased across apoE decreasing weighted and simple allele score groups (Supplementary material online, Figure S8).”
Quote in the paperNot a substantial claim - Findingown data
There was no interaction between seven groups of plasma apoE and sex on dementia-associated mortality (P for interaction = 0.10).
“We found interaction between seven groups of plasma apoE and sex on all-cause and cardiovascular mortality (P for interaction = 0.02 and 0.006), but no interaction for seven groups of plasma apoE and sex on dementia-associated and cancer mortality (P for interaction = 0.10 and 0.12).”
Quote in the paperNot a substantial claim - Findingown data
High plasma apoE levels were associated with increased risk of cardiovascular mortality in the APOE adjusted model and in ε33 carriers only.
“High plasma levels of apoE were associated with increased risk of cardiovascular and cancer mortality in the APOE adjusted model and in ɛ33 carriers only (Figure 4, left and right panels).”
Quote in the paperSubstantial claim- Rests on an assumption: Cause-specific deaths in the Danish Causes of Death Registry are accurately classified.
- Findingown data
Sensitivity analyses for risk of narrower cardiovascular mortality endpoints showed similar patterns as for all cardiovascular mortality.
“Sensitivity analyses for risk of narrower cardiovascular mortality endpoints showed similar patterns as for all cardiovascular mortality (compare Supplementary material online, Figure S14 with Figure 1).”
Quote in the paperNot a substantial claim- Rests on an assumption: Cause-specific deaths in the Danish Causes of Death Registry are accurately classified.
- Findingown data
Low plasma apoE levels were associated with increased dementia-associated mortality in the APOE adjusted model and in ε33 carriers only.
“Conversely, low plasma levels of apoE were associated with increased dementia-associated mortality, in the APOE adjusted model and in ɛ33 carriers only (Figure 4, middle panel).”
Quote in the paperSubstantial claim- Rests on an assumption: Cause-specific deaths in the Danish Causes of Death Registry are accurately classified.
- Findingown data
High plasma apoE levels were associated with increased risk of cancer mortality in the APOE adjusted model and in ε33 carriers only.
“High plasma levels of apoE were associated with increased risk of cardiovascular and cancer mortality in the APOE adjusted model and in ɛ33 carriers only (Figure 4, left and right panels).”
Quote in the paperSubstantial claim- Rests on an assumption: Cause-specific deaths in the Danish Causes of Death Registry are accurately classified.
- Findingown data
Plasma apoE decreased across apoE decreasing weighted and simple allele score groups.
“Plasma levels of apoE and HDL cholesterol decreased, while LDL cholesterol increased across apoE decreasing weighted and simple allele score groups (Supplementary material online, Figure S8).”
Quote in the paperNot a substantial claim - Findingown data
There was no interaction between seven groups of plasma apoE and sex on cancer mortality (P for interaction = 0.12).
“We found interaction between seven groups of plasma apoE and sex on all-cause and cardiovascular mortality (P for interaction = 0.02 and 0.006), but no interaction for seven groups of plasma apoE and sex on dementia-associated and cancer mortality (P for interaction = 0.10 and 0.12).”
Quote in the paperNot a substantial claim - Findingown data
In sensitivity analyses without adjustment for LDL cholesterol, HDL cholesterol, and triglycerides, risk of all-cause mortality increased with both increasing and decreasing plasma apoE levels relative to 4.5 mg/dL.
“In these analyses, risk of all-cause mortality increased with both increasing and decreasing levels of apoE relative to the reference value of 4.5 mg/dL, which defined the overall lowest all-cause mortality (Supplementary material online, Figures S9 and S10; compare with Figures 3 and 5).”
Quote in the paperNot a substantial claim - Findingown data
There was interaction between seven groups of plasma apoE and sex on all-cause mortality (P for interaction = 0.02).
“We found interaction between seven groups of plasma apoE and sex on all-cause and cardiovascular mortality (P for interaction = 0.02 and 0.006), but no interaction for seven groups of plasma apoE and sex on dementia-associated and cancer mortality (P for interaction = 0.10 and 0.12).”
Quote in the paperSubstantial claim - Findingown data
The present Mendelian randomization estimates suggest that the observational findings are not of a causal nature.
“The present Mendelian randomization estimates suggest however that the observational findings are not of a causal nature.”
Quote in the paperSubstantial claim - Findingown data
Our results did not change after adjustment for triglycerides, LDL cholesterol, and HDL cholesterol.
“although our results did not change after adjustment for triglycerides, LDL cholesterol, and HDL cholesterol.”
Quote in the paperSubstantial claim - Findingown data
High plasma levels of apoE were associated with cancer mortality.
“In conclusion, we found that high plasma levels of apoE were associated with all-cause, cardiovascular, and cancer mortality, however of a non-causal nature, while low apoE levels were causally associated with dementia-associated mortality.”
Quote in the paperSubstantial claim - Findingown data
High plasma levels of apoE were associated with all-cause mortality.
“In conclusion, we found that high plasma levels of apoE were associated with all-cause, cardiovascular, and cancer mortality, however of a non-causal nature, while low apoE levels were causally associated with dementia-associated mortality.”
Quote in the paperSubstantial claim - Findingown data
High plasma levels of apoE were associated with cardiovascular mortality.
“In conclusion, we found that high plasma levels of apoE were associated with all-cause, cardiovascular, and cancer mortality, however of a non-causal nature, while low apoE levels were causally associated with dementia-associated mortality.”
Quote in the paperSubstantial claim - Interpretationown data
Low plasma apoE levels are causally associated with increased dementia-associated mortality.
“High plasma levels of apoE were associated with increased all-cause, cardiovascular, and cancer mortality, however of a non-causal nature, while low levels were causally associated with increased dementia-associated mortality.”
Quote in the paperSubstantial claim- Rests on an assumption: The APOE allele score is a valid instrumental variable for plasma apoE, affecting cause-specific mortality only through plasma apoE and not through pleiotropic pathways.
- Premisecitation
Mechanisms underlying the association between high apoE levels and increased all-cause and cardiovascular mortality are likely due to apoE's key function in receptor-mediated endocytosis by binding to triglyceride-rich lipoproteins and serving as a ligand for the LDL receptor and LDL receptor Related Protein (LRP).
“Mechanisms underlying the association between high apoE levels and increased all-cause and cardiovascular mortality are likely due to the key function of apoE in receptor-mediated endocytosis by binding to triglyceride-rich lipoproteins, and serving as a ligand for the LDL receptor and LDL receptor Related Protein (LRP).9”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [9] Mahley, 2001
Not checked in the free run.
- Premisecitation
Triglyceride-rich lipoproteins are associated with mortality.
“and also associated with mortality,46,47”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [46] Varbo, 2015, Extreme nonfasting remnant cholesterol vs extreme LDL cholesterol as contributors to cardiovascular disease and all-cause mortality in 90000 individuals from the general population, Clin Chem source
- cites [47] Thomsen, 2014, Low nonfasting triglycerides and reduced all-cause mortality: a Mendelian randomization study, Clin Chem source
- Interpretationreasoning
ɛ22 carriers account for only a minor fraction of the overall findings of high plasma apoE and high all-cause and cardiovascular mortality.
“Only <1% of the general population are however ɛ22 carriers and will thus only account for a minor fraction of our overall findings of high plasma apoE and high all-cause and cardiovascular mortality.”
Quote in the paperNot a substantial claim- Rests on an assumption: Only <1% of the general population are ɛ22 carriers.
- Interpretationcitation
These robust findings of low apoE on dementia risk most likely explain the observed associations with dementia-associated mortality.
“These robust findings of low apoE on dementia risk most likely explain the observed associations with dementia-associated mortality.”
Quote in the paperSubstantial claim - Premisecitation
Levels of apoE in human cerebrospinal fluid display a similar genotype-dependent pattern as in plasma.
“Levels of apoE in human cerebrospinal fluid display a similar genotype-dependent pattern as in plasma,64”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [64] Cruchaga, 2012, Cerebrospinal fluid APOE levels: an endophenotype for genetic studies for Alzheimer's disease, Hum Mol Genet source
- Premisecitation
The effect of low apoE levels per se, independent of the ɛ4 allele, was observed to be associated with high risk of dementia in three independent prospective European cohorts.
“Also, recently the effect of low apoE levels per se, independent of the ɛ4 allele, was observed to be associated with high risk of dementia in three independent prospective European cohorts,17,23”
Quote in the paperSubstantial claim0 of 2 sources checked - Premisecitation
Previous work suggests a limited blood-brain barrier permeability to circulating lipid-poor apoE.
“Further, previous work suggest a limited blood–brain barrier permeability to circulating lipid-poor apoE,62”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [62] Martel, 2002, Isoform-specific effects of apolipoproteins E2, E3, and E4 on cerebral capillary sequestration and blood-brain barrier transport of circulating Alzheimer's amyloid beta, J Neurochem source
- Study design and conductcitation
Dementia diagnoses in the Danish registries have high diagnostic validity.
“Dementia diagnoses in the Danish registries have high diagnostic validity.24,76”
Quote in the paperSubstantial claim0 of 2 sources checked - Interpretationreasoning
The lipid and lipoprotein pleiotropic effects in the periphery will most likely not be an issue in the brain.
“Thus, the lipid and lipoprotein pleiotropic effects in the periphery will most likely not be an issue in the brain.”
Quote in the paperSubstantial claim- Rests on an assumption: The brain relies almost exclusively on HDL-like apoE-containing lipoprotein particles for its lipid transport and does not have apoB and apoB-containing lipoproteins.
- Study design and conductcitation
Myocardial infarction and cancer as a primary diagnosis or underlying cause of death has been shown to have high diagnostic validity.
“Further, myocardial infarction and cancer as a primary diagnosis or underlying cause of death has been shown to have high diagnostic validity.77,78”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [77] Madsen, 2003, The validity of the diagnosis of acute myocardial infarction in routine statistics: a comparison of mortality and hospital discharge data with the Danish MONICA registry, J Clin Epidemiol source
- cites [78] Asnaes, 1980, Uncertainty of determining mode and cause of death without autopsy: an autopsy study of medically unattended non-medicolegal deaths, Forensic Sci Int source
- Study design and conductown data
By performing APOE adjusted and stratified analyses we were able to differentiate the quantitative effects of apoE levels from the genetically determined isoform specific qualitative effects.
“Finally, by performing APOE adjusted and stratified analyses we were able to differentiate the quantitative effects of apoE levels from the genetically determined isoform specific qualitative effects.”
Quote in the paperSubstantial claim - Interpretationcitation
Plasma levels of apoE mirror levels in cerebrospinal fluid and brain, despite originating from two different compartments.
“Hence, we suggest that plasma levels of apoE mirror levels in cerebrospinal fluid and brain, despite originating from two different compartments.”
Quote in the paperSubstantial claim - Interpretationown data
Low plasma levels of apoE-mimicking brain apoE levels-are suggested to play a causal role in dementia-associated mortality.
“whereas low plasma levels of apoE—mimicking brain apoE levels—are suggested to play a causal role in dementia-associated mortality.”
Quote in the paperSubstantial claim - Interpretationown data
The association between high plasma apoE and cardiovascular mortality is non-causal.
“In conclusion, we found that high plasma levels of apoE were associated with all-cause, cardiovascular, and cancer mortality, however of a non-causal nature, while low apoE levels were causally associated with dementia-associated mortality.”
Quote in the paperSubstantial claim - Interpretationreasoning
Our results may not necessarily apply to other ethnicities.
“Our results may therefore not necessarily apply to other ethnicities, although we are not aware of data to suggest that our results should not be applicable to all humans.”
Quote in the paperNot a substantial claim - Interpretationown data
The association between high plasma apoE and cancer mortality is non-causal.
“In conclusion, we found that high plasma levels of apoE were associated with all-cause, cardiovascular, and cancer mortality, however of a non-causal nature, while low apoE levels were causally associated with dementia-associated mortality.”
Quote in the paperSubstantial claim - Study design and conductnone given
Given the Danish registration practice it is highly unlikely that an event of death would remain unregistered.
“Given the Danish registration practice it is highly unlikely that an event of death would remain unregistered.”
Quote in the paperNot a substantial claim - Interpretationown data
Low apoE levels were causally associated with dementia-associated mortality.
“In conclusion, we found that high plasma levels of apoE were associated with all-cause, cardiovascular, and cancer mortality, however of a non-causal nature, while low apoE levels were causally associated with dementia-associated mortality.”
Quote in the paperSubstantial claim - Interpretationown data
The association between high plasma apoE and all-cause mortality is non-causal.
“In conclusion, we found that high plasma levels of apoE were associated with all-cause, cardiovascular, and cancer mortality, however of a non-causal nature, while low apoE levels were causally associated with dementia-associated mortality.”
Quote in the paperSubstantial claim
- Classified as probably not a substantial claim. 15
- May combine two claims. 21
Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing).
PremisecitationMechanisms underlying the association between high apoE levels and increased cancer mortality could likely be due to apoE involvement in metastasis and angiogenesis.
“mechanisms underlying the association between high apoE levels and increased cancer mortality could likely be due to apoE involvement in metastasis and angiogenesis.49–56”
Quote in the paperNot a substantial claim4 of 8 sources checked- cites [49] Goodison, 2012, A multi-analyte assay for the non-invasive detection of bladder cancer, PLoS One source
The Discussion (page not specified) describes APOE in bladder tumor cells in terms of cell turnover and resistance to apoptosis, but does not link high APOE levels to cancer mortality, metastasis, or angiogenesis. A separate Discussion passage attributes angiogenic properties and metastasis in mouse models to IL-8, not APOE. Searches for APOE with mortality, metastasis, and angiogenesis found no passage supporting the claimed mechanism. (LLM, conf=0.76)
Experimental — accuracy not yet measured - cites [50] Pencheva, 2012, Convergent multi-miRNA targeting of ApoE drives LRP1/LRP8-dependent melanoma metastasis and angiogenesis, Cell source
The Discussion says ApoE suppresses melanoma metastatic progression and suggests that increasing ApoE levels could reduce melanoma mortality. The Results also identify systemic ApoE as a suppressor of metastatic angiogenesis. These findings point in the opposite direction from the proposed explanation for increased mortality with high ApoE levels. (LLM, conf=0.90)
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measured - cites [51] Boylan, 2010, Quantitative proteomic analysis by iTRAQ(R) for the identification of candidate biomarkers in ovarian cancer serum, Proteome Sci source
The Discussion (page not provided) reports that ApoE was elevated in ovarian cancer serum pools and cites its role in ovarian cancer-cell proliferation and survival. It does not link ApoE levels to cancer mortality or propose metastasis or angiogenesis as mechanisms; those are the central parts of the claim that remain unsupported. (LLM, conf=0.78)
Experimental — accuracy not yet measured - cites [52] Oue, 2004, Gene expression profile of gastric carcinoma: identification of genes and tags potentially involved in invasion, metastasis, and carcinogenesis by serial analysis of gene expression, Cancer Res source
- cites [53] Luo, 2016, Elevated serum apolipoprotein E is associated with metastasis and poor prognosis of non-small cell lung cancer, Tumour Biol source
- cites [54] Chen, 2013, Expression and clinical significance of complement C3, complement C4b1 and apolipoprotein E in pancreatic cancer, Oncol Lett source
The Discussion reports higher ApoE levels in pancreatic tumors with lymph-node metastasis than in those without it, supporting an association with metastasis. It does not establish that ApoE causes metastasis, or report an angiogenesis mechanism or an association between ApoE levels and cancer mortality. (LLM, conf=0.86)
Experimental — accuracy not yet measured - cites [55] Su, 2011, Apolipoprotein E expression promotes lung adenocarcinoma proliferation and migration and as a potential survival marker in lung cancer, Lung Cancer source
- cites [56] Chen, 2005, Apolipoprotein E is required for cell proliferation and survival in ovarian cancer, Cancer Res source
May combine two claims.
Findingown dataMultivariable instrumental variable analysis and a series of other relevant MR sensitivity analyses showed no major deviations and did not change conclusions from the main instrumental variable findings.
“These analyses showed no major deviations and did not change conclusions from the main instrumental variable findings.”
Quote in the paperSubstantial claim3 of 3 sources checked- cites [66] Burgess, 2015, Multivariable Mendelian randomization: the use of pleiotropic genetic variants to estimate causal effects, Am J Epidemiol source
The Simulation Study reports that some estimates did not change substantially across simulated parameters, but it does not assess the citing study’s instrumental-variable findings. I searched for sensitivity analyses showing no major deviations or unchanged conclusions; no passage in our copy reports that result. (LLM, conf=0.76)
Experimental — accuracy not yet measured - cites [67] Bowden, 2015, Mendelian randomization with invalid instruments: effect estimation and bias detection through Egger regression, Int J Epidemiol source
The paper presents MR-Egger regression as a sensitivity analysis, but its blood-pressure example does not show agreement with the main instrumental-variable findings. In “Causal effect of blood pressure on coronary artery disease risk” (page unavailable), the MR-Egger estimates differ from the IVW estimates and cast doubt on the robustness of the original claims. (LLM, conf=0.84)
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measured - cites [68] Bowden, 2016, Consistent estimation in Mendelian randomization with some invalid instruments using a weighted median estimator, Genet Epidemiol source
In the ‘Example: Lipid Concentrations and Coronary Artery Disease Risk’ section (page unavailable), the paper reports that sensitivity methods preserved the main findings for LDL-c and triglycerides. But they called the IVW finding for HDL-c into question, so the analyses did change a conclusion in that example. The cited paper also does not establish the result of the citing authors’ multivariable analysis. (LLM, conf=0.82)
Experimental — accuracy not yet measured
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationBoth APOE ε2 and ε4 alleles are associated with unfavourable lipid profiles.
“Both ɛ2 and ɛ4 alleles are associated with unfavourable lipid profiles,12–19”
Quote in the paperNot a substantial claim1 of 8 sources checked- cites [12] Bennet, 2007, Association of apolipoprotein E genotypes with lipid levels and coronary risk, JAMA source
- cites [13] 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.
- cites [14] Boerwinkle, 1988, Simultaneous effects of the apolipoprotein E polymorphism on apolipoprotein E, apolipoprotein B, and cholesterol metabolism, Am J Hum Genet
Not checked in the free run.
- cites [15] Smit, 1988, Apolipoprotein E polymorphism in The Netherlands and its effect on plasma lipid and apolipoprotein levels, Hum Genet source
- cites [16] Neale, 2000, ApoE polymorphism accounts for only part of the genetic variation in quantitative ApoE levels, Genet Epidemiol source
- cites [17] Rasmussen, 2015, Plasma levels of apolipoprotein E and risk of dementia in the general population, Ann Neurol source
- cites [18] Davignon, 1988, Apolipoprotein E polymorphism and atherosclerosis, Arteriosclerosis source
- cites [19] Frikke-Schmidt, 2000, Apolipoprotein E genotype: epsilon32 women are protected while epsilon43 and epsilon44 men are susceptible to ischemic heart disease: the Copenhagen City Heart Study, J Am Coll Cardiol source
The ‘APOE genotype and lipids and lipoproteins’ section reports high triglycerides for ε22 and ε44, supporting an unfavourable association for some carriers of each allele. But the Discussion describes ε32 women as having lower cholesterol and apoB, higher HDL cholesterol, and an antiatherogenic lipoprotein profile. The claim therefore overgeneralizes the association for ε2. (LLM, conf=0.88)
Experimental — accuracy not yet measured
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationThe APOE ε4 allele is a strong genetic risk factor for Alzheimer disease and is the strongest hit in genome-wide association studies of longevity.
“the ɛ4 allele is a strong genetic risk factor for Alzheimer disease,20 and by far the strongest hit in genome-wide association studies of longevity.21,22”
Quote in the paperNot a substantial claim2 of 3 sources checked- cites [20] Corder, 1993, Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families, Science source
- cites [21] Sebastiani, 2012, Genetic signatures of exceptional longevity in humans, PLoS One source
The Results (Single SNP Analysis; page unavailable) identify rs2075650 in the TOMM40/APOE region as the genome-wide-significant longevity hit, and the Discussion calls it the most significantly associated SNP. The paper describes rs2075650 as a proxy for SNPs defining APOE alleles, but does not establish that the ε4 allele itself was the strongest GWAS hit. The Alzheimer disease clause is attached to a different citation. (LLM, conf=0.83)
Experimental — accuracy not yet measured - cites [22] Brooks-Wilson, 2013, Genetics of healthy aging and longevity, Hum Genet source
The Genome-wide association studies section says that SNPs in or near APOE were the only genome-wide-significant longevity findings and reports a strong inverse association between APOE4 and longevity. It identifies the genome-wide-significant hits as nearby SNPs, however, rather than establishing that the ε4 allele itself was the strongest GWAS hit. The Linkage studies section describes apoE isoforms as Alzheimer disease risk factors, but does not specifically establish the strength of ε4’s risk. (LLM, conf=0.85)
Experimental — accuracy not yet measured
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationA 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”
Quote in the paperNot a substantial claim2 of 2 sources checkedMay combine two claims.
PremisecitationIncreased levels of apoE stimulate very low-density lipoprotein triglyceride production in the liver and impair lipoprotein lipase-mediated lipolysis, leading to hypertriglyceridaemia.
“increased levels of apoE stimulate very low-density lipoprotein triglyceride production in the liver and impairs lipoprotein lipase-mediated lipolysis, thus leading to hypertriglyceridaemia.42,43”
Quote in the paperSubstantial claim1 of 2 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing).
InterpretationcitationThe findings of high apoE levels and high cardiovascular mortality may be mediated by triglyceride-rich lipoproteins via remnant cholesterol content.
“our findings of high apoE levels and high cardiovascular mortality may be mediated by triglyceride-rich lipoproteins via remnant cholesterol content”
Quote in the paperNot a substantial claim1 of 4 sources checked- cites [44] Nordestgaard, 2016, Triglyceride-rich lipoproteins and atherosclerotic cardiovascular disease: new insights from epidemiology, genetics, and biology, Circ Res source
- cites [45] Nordestgaard, 2014, Triglycerides and cardiovascular disease, Lancet source
- cites [46] Varbo, 2015, Extreme nonfasting remnant cholesterol vs extreme LDL cholesterol as contributors to cardiovascular disease and all-cause mortality in 90000 individuals from the general population, Clin Chem source
- cites [47] Thomsen, 2014, Low nonfasting triglycerides and reduced all-cause mortality: a Mendelian randomization study, Clin Chem source
Classified as probably not a substantial claim. May combine two claims.
PremisecitationTriglyceride-rich lipoproteins are atherogenic and causally associated with cardiovascular disease.
“As triglyceride-rich lipoproteins are atherogenic and causally associated with cardiovascular disease,44,45”
Quote in the paperSubstantial claim1 of 2 sources checkedMay combine two claims.
PremisecitationPlausible mechanisms underlying the association between low apoE levels and dementia-associated mortality are not explained by peripheral lipid metabolism, but likely by the role of apoE in β-amyloid handling and in neurodegenerative processes.
“Plausible mechanisms underlying the association between low apoE levels and dementia-associated mortality are not explained by peripheral lipid metabolism, but likely by the role of apoE in β-amyloid handling and in neurodegenerative processes.57,58”
Quote in the paperSubstantial claim1 of 2 sources checked- cites [57] Yu, 2014, Apolipoprotein E in Alzheimer's disease: an update, Annu Rev Neurosci source
Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measured - cites [58] Wellington, 2016, Relation between plasma and brain lipids, Curr Opin Lipidol source
May combine two claims.
PremisecitationThe 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”
Quote in the paperSubstantial claim3 of 3 sources checked- cites [57] Yu, 2014, Apolipoprotein E in Alzheimer's disease: an update, Annu Rev Neurosci source
The sections on Aβ aggregation and clearance, tau pathology, neurotoxicity, mitochondrial dysfunction, and blood–brain barrier permeability describe the adverse APOE4-related effects listed in the claim. The section on APP trafficking and Aβ production is more qualified: some cell-culture studies suggest APOE4 enhances Aβ production, but others found no clear isoform-specific effect, and the authors call for in vivo investigation. The claim presents that production effect as established. (LLM, conf=0.88)
Experimental — accuracy not yet measured - cites [59] Mahley, 2012, Apolipoprotein e sets the stage: response to injury triggers neuropathology, Neuron source
- cites [60] Rasmussen, 2016, Plasma levels of apolipoprotein E, APOE genotype and risk of dementia and ischemic heart disease: a review, Atherosclerosis source
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
May combine two claims.
Findingown dataHazard ratios for all-cause mortality were 1.10 (1.06-1.14) for ε43 carriers and 1.43 (1.29-1.58) for ε44 carriers vs. ε33 carriers.
“Hazard ratios (HRs) for all-cause mortality were 1.10 (1.06–1.14) for ɛ43 carriers and 1.43 (1.29–1.58) for ɛ44 carriers vs. ɛ33 carriers (Figure 1), with similar patterns in women and men separately (Supplementary material online, Figure S4).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataAll-cause, cardiovascular, and dementia-associated mortality increased from ε32 to ε33/ε22 to ε42/ε43 to ε44.
“All-cause, cardiovascular, and dementia-associated mortality increased correspondingly from ɛ32 to ɛ33/ɛ22 to ɛ42/ɛ43 to ɛ44 (Figure 1).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataThere was no interaction between seven groups of plasma apoE and study (P for interaction = 0.26), so all further analyses were performed on the studies combined.
“We found no interaction between seven groups of plasma apoE and study (P for interaction = 0.26). Consequently, all further analyses were performed on the studies combined.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataResults were similar when excluding individuals contributing with more than one cause-specific event, or when using tertiles, quartiles, quintiles, or deciles instead of septiles.
“We found results similar to those in Figure 5, when excluding individuals contributing with more than one cause-specific event (Supplementary material online, Figure S11), or when using tertiles, quartiles, quintiles, or deciles instead of septiles (Supplementary material online, Figure S12).”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataCausal genetic estimates from instrumental variable analyses indicated a causal association between plasma apoE levels and dementia-associated mortality but not with cardiovascular or cancer mortality.
“We further substantiated our findings by causal genetic estimates from instrumental variable analyses, which indicated a causal association between plasma apoE levels and dementia-associated mortality but not with cardiovascular or cancer mortality.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataHigh plasma apoE levels are associated with increased all-cause, cardiovascular, and cancer mortality, but these associations are non-causal.
“High plasma levels of apoE were associated with increased all-cause, cardiovascular, and cancer mortality, however of a non-causal nature, while low levels were causally associated with increased dementia-associated mortality.”
Quote in the paperSubstantial claim- Rests on an assumption: The APOE allele score is a valid instrumental variable for plasma apoE, affecting cause-specific mortality only through plasma apoE and not through pleiotropic pathways.
May combine two claims.
Study design and conductown dataThere was no interaction between seven groups of plasma apoE and use of two different autoanalyzers on all-cause mortality (P for interaction = 0.80), and estimates before and after the change were similar.
“We found no interaction between seven groups of plasma apoE and use of two different autoanalyzers on all-cause mortality (P for interaction = 0.80) and estimates before and after the change were similar (Supplementary material online, Figure S13).”
Quote in the paperNot a substantial claimMay combine two claims.
Study design and conductreasoningCause-specific mortality follow-up was truncated on 31 December 2015, and 1839 of 13 693 deaths could not be classified by cause.
“End of follow-up for the national Danish Causes of Death Registry (31 December 2015) lags the Danish Civil Registration System (22 March 2017) by more than 1 year: as a consequence some deaths could not be classified by cause (1839 of 13 693 deaths), and cause-specific mortality follow-up was truncated accordingly on 31 December 2015.”
Quote in the paperSubstantial claim- Rests on an assumption: Cause-specific deaths in the Danish Causes of Death Registry are accurately classified.
May combine two claims.
Study design and conductown dataInstrumental variable sensitivity analyses showed no major deviations and did not change conclusions from the main findings.
“Instrumental variable sensitivity analyses showed no major deviations and did not change conclusions from the main findings in Figure 6 (compare with Supplementary material online, Table S1 and Figure S16).”
Quote in the paperNot a substantial claim- Rests on an assumption: The APOE allele score is a valid instrumental variable for plasma apoE, affecting cause-specific mortality only through plasma apoE and not through pleiotropic pathways.
Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenThere was no overlap of individuals between the two studies.
“There was no overlap of individuals between studies.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductown dataThere were no individuals lost to follow-up for all-cause mortality.
“Median follow-up was 8.5 years (range 0–25 years) for all-cause mortality, with no individuals lost to follow-up.”
Quote in the paperNot a substantial claimClassified as probably not a substantial claim.
PremisecitationLow levels of plasma apoE have been reported to be associated with increased risk of dementia.
“Interestingly, low levels of plasma apoE were recently reported to be associated with increased risk of dementia,17,23,24 whereas high levels were associated with increased risk of ischaemic heart disease.25”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [17] Rasmussen, 2015, Plasma levels of apolipoprotein E and risk of dementia in the general population, Ann Neurol source
- cites [23] Wolters, 2016, Serum apolipoprotein E is associated with long-term risk of Alzheimer's disease: the Rotterdam Study, Neurosci Lett source
- cites [24] Rasmussen, 2018, Plasma apolipoprotein E levels and risk of dementia: a Mendelian randomization study of 106,562 individuals, Alzheimers Dement source
Classified as probably not a substantial claim.
PremisecitationHigh levels of plasma apoE have been reported to be associated with increased risk of ischaemic heart disease.
“Interestingly, low levels of plasma apoE were recently reported to be associated with increased risk of dementia,17,23,24 whereas high levels were associated with increased risk of ischaemic heart disease.25”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [25] Rasmussen, 2016, Plasma levels of apolipoprotein E and risk of ischemic heart disease in the general population, Atherosclerosis source
Probably not a substantial claim: may not pass S4 (based).
Interpretationnone givenFor dementia and dementia-associated mortality, low apoE in plasma most likely mimics low apoE levels in the brain, resulting in decreased β-amyloid clearance.
“whereas for dementia and dementia-associated mortality, low apoE in plasma most likely mimic low apoE levels in the brain resulting in decreased β-amyloid clearance.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationLDL receptor affinity defective ɛ22 carriers have a propensity to develop type III hyperlipoproteinaemia.
“the well-known propensity of LDL receptor affinity defective ɛ22 carriers to develop type III hyperlipoproteinaemia support this understanding.9”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [9] Mahley, 2001
Not checked in the free run.
May combine two claims.
Interpretationown dataHigh plasma levels of apoE are not causally associated with cardiovascular and cancer mortality.
“high plasma levels of apoE are not causally associated with cardiovascular and cancer mortality”
Quote in the paperSubstantial claimMay combine two claims.
Study design and conductreasoningDue to the large sample size, we were able to perform analyses adjusted for APOE genotype as well as analyses for APOE ɛ33 carriers alone.
“Further, due to the large sample size, we were able to perform analyses adjusted for APOE genotype as well as analyses for APOE ɛ33 carriers alone.”
Quote in the paperSubstantial claimMay combine two claims.
Study design and conductreasoningThe instrument used consisted of five variants (three promoter variants and two common exonic variants), chosen because this combination reflects the quantitative effects of apoE as well as the qualitative, isoform-specific effects.
“We chose to use an instrument consisting of five variants (three promoter variants and two common exonic variants), because this combination of variants reflects the quantitative effects of apoE as well as the qualitative, isoform specific effects.”
Quote in the paperSubstantial claimMay combine two claims.
Study design and conductnone givenA major strength of the study is the large prospective general population design with no losses to follow-up: every single individual could be followed to end of follow-up, death, or emigration.
“A major strength of the study is the large prospective general population design with no losses to follow-up: that is, every single individual could be followed to end of follow-up, death, or emigration.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
InterpretationreasoningThe generalizability of our study results is limited by the fact that we studied only white individuals.
“Finally, another limitation could be that the generalizability of our study results is limited by the fact that we studied only white individuals.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.
Study design and conductnone givenUnregistered contributing causes of death would only lead to decreased power of our estimate and bias our results towards the null hypothesis.
“Unregistered contributing causes of death would only lead to decreased power of our estimate and bias our results towards the null hypothesis.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Study design and conductnone givenBlood samples were not drawn in the fasting state, which could add to random measurement error.
“Another potential limitation is that blood samples were not drawn in the fasting state, which could add to random measurement error.”
Quote in the paperNot a substantial claim
The paper relies on this without support.
The relationship of plasma apoE levels with all-cause and cause-specific mortality was unknown before this study.
“Beyond that, the relationship of plasma apoE levels with all-cause and cause-specific mortality is unknown.”
The paper relies on this without support.
The APOE allele score is a valid instrumental variable for plasma apoE, affecting cause-specific mortality only through plasma apoE and not through pleiotropic pathways.
“Using a Mendelian randomization design, we also studied genetically determined plasma apoE levels to examine if plasma apoE was causally associated with cause-specific mortality.”
The paper relies on this without support.
Cause-specific deaths in the Danish Causes of Death Registry are accurately classified.
“Endpoints are described in detail in the Supplementary material online.”
The paper relies on this without support.
Genotypes with low apoE are associated with an atherogenic lipid profile and thus with risk of cardiovascular disease and cardiovascular mortality.
“genotypes with low apoE in addition are associated with an atherogenic lipid profile, and thus risk of cardiovascular disease and cardiovascular mortality”
The paper relies on this without support.
Only <1% of the general population are ɛ22 carriers.
“Only <1% of the general population are however ɛ22 carriers”
The paper relies on this without support.
The brain relies almost exclusively on HDL-like apoE-containing lipoprotein particles for its lipid transport and does not have apoB and apoB-containing lipoproteins.
“the brain relies almost exclusively on HDL-like apoE-containing lipoprotein particles for its lipid transport and does not have apoB and apoB-containing lipoproteins (LDL and triglyceride-rich lipoproteins).”
The paper relies on this without support.
The national Danish Patient Registry includes all hospital visits, as well as out-patient visits.
“the national Danish Patient Registry includes all hospital visits, as well as out-patient visits.”
The paper relies on this without support.
APOE variants affect all other major lipid, lipoprotein, and apolipoprotein classes.
“APOE variants not only affect plasma levels of apoE but also all other major lipid, lipoprotein, and apolipoprotein classes—a well-established biological fact due to the fundamental role of apoE in lipid metabolism”
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?
For more clear-cut atherosclerotic manifestations as IHD and PAD, plasma levels of apoE are not the causal factor but rather reflects levels of atherogenic lipoproteins.
“For more clear-cut atherosclerotic manifestations as IHD and PAD, plasma levels of apoE are not the causal factor but rather reflects levels of atherogenic lipoproteins [8].”
From APOE and vascular disease: Sequencing and genotyping in general population cohorts (2023) · cites this paper as [8]
The Discussion (page not available in our copy) says high plasma apoE correlates with atherogenic triglyceride-rich lipoproteins and that genetic estimates did not indicate a causal association with cardiovascular mortality. It discusses ischaemic heart disease risk, but does not establish the same noncausal conclusion for IHD or PAD specifically; its causal analysis concerns mortality, not those disease outcomes. (LLM, conf=0.87)
Experimental — accuracy not yet measuredε4 is associated with an adverse lipid profile and ε22 carriers have a propensity to develop a recessive form of dysbetalipoproteinemia.
“it is also well‐known that ε4 is associated with an adverse lipid profile and that ε22 carriers have a propensity to develop a recessive form of dysbetalipoproteinemia (formerly known as type III hyperlipoproteinemia). 15 , 18”
From <i>APOE</i> and dementia – resequencing and genotyping in 105,597 individuals (2020) · cites this paper as [18]
The Introduction says the ε4 allele is associated with an unfavourable lipid profile, and the Results report higher LDL cholesterol and apolipoprotein B in ε4 carriers. The Discussion states that ε22 carriers have a propensity to develop type III hyperlipoproteinaemia, identified in the References as dysbetalipoproteinemia. Our copy does not characterize that condition as a recessive form. (LLM, conf=0.84)
Experimental — accuracy not yet measuredBoth the ε2 and the ε4 alleles are associated with unfavorable lipid profiles.
“Both the ε2 and the ε4 alleles are associated with unfavorable lipid profiles [8][9][10][11][12][13].”
From APOE and vascular disease: Sequencing and genotyping in general population cohorts (2023) · cites this paper as [8]
The ε4 allele is associated with an atherogenic lipid profile with a moderate increase in both plasma LDL cholesterol and triglycerides for ε44 versus the ε33 genotype.
“the ε4 allele is associated with an atherogenic lipid profile with a moderate increase in both plasma LDL cholesterol and triglycerides for ε44 versus the ε33 genotype [8].”
From APOE and vascular disease: Sequencing and genotyping in general population cohorts (2023) · cites this paper as [8]
Previous work on common APOE variants found that genetically low plasma apoE level was associated with increased risk of dementia and dementia-associated mortality.
“These findings are in accordance with our previous work on common APOE variants, where genetically low plasma apoE level was associated with increased risk of dementia and dementia‐associated mortality. 18 , 19”
From <i>APOE</i> and dementia – resequencing and genotyping in 105,597 individuals (2020) · cites this paper as [18]
Previous studies showed genotype-dependent differences in ApoE concentrations.
“consistent with previous studies showing genotype-dependent differences in ApoE concentrations [31, 32]”
From Plasma ApoE proteotyping for ApoE ε4 stratification in the anti-amyloid therapies era (2026) · cites this paper as [31]
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Self-citationFrontiers in lipid research: lipoprotein(a), apolipoprotein C-III and E, and PCSK9 and inflammation
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Schachtl‐Riess, J. F., Schönherr, S., Lamina, C., Forer, L., Coassin, S., Streiter, G., Kheirkhah, A., Li, Y., Meiselbach, H., Maio, S. D., et al. (2023) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2023.01.022 · Cited by 9 · see citing works
The current state of apolipoprotein E in dyslipidemia
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Nordestgaard, L. T., Christoffersen, M., Afzal, S., Nordestgaard, B. G., Tybjærg‐Hansen, A., & Frikke‐Schmidt, R. (2023) · European Journal of Epidemiology · doi:10.1007/s10654-023-01021-4 · Cited by 6 · see citing works
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PON1, APOE and SDF-1 Gene Polymorphisms and Risk of Retinal Vein Occlusion: A Case-Control Study
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The role of lipase maturation factor 1 in hypertriglyceridaemia and atherosclerosis: An update
Dabravolski, S. A., Churov, A. V., Sukhorukov, V. N., Kovyanova, T. I., Beloyartsev, D. F., Lyapina, I. N., & Orekhov, A. N. (2024) · SAGE Open Medicine · doi:10.1177/20503121241289828 · Cited by 5 · see citing works
Plasma Concentrations of Calcium and Risk of Alzheimer Disease—Observational and Genetic Studies
Thomassen, J. Q., Nordestgaard, B. G., Tybjærg‐Hansen, A., & Frikke‐Schmidt, R. (2023) · Clinical Chemistry · doi:10.1093/clinchem/hvad030 · Cited by 5 · see citing works
Self-citationThe health impacts and genetic architecture of food liking in cardio-metabolic diseases
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Common genetic variation in the APOE gene and risk of cancer: a systematic review and meta-analysis
Barakji, Y. A., Hupfeld, N. B., Bertelsen, C. A., Frikke‐Schmidt, R., Nielsen, S. F., & Rasmussen, K. L. (2025) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2025.120568 · Cited by 4 · see citing works
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O Estilo de Vida dos Muito Idosos Importa
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COVID-19 Mortality and the Cytokine Storm: An Added Value for APOE Genotyping
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Apolipoprotein E isoforms differentially affect LCAT-dependent cholesterol esterification
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Self-citationSperling, J. D., Frikke‐Schmidt, R., Scheike, T., Kessing, L. V., Miskowiak, K. W., & Vinberg, M. (2024) · Journal of Clinical Medicine · doi:10.3390/jcm13082361 · Cited by 2 · see citing works
Self-citationCommon hereditary variants of the APOE gene and posttransplant outcome in acute myeloid leukemia
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Self-citationPlasma ApoE proteotyping for ApoE ε4 stratification in the anti-amyloid therapies era
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Atherosclerosis and dementia - causal aspects and preventive potential
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The role of APOE gene polymorphisms in lung adenocarcinoma susceptibility and lipid profile
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LOESS-based normalization workflow for targeted HDL glycoproteomics in an Alzheimer's disease cohort
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Plasma Apolipoprotein E Levels and Adverse Clinical Outcomes After Ischemic Stroke
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The Association Between APOE Genotype, Race, and Dementia
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Self-citation
- Authors
- Rasmussen, K. L., Tybjærg-Hansen, A., Nordestgaard, B. G., & Frikke-Schmidt, R.
- Affiliations
- Herlev Hospital (DK)
- Department of Clinical Biochemistry, Rigshospitalet, Blegdamsvej 9, DK Copenhagen, Denmark
- University of Copenhagen (DK)
- Venue
- European Heart Journal
- Publisher
- Oxford University Press (OUP)
- Published
- 2019-06-24
- Volume
- 40
- Issue
- 33
- Pages
- 2813-2824
- ISSN
- 0195-668X (ISSN-L)
- 1522-9645
- PMC
- PMC6735871
- OpenAlex
- W2953870505
- Semantic Scholar
- 22fbcab7f50c34e27f0043f5ad7d38224ccaabe4
- Cited by
- 86
- References
- 82
- Citations by year
- 2026: 12 · 2025: 17 · 2024: 16 · 2023: 10 · 2022: 13 · 2021: 10 · 2020: 7 · 2019: 1
- FWCI
- 7.41
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- European Heart Journal (publishedVersion, cc-by-nc)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (publishedVersion, cc-by-nc)
- Funders
- Independent Research Fund Denmark (10-081618)
- Research Council at Rigshospitalet
- Lundbeck Foundation
- Danish Heart Foundation
- Danish Alzheimer Research Fund
- Gunnar Hansen’s Fund
- Research Fund at the Capital Region of Denmark
- Topics
- Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Paraoxonase enzyme and polymorphisms
- Keywords
- apolipoprotein E, APOE genotype, all-cause mortality, cardiovascular mortality, cancer mortality, causal inference
- MeSH terms
- Apolipoproteins E, Cardiovascular Diseases, Cause of Death, Dementia, Denmark, Female, Genotype, Humans, Male, Middle Aged, Neoplasms, Cohort Studies, White People
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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.
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