APOE and dementia – resequencing and genotyping in 105,597 individuals
Open accessAbstract
Introduction: The mechanism behind the strong association between the ɛ2/ɛ3/ɛ4 apolipoprotein E gene (APOE) polymorphism and Alzheimer's disease is not well‐characterized. Because low plasma levels of apoE associate with risk of dementia, genetic variants altering apoE levels in general may also associate with dementia. Methods: The APOE gene was sequenced in 10,369 individuals, and nine amino acid–changing variants with frequencies ≥2/10,000 were further genotyped in 95,228 individuals. Plasma apoE levels were measured directly. Results: Risk of all dementia and Alzheimer's disease (AD) increased with decreasing genetically determined apoE levels (P = 5 × 10−4 and P = 1 × 10−4 after APOE ɛ2/ɛ3/ɛ4 adjustment). Hazard ratios (95% confidence intervals) for all dementia and AD were 2.76 (1.39 to 5.47) and 4.92 (2.36 to 10.29) for the group with the genetically lowest apoE versus ɛ33. Discussion: We found that genetically low apoE levels increase and genetically high levels decrease risk, beyond ɛ2/ɛ3/ɛ4. This underscores that dementia risk more likely relates to variants affecting levels of apoE.
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Written from the paper’s full text.
TL;DR
Resequencing and genotyping of *APOE* in 105,597 Danish general-population individuals found that genetically low plasma apoE levels increase risk of all dementia and Alzheimer’s disease, while genetically high levels decrease risk, beyond the common ε2/ε3/ε4 polymorphism. Rare amino acid–changing *APOE* variants contribute to dementia risk, suggesting *APOE*-associated risk relates more broadly to variants affecting apoE levels.
Key findings
- Risk of all dementia and Alzheimer’s disease increased with decreasing genetically determined apoE levels: P = 5 × 10⁻⁴ and P = 1 × 10⁻⁴ after *APOE* ε2/ε3/ε4 adjustment.
- For the genetically lowest apoE group versus ε33, hazard ratios (95% CIs) were 2.76 (1.39–5.47) for all dementia and 4.92 (2.36–10.29) for Alzheimer’s disease after ε2/ε3/ε4 adjustment; unadjusted estimates were 5.25 (4.61–5.98) and 7.54 (6.46–8.79).
- For a 1 mg/dL genetic decrease in plasma apoE, hazard ratios were 2.18 (1.35–3.50) for all dementia and 2.66 (1.49–4.77) for Alzheimer’s disease after ε2/ε3/ε4 adjustment.
- Individual rare variants showed risk associations: Leu46Pro heterozygotes had HR 1.87 (1.39–2.51) for all dementia and 2.36 (1.66–3.34) for Alzheimer’s disease; Glu114Lys heterozygotes had HR 2.75 (1.37–5.51) and 3.64 (1.63–8.13), respectively.
Methods
- Two Danish general-population cohorts, the Copenhagen City Heart Study (CCHS) and Copenhagen General Population Study (CGPS), included 105,597 individuals; 3,444 developed dementia. The translated *APOE* region was resequenced in 10,369 CCHS individuals, identifying 27 rare variants; nine amino acid–changing variants with frequency ≥2/10,000 were genotyped in 95,228 CGPS individuals. Plasma apoE was measured directly.
- Cox regression models adjusted for age (time scale), sex, body mass index, smoking, hypertension, diabetes, lipid-lowering therapy, alcohol consumption, physical inactivity, postmenopausal status, hormonal replacement therapy, and education, and further for *APOE* ε2/ε3/ε4 genotype. An apoE-weighted allele score using 11 apoE-changing variants was categorized into five groups and 13 groups, with an unweighted allele score sensitivity analysis.
Limitations
- The paper states that dementia diagnosis validity is a potential concern, but Danish registry dementia diagnoses have high diagnostic validity; unregistered events would decrease power and bias results toward the null.
- The paper states that generalizability is limited because participants were white individuals only, and that the allele-score weights were estimated from the same data to which they were applied, creating potential overfitting and possibly poorer performance in other populations.
- Evident from the text: several rare-variant analyses had no events or very wide confidence intervals, and the observational plasma apoE analyses began at study entry and included only individuals with available plasma apoE measurements.
Model-written summary. Check it against the paper before relying on it.
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Cites
Statistics
Claims the paper makes
20 of 45 cited sources checked · 6 supported · 0 flagged · accuracy not yet measured
- Premisecitation
Two case-studies of patients with frameshift mutations and premature stop codons in exon 4 did not observe clear neurocognitive defects.
“Furthermore, two case‐studies of patients with frameshift mutations and premature stop codons in exon 4 did not observe clear neurocognitive defects, and one case‐control study found a higher frequency of a combined Glu262Lys and Glu263Lys variant in patients with memory complaints (P = .08) 39 , 40 , 41”
Quote in the paperNot a substantial claim2 of 3 sources checked- cites [39] Youn YC, Lim YK, Giau VV, et al. Apolipoprotein epsilon7 allele in memory complaints: insights through protein structure prediction. Clin Interv Aging. 2017; 12: 1095‐ 1102. 28744113 PMC5513808 source
The Results (APOE genotype frequencies; page unavailable) describe three carriers of an APOE ε7 variant, including two with cognitive impairment and one with subjective memory complaints. Our copy does not report the two case studies involving frameshift mutations and premature stop codons in exon 4. Searches for those terms found no passage addressing the claimed cases. (LLM, conf=0.75)
Experimental — accuracy not yet measured - cites [40] Mak AC, Pullinger CR, Schwarz JM, et al. Effects of the absence of apolipoprotein e on lipoproteins, neurocognitive function, and retinal function. JAMA Neurol. 2014; 71: 1228‐ 1236. 25111166 PMC4714860 source
- cites [41] Lohse P, Brewer HB, III, Meng MS, Skarlatos SI, LaRosa JC, Brewer HB, Jr. Familial apolipoprotein E deficiency and type III hyperlipoproteinemia due to a premature stop codon in the apolipoprotein E gene. J Lipid Res. 1992; 33: 1583‐ 1590. 1361196 source
- Interpretationcitation
The ε2-like and ε4-like deviations of the structure of apoE have potential important biologic and therapeutic implications.
“Taken together, and in light of the potential amyloid‐neutralizing effect of an apoE‐increasing mutation, 26 these ε2‐like and ε4‐like deviations of the structure of apoE have potential important biologic and therapeutic implications.”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [26] Arboleda‐Velasquez JF, Lopera F, Delgado‐Tirado S, et al. Resistance to autosomal dominant Alzheimer's disease in an APOE3 Christchurch homozygote: a case report. Nat Med. 2019; 25: 1680‐ 1683. 31686034 PMC6898984 source
The citation is attached to the proposed amyloid-neutralizing effect of a mutation, not to the citing authors’ conclusion about ε2-like and ε4-like structure. The paper’s amyloid-aggregation passage (labelled Abstract in our copy; no page given) reports less Aβ42 aggregation with ApoE3 Christchurch than with ordinary ApoE3 in vitro. It does not describe Christchurch as an apoE-increasing mutation; its concluding passage instead proposes lowering apoE expression as a possible intervention. (LLM, conf=0.85)
Experimental — accuracy not yet measured
- Premisecitation
A novel report on the APOE Arg154Ser mutation (APOE3 Christchurch) found that the effect of a dominant presenilin 1 mutation was neutralized in a woman from a large Colombian kindred with autosomal dominant AD.
“Of interest, this is highly supported by a novel report on the APOE Arg154Ser mutation (APOE3 Christchurch, old nomenclature Arg136Ser), where the effect of a dominant presenilin 1 mutation was neutralized in a woman from a large Columbian kindred with autosomal dominant AD. 26”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [26] Arboleda‐Velasquez JF, Lopera F, Delgado‐Tirado S, et al. Resistance to autosomal dominant Alzheimer's disease in an APOE3 Christchurch homozygote: a case report. Nat Med. 2019; 25: 1680‐ 1683. 31686034 PMC6898984 source
The Abstract (page not provided) describes a woman from a Colombian autosomal dominant Alzheimer’s disease kindred who carried PSEN1 E280A and was homozygous for APOE3 Christchurch, the Arg136Ser substitution corresponding to codon 154. It reports that she developed mild cognitive impairment in her seventies, nearly three decades later than expected. Thus the clinical effect was markedly delayed, not shown to be neutralized. (LLM, conf=0.90)
Experimental — accuracy not yet measured
- Premisecitation
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”
Quote in the paperSubstantial claim1 of 2 sources checked- cites [18] Rasmussen KL, Tybjaerg‐Hansen A, Frikke‐Schmidt R. Plasma levels of apolipoprotein E, APOE genotype, and all‐cause and cause‐specific mortality in 105 949 individuals from a white general population cohort. Eur Heart J. 2019; 40: 2813‐ 2824. 31236578 PMC6735871 source
- cites [19] Rasmussen KL, Tybjaerg‐Hansen A, Nordestgaard BG, Frikke‐Schmidt R. Plasma apolipoprotein E levels and risk of dementia: a Mendelian randomization study of 106,562 individuals. Alzheimers Dement. 2018; 14: 71‐ 80. 28774656 source
- Findingown data
Plasma apoE levels were decreased for the rare variant Arg269Gly.
“Plasma apoE levels were increased for Gly145Asp and Arg154Cys (P ≤ 8 × 10−9); were decreased for Ala23Val, Leu46Pro, Glu114Lys, and Arg269Gly (P ≤ 4 × 10−5); and were unaltered from the population median for Thr11Ser, Glu31Lys, and Val254Glu (P ≥ .35) (Figure S1).”
Quote in the paperNot a substantial claim
- Findingown data
The hazard ratio for Alzheimer's disease for the group with the genetically lowest apoE versus ε33 was 4.92 (95% CI 2.36 to 10.29).
“Hazard ratios (95% confidence intervals) for all dementia and AD were 2.76 (1.39 to 5.47) and 4.92 (2.36 to 10.29) for the group with the genetically lowest apoE versus ɛ33.”
Quote in the paperSubstantial claim - Findingown data
Plasma apoE levels were decreased for the rare variant Ala23Val.
“Plasma apoE levels were increased for Gly145Asp and Arg154Cys (P ≤ 8 × 10−9); were decreased for Ala23Val, Leu46Pro, Glu114Lys, and Arg269Gly (P ≤ 4 × 10−5); and were unaltered from the population median for Thr11Ser, Glu31Lys, and Val254Glu (P ≥ .35) (Figure S1).”
Quote in the paperNot a substantial claim - Findingown data
Plasma apoE levels were decreased for the rare variant Leu46Pro.
“Plasma apoE levels were increased for Gly145Asp and Arg154Cys (P ≤ 8 × 10−9); were decreased for Ala23Val, Leu46Pro, Glu114Lys, and Arg269Gly (P ≤ 4 × 10−5); and were unaltered from the population median for Thr11Ser, Glu31Lys, and Val254Glu (P ≥ .35) (Figure S1).”
Quote in the paperNot a substantial claim - Findingown data
Plasma apoE levels were unaltered from the population median for the rare variant Val254Glu.
“Plasma apoE levels were increased for Gly145Asp and Arg154Cys (P ≤ 8 × 10−9); were decreased for Ala23Val, Leu46Pro, Glu114Lys, and Arg269Gly (P ≤ 4 × 10−5); and were unaltered from the population median for Thr11Ser, Glu31Lys, and Val254Glu (P ≥ .35) (Figure S1).”
Quote in the paperNot a substantial claim - Findingown data
Plasma apoE levels were increased for the rare variant Arg154Cys.
“Plasma apoE levels were increased for Gly145Asp and Arg154Cys (P ≤ 8 × 10−9); were decreased for Ala23Val, Leu46Pro, Glu114Lys, and Arg269Gly (P ≤ 4 × 10−5); and were unaltered from the population median for Thr11Ser, Glu31Lys, and Val254Glu (P ≥ .35) (Figure S1).”
Quote in the paperNot a substantial claim - Findingown data
Risk of all dementia and Alzheimer's disease increased with decreasing genetically determined apoE levels after adjustment for APOE ε2/ε3/ε4.
“Risk of all dementia and Alzheimer's disease (AD) increased with decreasing genetically determined apoE levels (P = 5 × 10−4 and P = 1 × 10−4 after APOE ɛ2/ɛ3/ɛ4 adjustment).”
Quote in the paperSubstantial claim - Findingown data
Allele frequencies for the nine rare APOE variants ranged from 0.01% to 0.36%.
“Allele frequencies for the nine rare variants ranged from 0.01% to 0.36%.”
Quote in the paperNot a substantial claim - Findingown data
Plasma apoE levels were unaltered from the population median for the rare variant Glu31Lys.
“Plasma apoE levels were increased for Gly145Asp and Arg154Cys (P ≤ 8 × 10−9); were decreased for Ala23Val, Leu46Pro, Glu114Lys, and Arg269Gly (P ≤ 4 × 10−5); and were unaltered from the population median for Thr11Ser, Glu31Lys, and Val254Glu (P ≥ .35) (Figure S1).”
Quote in the paperNot a substantial claim - Findingown data
Plasma apoE levels were unaltered from the population median for the rare variant Thr11Ser.
“Plasma apoE levels were increased for Gly145Asp and Arg154Cys (P ≤ 8 × 10−9); were decreased for Ala23Val, Leu46Pro, Glu114Lys, and Arg269Gly (P ≤ 4 × 10−5); and were unaltered from the population median for Thr11Ser, Glu31Lys, and Val254Glu (P ≥ .35) (Figure S1).”
Quote in the paperNot a substantial claim - Findingown data
No dementia events were observed for heterozygote carriers of Thr11Ser.
“No events were observed for heterozygote carriers of Thr11Ser, Gly145Asp, and Arg154Cys, and for homozygote carriers of Leu46Pro.”
Quote in the paperNot a substantial claim - Findingown data
Plasma apoE levels were decreased for the rare variant Glu114Lys.
“Plasma apoE levels were increased for Gly145Asp and Arg154Cys (P ≤ 8 × 10−9); were decreased for Ala23Val, Leu46Pro, Glu114Lys, and Arg269Gly (P ≤ 4 × 10−5); and were unaltered from the population median for Thr11Ser, Glu31Lys, and Val254Glu (P ≥ .35) (Figure S1).”
Quote in the paperNot a substantial claim - Findingown data
The hazard ratio for all dementia for the group with the genetically lowest apoE versus ε33 was 2.76 (95% CI 1.39 to 5.47).
“Hazard ratios (95% confidence intervals) for all dementia and AD were 2.76 (1.39 to 5.47) and 4.92 (2.36 to 10.29) for the group with the genetically lowest apoE versus ɛ33.”
Quote in the paperSubstantial claim - Findingown data
Plasma apoE levels were increased for the rare variant Gly145Asp.
“Plasma apoE levels were increased for Gly145Asp and Arg154Cys (P ≤ 8 × 10−9); were decreased for Ala23Val, Leu46Pro, Glu114Lys, and Arg269Gly (P ≤ 4 × 10−5); and were unaltered from the population median for Thr11Ser, Glu31Lys, and Val254Glu (P ≥ .35) (Figure S1).”
Quote in the paperNot a substantial claim - Findingown data
Twenty-seven rare APOE variants were identified by resequencing APOE in the Copenhagen City Heart Study.
“Twenty‐seven rare APOE variants were identified by resequencing APOE in the CCHS, and consequently nine amino acid–changing rare variants with frequencies ≥2/10,000 were further genotyped in the CGPS (Figure 1).”
Quote in the paperSubstantial claim - Findingown data
The hazard ratio for Alzheimer's disease for Leu46Pro heterozygotes versus non-carriers was 2.36 (95% CI 1.66 to 3.34).
“Corresponding HRs for AD were 1.88 (0.26 to 13.37), 5.79 (0.81 to 41.42), 2.36 (1.66 to 3.34), 3.64 (1.63 to 8.13), 0.57 (0.14 to 2.28), and 1.16 (0.29 to 4.64), respectively.”
Quote in the paperSubstantial claim - Findingown data
The hazard ratio for all dementia for Ala23Val heterozygotes versus non-carriers was 0.87 (95% CI 0.12 to 6.17).
“Hazard ratios (HRs) (95% confidence intervals [CIs]) for heterozygotes versus non‐carriers for all dementia were 0.87 (0.12 to 6.17) for Ala23Val, 3.34 (0.47 to 23.85) for Glu31Lys, 1.87 (1.39 to 2.51) for Leu46Pro, 2.75 (1.37 to 5.51) for Glu114Lys, 0.30 (0.08 to 1.22) for Val254Glu, and 1.04 (0.34 to 3.23) for Arg269Gly.”
Quote in the paperNot a substantial claim - Findingown data
The hazard ratio for Alzheimer's disease for Val254Glu heterozygotes versus non-carriers was 0.57 (95% CI 0.14 to 2.28).
“Corresponding HRs for AD were 1.88 (0.26 to 13.37), 5.79 (0.81 to 41.42), 2.36 (1.66 to 3.34), 3.64 (1.63 to 8.13), 0.57 (0.14 to 2.28), and 1.16 (0.29 to 4.64), respectively.”
Quote in the paperNot a substantial claim - Findingown data
After APOE ɛ2/ɛ3/ɛ4 adjustment, the hazard ratio for Alzheimer's disease for the very low weighted allele score group versus ɛ33 was 4.92 (95% CI 2.36 to 10.29).
“Corresponding estimates after APOE ɛ2/ɛ3/ɛ4 adjustment were 2.76 (1.39 to 5.47) and 4.92 (2.36 to 10.29).”
Quote in the paperSubstantial claim - Findingown data
No dementia events were observed for heterozygote carriers of Gly145Asp.
“No events were observed for heterozygote carriers of Thr11Ser, Gly145Asp, and Arg154Cys, and for homozygote carriers of Leu46Pro.”
Quote in the paperNot a substantial claim - Findingown data
The significant hazard ratio estimates for Leu46Pro heterozygotes disappeared after APOE ε2/ε3/ε4 adjustment.
“Estimates for Glu31Lys and Glu114Lys improved after APOE ɛ2/ɛ3/ɛ4 adjustment, whereas the significant estimates for Leu46Pro heterozygotes disappeared.”
Quote in the paperSubstantial claim - Findingown data
The apoE-weighted allele score in five groups and sex or cohort did not interact in predicting risk of all dementia and Alzheimer's disease.
“ApoE‐weighted allele score in five groups and sex or cohort did not interact in predicting risk of all dementia and AD (all P‐values ≥ .10).”
Quote in the paperSubstantial claim - Findingown data
For ε33 individuals only, the hazard ratio for all dementia for a 1 mg/dL genetic decrease in plasma apoE was 2.48 (95% CI 1.44 to 2.25).
“Corresponding HRs for the weighted allele score in ε33 individuals only were 2.48 (1.44 to 2.25) and 3.63 (1.98 to 6.66), respectively (Figure 5).”
Quote in the paperNot a substantial claim - Findingown data
The hazard ratio for all dementia for Arg269Gly heterozygotes versus non-carriers was 1.04 (95% CI 0.34 to 3.23).
“Hazard ratios (HRs) (95% confidence intervals [CIs]) for heterozygotes versus non‐carriers for all dementia were 0.87 (0.12 to 6.17) for Ala23Val, 3.34 (0.47 to 23.85) for Glu31Lys, 1.87 (1.39 to 2.51) for Leu46Pro, 2.75 (1.37 to 5.51) for Glu114Lys, 0.30 (0.08 to 1.22) for Val254Glu, and 1.04 (0.34 to 3.23) for Arg269Gly.”
Quote in the paperNot a substantial claim - Findingown data
A 1 mg/dL decrease in genetically determined plasma apoE levels increased risk of dementia two- to fourfold.
“A 1 mg/dL decrease in genetically determined plasma apoE levels increased risk of dementia two‐ to fourfold.”
Quote in the paperSubstantial claim - Findingown data
The hazard ratio for all dementia for Leu46Pro heterozygotes versus non-carriers was 1.87 (95% CI 1.39 to 2.51).
“Hazard ratios (HRs) (95% confidence intervals [CIs]) for heterozygotes versus non‐carriers for all dementia were 0.87 (0.12 to 6.17) for Ala23Val, 3.34 (0.47 to 23.85) for Glu31Lys, 1.87 (1.39 to 2.51) for Leu46Pro, 2.75 (1.37 to 5.51) for Glu114Lys, 0.30 (0.08 to 1.22) for Val254Glu, and 1.04 (0.34 to 3.23) for Arg269Gly.”
Quote in the paperSubstantial claim - Findingown data
For a 1 mg/dL genetic decrease in plasma apoE, the hazard ratio for all dementia was 2.18 (95% CI 1.35 to 3.50) for the weighted allele score after ε2/ε3/ε4 adjustment.
“HRs for a 1 mg/dL genetic decrease in plasma apoE were 2.18 (1.35 to 3.50) for all dementia and 2.66 (1.49 to 4.77) for AD for the weighted allele score after ε2/ε3/ε4 adjustment (Figure 5).”
Quote in the paperSubstantial claim - Findingown data
The hazard ratio for Alzheimer's disease for Arg269Gly heterozygotes versus non-carriers was 1.16 (95% CI 0.29 to 4.64).
“Corresponding HRs for AD were 1.88 (0.26 to 13.37), 5.79 (0.81 to 41.42), 2.36 (1.66 to 3.34), 3.64 (1.63 to 8.13), 0.57 (0.14 to 2.28), and 1.16 (0.29 to 4.64), respectively.”
Quote in the paperNot a substantial claim - Findingown data
For 12 groups of clean ε22, ε32, ε42, ε33, ε43, and ε44 genotypes and the same genotypes with additional rare variation, a similar pattern of risk as for the weighted allele score in 13 groups was observed (P for trends ≤5 × 10−100).
“For 12 groups of the clean ε22, ε32, ε42, ε33, ε43, and ε44 genotypes, as well as the same genotypes with additional rare variation (ε22+, ε32+, ε42+, ε33+, ε43+, and ε44+) a similar pattern as for the weighted allele score in 13 groups was observed (Figure S3; P for trends were ≤5 × 10−100).”
Quote in the paperNot a substantial claim - Findingown data
For a 1 mg/dL genetic decrease in plasma apoE, the hazard ratio for Alzheimer's disease was 2.66 (95% CI 1.49 to 4.77) for the weighted allele score after ε2/ε3/ε4 adjustment.
“HRs for a 1 mg/dL genetic decrease in plasma apoE were 2.18 (1.35 to 3.50) for all dementia and 2.66 (1.49 to 4.77) for AD for the weighted allele score after ε2/ε3/ε4 adjustment (Figure 5).”
Quote in the paperSubstantial claim - Findingown data
The hazard ratio for all dementia for Glu31Lys heterozygotes versus non-carriers was 3.34 (95% CI 0.47 to 23.85).
“Hazard ratios (HRs) (95% confidence intervals [CIs]) for heterozygotes versus non‐carriers for all dementia were 0.87 (0.12 to 6.17) for Ala23Val, 3.34 (0.47 to 23.85) for Glu31Lys, 1.87 (1.39 to 2.51) for Leu46Pro, 2.75 (1.37 to 5.51) for Glu114Lys, 0.30 (0.08 to 1.22) for Val254Glu, and 1.04 (0.34 to 3.23) for Arg269Gly.”
Quote in the paperNot a substantial claim - Findingown data
For ε33 individuals only, the hazard ratio for Alzheimer's disease for a 1 mg/dL genetic decrease in plasma apoE was 3.63 (95% CI 1.98 to 6.66).
“Corresponding HRs for the weighted allele score in ε33 individuals only were 2.48 (1.44 to 2.25) and 3.63 (1.98 to 6.66), respectively (Figure 5).”
Quote in the paperNot a substantial claim - Findingown data
The hazard ratio for all dementia for Val254Glu heterozygotes versus non-carriers was 0.30 (95% CI 0.08 to 1.22).
“Hazard ratios (HRs) (95% confidence intervals [CIs]) for heterozygotes versus non‐carriers for all dementia were 0.87 (0.12 to 6.17) for Ala23Val, 3.34 (0.47 to 23.85) for Glu31Lys, 1.87 (1.39 to 2.51) for Leu46Pro, 2.75 (1.37 to 5.51) for Glu114Lys, 0.30 (0.08 to 1.22) for Val254Glu, and 1.04 (0.34 to 3.23) for Arg269Gly.”
Quote in the paperNot a substantial claim - Findingown data
No dementia events were observed for homozygote carriers of Leu46Pro.
“No events were observed for heterozygote carriers of Thr11Ser, Gly145Asp, and Arg154Cys, and for homozygote carriers of Leu46Pro.”
Quote in the paperNot a substantial claim - Findingown data
No dementia events were observed for heterozygote carriers of Arg154Cys.
“No events were observed for heterozygote carriers of Thr11Ser, Gly145Asp, and Arg154Cys, and for homozygote carriers of Leu46Pro.”
Quote in the paperNot a substantial claim - Findingown data
Excluding three or six variants in the weighted allele score did not change estimates substantially.
“Excluding three or six variants in the weighted allele score did not change estimates substantially (Figures S4 and S5).”
Quote in the paperNot a substantial claim - Findingown data
The hazard ratio for all dementia for Glu114Lys heterozygotes versus non-carriers was 2.75 (95% CI 1.37 to 5.51).
“Hazard ratios (HRs) (95% confidence intervals [CIs]) for heterozygotes versus non‐carriers for all dementia were 0.87 (0.12 to 6.17) for Ala23Val, 3.34 (0.47 to 23.85) for Glu31Lys, 1.87 (1.39 to 2.51) for Leu46Pro, 2.75 (1.37 to 5.51) for Glu114Lys, 0.30 (0.08 to 1.22) for Val254Glu, and 1.04 (0.34 to 3.23) for Arg269Gly.”
Quote in the paperSubstantial claim - Findingown data
The hazard ratio for Alzheimer's disease for the very low weighted allele score group versus ɛ33 was 7.54 (95% CI 6.46 to 8.79).
“HRs (95% CIs) for all dementia and AD were 5.25 (4.61 to 5.98) and 7.54 (6.46 to 8.79) for the very low weighted allele score group versus ɛ33 (Figure 3).”
Quote in the paperSubstantial claim - Findingown data
After APOE ɛ2/ɛ3/ɛ4 adjustment, the hazard ratio for all dementia for the very low weighted allele score group versus ɛ33 was 2.76 (95% CI 1.39 to 5.47).
“Corresponding estimates after APOE ɛ2/ɛ3/ɛ4 adjustment were 2.76 (1.39 to 5.47) and 4.92 (2.36 to 10.29).”
Quote in the paperSubstantial claim - Findingown data
For apoE-weighted allele score in 13 groups arranged according to APOE ε2/ε3/ε4 genotype, there was an overall increased risk of all dementia and Alzheimer's disease with decreasing apoE-weighted allele score groups (P for trends ≤1 × 10−100).
“For apoE‐weighted allele score in 13 groups arranged according to APOE ε2/ε3/ε4 genotype (ε22, ε32, ε42, ε33, ε43, and ε44 without rare variation), there was an overall increased risk with decreasing apoE‐weighted allele score groups for both all dementia and AD (Figure 4; P for trends ≤1 × 10−100).”
Quote in the paperSubstantial claim - Findingown data
The hazard ratio for Alzheimer's disease for Glu114Lys heterozygotes versus non-carriers was 3.64 (95% CI 1.63 to 8.13).
“Corresponding HRs for AD were 1.88 (0.26 to 13.37), 5.79 (0.81 to 41.42), 2.36 (1.66 to 3.34), 3.64 (1.63 to 8.13), 0.57 (0.14 to 2.28), and 1.16 (0.29 to 4.64), respectively.”
Quote in the paperSubstantial claim - Findingown data
Risk estimates for Glu31Lys, Glu114Lys, and Val254Glu did not change after exclusion of the three compound heterozygotes.
“and risk estimates for Glu31Lys, Glu114Lys, and Val254Glu did not change after exclusion of the three compound heterozygotes (data not shown).”
Quote in the paperNot a substantial claim - Findingown data
The rs769452 (Leu46Pro) variant is not associated with any expression quantitative trait loci.
“The three promoter variants and the ɛ2/ɛ3/ɛ4 polymorphism are associated with expression quantitative trait loci (eQTLs) of APOE or nearby genes in linkage disequilibrium with APOE, whereas the rs769452 (Leu46Pro) is not associated with any eQTLs (Table S4).”
Quote in the paperNot a substantial claim - Findingown data
The hazard ratio for Alzheimer's disease for Ala23Val heterozygotes versus non-carriers was 1.88 (95% CI 0.26 to 13.37).
“Corresponding HRs for AD were 1.88 (0.26 to 13.37), 5.79 (0.81 to 41.42), 2.36 (1.66 to 3.34), 3.64 (1.63 to 8.13), 0.57 (0.14 to 2.28), and 1.16 (0.29 to 4.64), respectively.”
Quote in the paperNot a substantial claim - Findingown data
The hazard ratio for all dementia for the very low weighted allele score group versus ɛ33 was 5.25 (95% CI 4.61 to 5.98).
“HRs (95% CIs) for all dementia and AD were 5.25 (4.61 to 5.98) and 7.54 (6.46 to 8.79) for the very low weighted allele score group versus ɛ33 (Figure 3).”
Quote in the paperSubstantial claim - Findingown data
The three APOE promoter variants and the ε2/ε3/ε4 polymorphism are associated with expression quantitative trait loci of APOE or nearby genes in linkage disequilibrium with APOE.
“The three promoter variants and the ɛ2/ɛ3/ɛ4 polymorphism are associated with expression quantitative trait loci (eQTLs) of APOE or nearby genes in linkage disequilibrium with APOE, whereas the rs769452 (Leu46Pro) is not associated with any eQTLs (Table S4).”
Quote in the paperNot a substantial claim - Findingown data
The hazard ratio for Alzheimer's disease for Glu31Lys heterozygotes versus non-carriers was 5.79 (95% CI 0.81 to 41.42).
“Corresponding HRs for AD were 1.88 (0.26 to 13.37), 5.79 (0.81 to 41.42), 2.36 (1.66 to 3.34), 3.64 (1.63 to 8.13), 0.57 (0.14 to 2.28), and 1.16 (0.29 to 4.64), respectively.”
Quote in the paperNot a substantial claim - Findingreasoning
The association between the weighted allele score groups and risk of dementia becomes more linear after adjusting for the ɛ2/ɛ3/ɛ4 polymorphism.
“This general statement is highly supported by the fact that the association between the weighted allele score groups and risk of dementia becomes more linear after adjusting for the ɛ2/ɛ3/ɛ4 polymorphism.”
Quote in the paperSubstantial claim - Findingown data
The combined Glu262Lys and Glu263Lys variant was not found in our population.
“however, these variants were not found in our population.”
Quote in the paperNot a substantial claim - Findingreasoning
After adjustment, the weighted allele score groups reflect that genetically high apoE levels in general are associated with low risk.
“However, after adjustment, the weighted allele score groups reflect that genetically high apoE levels in general are associated with low risk.”
Quote in the paperSubstantial claim - Interpretationnone given
Structural changes in apoE beyond the common APOE ε2/ε3/ε4 polymorphism contribute to risk of dementia.
“Structural changes in apoE beyond the common apolipoprotein E gene (APOE) ε2/ε3/ε4 polymorphism contribute to risk of dementia, where genetically low apoE levels increase and genetically high apoE decrease risk.”
Quote in the paperSubstantial claim - Interpretationown data
Dementia risk more likely relates to variants affecting levels of apoE.
“This underscores that dementia risk more likely relates to variants affecting levels of apoE.”
Quote in the paperSubstantial claim - Study design and conductreasoning
The apoE-weighted allele score was constructed to capture contributions from both the common APOE ɛ2/ɛ3/ɛ4 polymorphism and the nine rare variants while accounting for linkage disequilibrium between all variants.
“By doing so, we ensured that the contribution from both the common APOE ɛ2/ɛ3/ɛ4 polymorphism and the nine rare variants were captured, and at the same time ensured that linkage disequilibrium between all variants were accounted for (Table 1).”
Quote in the paperSubstantial claim - Interpretationown data
Variation near the ε4-defining residue Cys130Arg results in an ε4-like increased risk of dementia.
“Second, variation near the ε4‐defining residue Cys130Arg results in an ε4‐like increased risk of dementia.”
Quote in the paperSubstantial claim - Interpretationnone given
This is the first time that the full spectrum of genetic variation in the coding parts of the APOE gene, corresponding effects on the direct gene product, levels of apoE, and risk of dementia are presented in a large general population cohort.
“This is the first time that the full spectrum of genetic variation in the coding parts of the APOE gene, corresponding effects on the direct gene product, levels of apoE, and risk of dementia are presented in a large general population cohort.”
Quote in the paperSubstantial claim - Premisenone given
That resequencing study was unable to investigate the effects of the identified rare variants for development of dementia in a large prospective set-up with an unselected population with long follow-up.
“However, that study was unable to investigate the effects of the identified rare variants for development of dementia in a large prospective set‐up with an unselected population with long follow‐up.”
Quote in the paperNot a substantial claim - Study design and conductreasoning
No individuals were lost to follow-up due to the completeness of the Danish nationwide registries.
“Median follow‐up from start of the registries was 40 years (range 0 to 41 years) for all dementia, with no individuals lost to follow‐up due to the completeness of the Danish nationwide registries.”
Quote in the paperSubstantial claim - Interpretationown data
The risk increase conferred by the APOE gene is not a property solely related to the common ε2/ɛ3/ɛ4 polymorphism, but more likely relates to variants affecting levels of apoE in general.
“These novel findings underscore the importance of structurally well‐functioning apoE in dementia risk and that risk increase conferred by the APOE gene is not a property solely related to the common ε2/ɛ3/ɛ4 polymorphism, but more likely relates to variants affecting levels of apoE in general.”
Quote in the paperSubstantial claim - Interpretationreasoning
The higher risk and higher apoE levels of the ɛ42 genotype result in a less linear trend for the weighted allele score group before adjustment, because the 'high' weighted allele score group contains the majority of ɛ42 individuals.
“This results in a less linear trend for the weighted allele score group before adjustment, because the “high” weighted allele score group contains the majority of ɛ42 individuals.”
Quote in the paperSubstantial claim - Study design and conductreasoning
Due to the large sample size, the study was able to conduct survival analyses with meaningful power despite allele frequencies for the nine rare variants being ≤0.4%.
“In addition, due to the large sample size, we were able to conduct survival analyses with a meaningful power despite the fact that allele frequencies for the nine rare variants were ≤0.4%.”
Quote in the paperSubstantial claim - Study design and conductown data
Because the weights for the 11 apoE-changing variants were estimated from the data to which they were applied, risk of overfitting is a potential limitation.
“Third, as the present large prospective cohort study is the only study with measurements of both plasma apoE and genetic variation, the weights for the 11 apoE‐changing variants were estimated from the data to which they were applied. Therefore, risk of overfitting is a potential limitation”
Quote in the paperNot a substantial claim - Interpretationreasoning
Rare genetic variation in APOE may add to explain missing heritability for dementia.
“Rare genetic variation in APOE may thus add to explain missing heritability for dementia.”
Quote in the paperSubstantial claim - Study design and conductreasoning
As the score is generated in a very homogeneous sample, it may be less likely to perform as well in other populations.
“and as the score is generated in a very homogeneous sample, it may be less likely to perform as well in other populations.”
Quote in the paperNot a substantial claim
- Classified as probably not a substantial claim. 20
- May combine two claims. 40
- The quote only partly states this claim. 1
Classified as probably not a substantial claim.
PremisecitationThe APOE gene is an impressive genome-wide association signal for risk of Alzheimer's disease.
“In genome‐wide association studies (GWASs) the apolipoprotein E (APOE) gene stands out as an impressive signal for risk of Alzheimer's disease (AD), 6 , 7”
Quote in the paperSubstantial claim1 of 2 sources checked- cites [6] Lambert JC, Ibrahim‐Verbaas CA, Naj AC, et al. Meta‐analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer's disease. Nat Genet. 2013; 45: 1452‐ 1458. 24162737 PMC3896259 source
- cites [7] Kunkle BW, Grenier‐Boley B, Bis JC, et al. Genetic meta‐analysis of diagnosed Alzheimer's disease identifies new risk loci and implicates Abeta, tau, immunity and lipid processing. Nat Genet. 2019; 51: 414‐ 430. 30820047 PMC6463297 source
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationBrain apoE plays a major role in brain amyloid metabolism, in blood-brain barrier integrity, and in supplying cholesterol and phospholipids to neuronal cells.
“Whereas brain apoE plays a major role in brain amyloid metabolism, in blood‐brain barrier integrity, and in supplying cholesterol and phospholipids to neuronal cells, 12 , 13 , 14 , 16 , 30 , 31”
Quote in the paperNot a substantial claim1 of 3 sources checked- cites [12] Bell RD, Winkler EA, Sagare AP, et al. Apolipoprotein E controls cerebrovascular integrity via cyclophilin A. Nature. 2012; 485: 512‐ 516. 22622580 PMC4047116 source
The paper’s main text (indexed under Abstract; no page given) reports that APOE2 and APOE3 maintain blood–brain barrier integrity in mice, while APOE4 promotes its disruption. The passages found do not establish the other attributed roles—brain amyloid metabolism or supplying cholesterol and phospholipids to neuronal cells (searched those terms and amyloid-beta clearance). (LLM, conf=0.87)
Experimental — accuracy not yet measured - cites [13] Rasmussen KL. Plasma levels of apolipoprotein E, APOE genotype and risk of dementia and ischemic heart disease: a review. Atherosclerosis. 2016; 255: 145‐ 144. 28340945
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [14] Wellington CL, Frikke‐Schmidt R. Relation between plasma and brain lipids. Curr Opin Lipidol. 2016; 27: 225‐ 232. 27149391 source
May combine two claims.
PremisecitationHSPG binding studies have shown that apoE4 had higher affinity than apoE3, apoE2 and apoE3 Christchurch, and antibodies raised against the receptor-binding region mimicked the protective effect of apoE2 and apoE3 Christchurch.
“It is important to note that HSPGs binding studies have shown that apoE4 had higher affinity than apoE3, apoE2 and apoE3 Christchurch, 29 and antibodies raised against the receptor‐binding region mimicked the protective effect of apoE2 and apoE3 Christchurch, 26”
Quote in the paperNot a substantial claim2 of 2 sources checked- cites [29] Yamauchi Y, Deguchi N, Tanaka M, et al. Role of the N‐ and C‐terminal domains in binding of apolipoprotein E isoforms to heparan sulfate and dermatan sulfate: a surface plasmon resonance study. Biochemistry. 2008; 47: 6702‐ 6710. 18507396 PMC2844924 source
The Results (page unavailable) report greater apoE4 binding to heparan sulfate and dermatan sulfate than apoE2 or apoE3, supporting the comparison with those two isoforms. They do not report a comparison with apoE3 Christchurch; they also say equilibrium affinity differed little among the tested lipidated isoforms. The antibody finding carries a separate citation in the citing sentence and is not attributed to this paper. (LLM, conf=0.88)
Experimental — accuracy not yet measured - cites [26] Arboleda‐Velasquez JF, Lopera F, Delgado‐Tirado S, et al. Resistance to autosomal dominant Alzheimer's disease in an APOE3 Christchurch homozygote: a case report. Nat Med. 2019; 25: 1680‐ 1683. 31686034 PMC6898984 source
Citation 26 is attached to the antibody claim. The paper’s Abstract reports that an antibody against ApoE amino acids 130–143 reduced ApoE3 heparin binding in vitro to the level seen with ApoE3 Christchurch. It suggests this could reproduce a potentially protective effect, but does not demonstrate protection or show that the antibody mimics an effect of ApoE2. (LLM, conf=0.87)
Experimental — accuracy not yet measured
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationHSPGs are suggested to play a role in neuronal uptake of tau and in amyloid beta metabolism, and apoE binding may play an important role here.
“HSPGs are suggested to play a role in neuronal uptake of tau and in amyloid beta metabolism, and apoE binding may play an important role here. 26 , 27”
Quote in the paperNot a substantial claim2 of 2 sources checked- cites [26] Arboleda‐Velasquez JF, Lopera F, Delgado‐Tirado S, et al. Resistance to autosomal dominant Alzheimer's disease in an APOE3 Christchurch homozygote: a case report. Nat Med. 2019; 25: 1680‐ 1683. 31686034 PMC6898984 source
- cites [27] Rauch JN, Chen JJ, Miller GM, et al. Tau internalization is regulated by 6‐O sulfation on Heparan Sulfate Proteoglycans (HSPGs). Sci Rep. 2018; 8: 6382. 29686391 PMC5913225 source
The Introduction and Results report that HSPG-modifying enzymes influence tau uptake, including in iPS-derived neurons. The cited paper does not address HSPGs in amyloid beta metabolism or a role for apoE binding; searches for those terms found no relevant passage. (LLM, conf=0.90)
Experimental — accuracy not yet measured
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Premisecitationε4 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”
Quote in the paperNot a substantial claim1 of 2 sources checked- cites [15] Mahley RW, Jr, Rall SC. Type III hyperlipoproteinemia (dysbetalipoproteinemia): the role of apolipoprotein E in normal and abnormal lipoprotein metabolism. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The Metabolic and Molecular Bases of Inherited Disease. 8th ed. New York, NY: McGraw‐Hill; 2001: 2835‐ 2862.
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [18] Rasmussen KL, Tybjaerg‐Hansen A, Frikke‐Schmidt R. Plasma levels of apolipoprotein E, APOE genotype, and all‐cause and cause‐specific mortality in 105 949 individuals from a white general population cohort. Eur Heart J. 2019; 40: 2813‐ 2824. 31236578 PMC6735871 source
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 measured
May combine two claims.
Findingown dataLeu46Pro is in linkage disequilibrium with ε4, and Leu46Pro did not increase risk of Alzheimer's disease beyond ε4.
“In accordance with previous studies, we found Leu46Pro in linkage disequilibrium with ε4, and whereas some studies reported Leu46Pro to add risk beyond ε4 33 , 34 through a destabilized apoE structure, 35 others found that Leu46Pro did not increase risk of AD beyond ε4. 36 , 37 Our study confirmed the latter.”
Quote in the paperSubstantial claim1 of 2 sources checked- cites [36] Medway CW, Abdul‐Hay S, Zou F, et al. ApoE variant p.V236E is associated with markedly reduced risk of Alzheimer's disease. Mol Neurodegener. 2014; 9: 11. 24607147 PMC3995879 source
- cites [37] Baron M, Jimenez‐Escrig A, Simon J,et al. Apolipoprotein E Pittsburgh variant is not associated with the risk of late‐onset Alzheimer's disease in a Spanish population. Am J Med Genet B Neuropsychiatr Genet. 2003; 120B: 121‐ 124. 12815750 source
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationNo tau pathology develops because apoE binding may be necessary for neuronal uptake of extracellular tau.
“Consequently, no tau pathology develops because apoE binding may be necessary for neuronal uptake of extracellular tau. 27”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [27] Rauch JN, Chen JJ, Miller GM, et al. Tau internalization is regulated by 6‐O sulfation on Heparan Sulfate Proteoglycans (HSPGs). Sci Rep. 2018; 8: 6382. 29686391 PMC5913225 source
The Introduction (page unavailable) links neuronal uptake of extracellular tau to the spread of tau pathology. But neither it nor the Discussion (page unavailable) addresses apoE binding or shows that a lack of apoE binding prevents tau pathology; the paper studies HSPG-dependent uptake of tau. (LLM, conf=0.76)
Experimental — accuracy not yet measured
May combine two claims.
FindingcitationThe risk of dementia for carriers of rare APOE variants was substantial, with effect sizes similar to those for ɛ4 and other rare variants in dementia risk genes such as TREM2.
“the risk of dementia for carriers of rare APOE variants was also substantial, with effect sizes similar to those for ɛ4 as well as other rare variants in dementia risk genes such as TREM2. 43”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [43] Jonsson T, Stefansson H, Steinberg P, et al. Variant of TREM2 associated with the risk of Alzheimer's disease. N Engl J Med. 2013; 368: 107‐ 116. 23150908 PMC3677583 source
The Results (Association with APOE ε4) report that the rare TREM2 variant rs75932628-T had an Alzheimer’s disease odds ratio similar to that of APOE ε4 (2.92 versus 3.08). The paper does not establish the claimed risk or effect sizes for carriers of rare APOE variants; it compares TREM2 with the ε4 allele. (LLM, conf=0.87)
Experimental — accuracy not yet measured
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationOne case-control study found a higher frequency of a combined Glu262Lys and Glu263Lys variant in patients with memory complaints (P = .08).
“Furthermore, two case‐studies of patients with frameshift mutations and premature stop codons in exon 4 did not observe clear neurocognitive defects, and one case‐control study found a higher frequency of a combined Glu262Lys and Glu263Lys variant in patients with memory complaints (P = .08) 39 , 40 , 41”
Quote in the paperNot a substantial claim2 of 3 sources checked- cites [39] Youn YC, Lim YK, Giau VV, et al. Apolipoprotein epsilon7 allele in memory complaints: insights through protein structure prediction. Clin Interv Aging. 2017; 12: 1095‐ 1102. 28744113 PMC5513808 source
The Results (APOE genotype frequencies; page unavailable) report that all three APOE ε7 carriers were in the memory-complaint group and none were in the control group, supporting the higher-frequency comparison. The paper describes the paired substitutions as Glu244Lys and Glu245Lys, not Glu262Lys and Glu263Lys; no passage found reports P = .08 for this comparison. (LLM, conf=0.82)
Experimental — accuracy not yet measured - cites [40] Mak AC, Pullinger CR, Schwarz JM, et al. Effects of the absence of apolipoprotein e on lipoproteins, neurocognitive function, and retinal function. JAMA Neurol. 2014; 71: 1228‐ 1236. 25111166 PMC4714860 source
The Results sections describe a single patient with an APOE frameshift mutation and largely normal neuropsychological testing, not a case-control study. Searches for Glu262Lys, Glu263Lys, memory complaints, and P = .08 found no passage in our copy addressing the claimed association. (LLM, conf=0.78)
Experimental — accuracy not yet measured - cites [41] Lohse P, Brewer HB, III, Meng MS, Skarlatos SI, LaRosa JC, Brewer HB, Jr. Familial apolipoprotein E deficiency and type III hyperlipoproteinemia due to a premature stop codon in the apolipoprotein E gene. J Lipid Res. 1992; 33: 1583‐ 1590. 1361196 source
May combine two claims.
PremisecitationAPOE ε4 is the main contributor to late-onset AD and has provided the clearest and most consistent signal in GWASs.
“Whereas APOE ε4 is the main contributor to late‐onset AD, and has provided the clearest and most consistent signal in GWASs, 6 , 7”
Quote in the paperNot a substantial claim1 of 2 sources checked- cites [6] Lambert JC, Ibrahim‐Verbaas CA, Naj AC, et al. Meta‐analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer's disease. Nat Genet. 2013; 45: 1452‐ 1458. 24162737 PMC3896259 source
- cites [7] Kunkle BW, Grenier‐Boley B, Bis JC, et al. Genetic meta‐analysis of diagnosed Alzheimer's disease identifies new risk loci and implicates Abeta, tau, immunity and lipid processing. Nat Genet. 2019; 51: 414‐ 430. 30820047 PMC6463297 source
The introductory passage (page unavailable) treats APOE as an established late-onset Alzheimer’s disease risk locus, identifying 19 other genome-wide-significant signals in addition to it. The Results section on candidate gene prioritization (page unavailable) also identifies APOE as a risk gene. Our copy does not specifically establish that the ε4 allele is the main contributor or that it has produced the clearest and most consistent GWAS signal. (LLM, conf=0.82)
Experimental — accuracy not yet measured
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationVal254Glu and Arg269Gly are located in the lipid-binding carboxyl-terminal domain (amino acids ≈243 to 317).
“Val254Glu and Arg269Gly are located in the lipid‐binding carboxyl‐terminal domain (amino acids ≈243 to 317). 28 , 42”
Quote in the paperNot a substantial claim1 of 2 sources checked- cites [28] Weisgraber KH. Apolipoprotein E: structure‐function relationships. Adv Protein Chem. 1994; 45: 249‐ 302. 8154371
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [42] Mahley RW, Weisgraber KH, Huang Y. Apolipoprotein E: structure determines function, from atherosclerosis to Alzheimer's disease to AIDS. J Lipid Res. 2009; 50(Suppl): S183‐ S188. 19106071 PMC2674716 source
The section “ApoE4: insights into lipid binding, domain interaction, and atherosclerosis” (page unavailable) places residues 254 and 269 within apoE’s lipid-binding region, amino acids 244–272, and its C-terminal domain. It gives the C-terminal domain as amino acids 225–299, not approximately 243–317, and does not identify the two named substitutions. (LLM, conf=0.88)
Experimental — accuracy not yet measured
May combine two claims. The quote only partly states this claim.
Findingown dataWe did not find risk associations for Val254Glu and Arg269Gly, although Val254Glu was previously reported to be protective.
“We did not find risk associations, although Val254Glu was previously reported to be protective. 36”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [36] Medway CW, Abdul‐Hay S, Zou F, et al. ApoE variant p.V236E is associated with markedly reduced risk of Alzheimer's disease. Mol Neurodegener. 2014; 9: 11. 24607147 PMC3995879 source
May combine two claims.
Findingown dataGlu114Lys is associated with decreased apoE levels and increased risk of dementia, similar to ε4.
“Of interest, this variant is associated with decreased apoE levels and increased risk of dementia, similar to ε4.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataEstimates for single rare variants and for apoE-weighted allele score in five groups remained largely unchanged after adjustment for LDL cholesterol, HDL cholesterol, and triglycerides and after stratification by ≥60 years at study entry.
“Estimates for single rare variants and for apoE‐weighted allele score in five groups remained largely unchanged after adjustment for low‐density lipoprotein (LDL) cholesterol, high‐density lipoprotein (HDL) cholesterol, and triglycerides (data not shown and Figure S6, respectively) and after stratification by ≥60 years at study entry (Figures S7 and S8).”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataThe three compound heterozygotes and the two Leu46Pro homozygotes did not contribute to estimates with any dementia events.
“The three compound heterozygotes (Glu31Lys/Arg269Gly, Leu46Pro/Glu114Lys, and Leu46Pro/Val254Glu) and the two Leu46Pro homozygotes did not contribute to estimates with any dementia events”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataFor genetically determined plasma apoE levels categorized into five groups, risk of all dementia and Alzheimer's disease increased with decreasing plasma apoE level (P for trends 9 × 10−104 and 6 × 10−107 from the very high to high to ɛ33 to low to very low groups, and 5 × 10−4 and 1 × 10−4 after APOE ɛ2/ɛ3/ɛ4 adjustment).
“as well as for genetically determined plasma apoE levels in five groups (P for trends 9 × 10−104 and 6 × 10−107 from the very high to high to ɛ33 to low to very low groups, and 5 × 10−4 and 1 × 10−4 after APOE ɛ2/ɛ3/ɛ4 adjustment).”
Quote in the paperSubstantial claimMay combine two claims.
Findingnone givenGlu114Lys is the rare variant located closest to Cys130Arg but is not in linkage disequilibrium with ε4.
“Glu114Lys is the rare variant located closest to Cys130Arg but is not in linkage disequilibrium with ε4.”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataRisk of all dementia and Alzheimer's disease increased with decreasing plasma apoE level on the continuous scale, both observationally and genetically determined.
“Risk of all dementia and AD increased with decreasing plasma apoE level on the continuous scale, observationally and genetically determined (Figure 2)”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataGly145Asp and Arg154Cys are located in the receptor binding region (amino acids ≈148 to 168) and display a phenotype similar to the ɛ2-defining Arg176Cys residue with high apoE levels and seemingly low risk of dementia (no events).
“Additional support comes from the present data, where Gly145Asp and Arg154Cys are located in the receptor binding region (amino acids ≈148 to 168) 28 and display a phenotype similar to the ɛ2‐defining Arg176Cys residue with high apoE levels and seemingly low risk of dementia (no events).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [28] Weisgraber KH. Apolipoprotein E: structure‐function relationships. Adv Protein Chem. 1994; 45: 249‐ 302. 8154371 source
May combine two claims.
Interpretationown dataGenetically low apoE levels increase and genetically high apoE levels decrease risk of dementia, beyond APOE ε2/ε3/ε4.
“We found that genetically low apoE levels increase and genetically high levels decrease risk, beyond ɛ2/ɛ3/ɛ4.”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationThe common APOE ε4 allele is an important risk marker for Alzheimer's disease, first reported by Corder et al. and validated in major cohorts around the globe.
“thereby confirming the identification of the common APOE ɛ4 allele as an important risk marker first reported by Corder et al., 8 and since validated in major cohorts around the globe. 9 , 10”
Quote in the paperSubstantial claim0 of 3 sources checked- cites Corder et al., 8
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [9] Livingston G, Sommerlad A, Costafreda SG, et al. Dementia prevention, intervention, and care. Lancet. 2017; 390: 2673‐ 2734. 28735855 source
- cites [10] Rasmussen KL, Tybjaerg‐Hansen A, Borge G, Frikke‐Schmidt R. Plasma levels of apolipoprotein E and risk of dementia in the general population. Ann Neurol. 2015; 77: 301‐ 311. 25469919 source
May combine two claims.
InterpretationreasoningAPOE-associated dementia risk is not a property solely related to the strong ε4 allele, but more likely relates to variants affecting levels of apoE in general.
“Consequently, APOE‐associated dementia risk is not a property solely related to the strong ε4 allele, but more likely relates to variants affecting levels of apoE in general.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim.
PremisecitationLow plasma levels of apoE are associated with increased risk of dementia.
“Of interest, low levels of plasma apoE per se were recently reported to be associated with increased risk of dementia, 10 , 17”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [10] Rasmussen KL, Tybjaerg‐Hansen A, Borge G, Frikke‐Schmidt R. Plasma levels of apolipoprotein E and risk of dementia in the general population. Ann Neurol. 2015; 77: 301‐ 311. 25469919 source
- cites [17] Wolters FJ, Koudstaal PJ, Hofman A, Duijn CM, Ikram AF. Serum apolipoprotein E is associated with long‐term risk of Alzheimer's disease: The Rotterdam Study. Neurosci Lett. 2016; 617: 139‐ 142. 26876448 source
May combine two claims.
PremisecitationHeterozygotes for Arg176Cys (ε32) are associated with a decreased risk of dementia, likely explained by higher apoE levels caused by decreased affinity of the apoE2 isoform to LDL receptors due to the ligand-defect of 176Cys.
“First, it is well established that heterozygotes for Arg176Cys (ε32) are associated with a decreased risk of dementia, likely explained by higher apoE levels caused by decreased affinity of the apoE2 isoform to LDL receptors due to the well‐established ligand‐defect of 176Cys. 15”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [15] Mahley RW, Jr, Rall SC. Type III hyperlipoproteinemia (dysbetalipoproteinemia): the role of apolipoprotein E in normal and abnormal lipoprotein metabolism. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The Metabolic and Molecular Bases of Inherited Disease. 8th ed. New York, NY: McGraw‐Hill; 2001: 2835‐ 2862.
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Classified as probably not a substantial claim.
Study design and conductown dataCox regression models were adjusted for known biologically relevant risk factors and markers of lifestyle, and further for APOE ε2/ε3/ε4 genotype.
“To test whether rare APOE variants were associated with increased risk of dementia, we used Cox regression models adjusted for known biologically relevant risk factors and markers of lifestyle: age (time scale), sex, body mass index, smoking, hypertension, diabetes, lipid‐lowering therapy, alcohol consumption, physical inactivity, postmenopausal status, hormonal replacement therapy, and education,”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenThere was no overlap of individuals between the Copenhagen City Heart Study and the Copenhagen General Population Study.
“There was no overlap of individuals between studies.”
Quote in the paperNot a substantial claimMay combine two claims.
PremisecitationMutations in the LDL receptor-binding domain, including APOE Arg154Ser Christchurch and the presently identified Gly145Asp and Arg154Cys mutations, are associated with dysbetalipoproteinemia, which is treatable with standard lipid medications.
“Mutations in the LDL receptor–binding domain, as the APOE Arg154Ser Christchurch, as well as the presently identified Gly145Asp and Arg154Cys mutations, are also associated with dysbetalipoproteinemia—a condition that is, however, treatable with standard lipid medications. 32”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [32] Hegele RA, Boren J, Arca M, et al. Rare dyslipidaemias, from phenotype to genotype to management: a European Atherosclerosis Society task force consensus statement. Lancet Diabetes Endocrinol. 2019. 31582260 source
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Study design and conductnone givenNo genotypes, endpoints, or plasma apoE levels were imputed.
“No genotypes, endpoints, or plasma apoE levels were imputed.”
Quote in the paperNot a substantial claimClassified as probably not a substantial claim.
Study design and conductnone givenIndividuals were selected randomly from the national Danish Civil Registration System to reflect the adult population aged 20 through 100+ years.
“Individuals were selected randomly from the national Danish Civil Registration System to reflect the adult population aged 20 through 100+ years.”
Quote in the paperSubstantial claimMay combine two claims.
Study design and conductnone givenA substantial fraction of heterozygote calls and all homozygote calls for rare variants were validated by Sanger sequencing.
“A substantial fraction of heterozygote calls and all homozygote calls for rare variants were validated by Sanger sequencing.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationThe clean ε33 group displays intermediate levels of genetically determined apoE and is the most prevalent group of individuals in most populations.
“with a “clean” ɛ33 group as the reference group displaying intermediate levels of genetically determined apoE and being the most prevalent group of individuals in most populations. 15”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [15] Mahley RW, Jr, Rall SC. Type III hyperlipoproteinemia (dysbetalipoproteinemia): the role of apolipoprotein E in normal and abnormal lipoprotein metabolism. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The Metabolic and Molecular Bases of Inherited Disease. 8th ed. New York, NY: McGraw‐Hill; 2001: 2835‐ 2862.
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
May combine two claims.
Interpretationown dataRare amino acid-changing variants in the APOE gene contribute to risk of dementia beyond the strong ɛ2/ɛ3/ɛ4 polymorphism, with genetically low apoE levels increasing and genetically high levels decreasing risk.
“The principal findings of this study are that rare amino acid–changing variants in the APOE gene contribute to a risk of dementia beyond the strong ɛ2/ɛ3/ɛ4 polymorphism where genetically low apoE levels increase and genetically high levels decrease risk.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductown dataIdentified APOE variants were confirmed by a second round of Sanger sequencing.
“Identified variants were confirmed by a second round of Sanger sequencing.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Study design and conductown dataMissing data (<0.4%) were imputed from age and sex in each population separately, and results were similar when only individuals with complete data were included.
“Missing data (<0.4%) were imputed from age and sex in each population separately, using multinomial logistic regression for categorical variables and linear regression for continuous variables; however, if only individuals with complete data were included, results were like those reported.”
Quote in the paperNot a substantial claimClassified as probably not a substantial claim. May combine two claims.
Premisenone givenThe current literature on the full spectrum of APOE genetic variation and dementia risk is sparse and consists mostly of case reports and smaller studies.
“The current literature is sparse on this issue and consists mostly of case reports and smaller studies.”
Quote in the paperSubstantial claimMay combine two claims.
InterpretationreasoningIf receptor binding-inhibiting therapies are developed, a natural side effect will be introduction of dysbetalipoproteinemia, unless the therapy can be limited to the brain.
“Therefore, if receptor binding– inhibiting therapies will be developed, a natural side effect will be introduction of dysbetalipoproteinemia, unless the therapy can be limited to the brain.”
Quote in the paperNot a substantial claimClassified as probably not a substantial claim.
PremisecitationFunctional studies have suggested that the beneficial effect of APOE3 Christchurch is related to decreased affinity for LDL receptor family members and heparan sulfate proteoglycans (HSPGs).
“Functional studies have suggested that the beneficial effect is related to decreased affinity for LDL receptor family members and heparan sulfate proteoglycans (HSPGs).”
Quote in the paperSubstantial claimMay combine two claims.
Study design and conductown dataProportionality of hazards over time was assessed, and there was no suspicion of nonproportionality.
“For Cox regression models, proportionality of hazards over time was assessed by plotting ‐ln(‐ln[survival]) versus ln(analysis time). There was no suspicion of nonproportionality.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationA resequencing study of 376 healthy individuals ≥85 years of age and 376 controls 41 to 54 years of age found no excess of rare variants in the 85+ year olds.
“A resequencing study of 376 healthy individuals ≥85 years of age and 376 controls 41 to 54 years of age found no excess of rare variants in the 85+ year olds. 38”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [38] Tindale LC, Leach S, Daley D, et al. Rare and common variants in the Apolipoprotein E gene in healthy oldest old. Neurobiol Aging. 2014; 35: 727‐ 3. 24126160 source
May combine two claims.
Interpretationown dataThese findings underscore the importance of structurally well-functioning apoE in dementia risk and that this is not a property related solely to the common ε2/ɛ3/ɛ4 polymorphism, but more likely relates to variants affecting levels of apoE.
“These findings underscore the importance of structurally well‐functioning apoE in dementia risk and that this is not a property related solely to the common ε2/ɛ3/ɛ4 polymorphism, but more likely relates to variants affecting levels of apoE.”
Quote in the paperSubstantial claimMay combine two claims.
InterpretationreasoningBoth rare and common variants in APOE contribute to plasma levels of apoE, likely mimicking brain apoE levels, and to risk of dementia in the general population.
“Hence, we now suggest that both rare and common variants in APOE contribute to plasma levels of apoE, likely mimicking brain apoE levels, and to risk of dementia in the general population. 10 , 19”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [10] Rasmussen KL, Tybjaerg‐Hansen A, Borge G, Frikke‐Schmidt R. Plasma levels of apolipoprotein E and risk of dementia in the general population. Ann Neurol. 2015; 77: 301‐ 311. 25469919 source
- cites [19] Rasmussen KL, Tybjaerg‐Hansen A, Nordestgaard BG, Frikke‐Schmidt R. Plasma apolipoprotein E levels and risk of dementia: a Mendelian randomization study of 106,562 individuals. Alzheimers Dement. 2018; 14: 71‐ 80. 28774656 source
May combine two claims.
Premisereasoningɛ4 is a strong risk-increasing allele and ɛ2 is a strong apoE-increasing allele, and the ɛ42 genotype displays a higher risk than ɛ33 but also higher apoE levels than ɛ33.
“Because ɛ4 is a strong risk‐increasing allele and ɛ2 is a strong apoE‐increasing allele, the ɛ42 genotype displays a higher risk than ɛ33 but also higher apoE levels than ɛ33.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataRare functional genetic variation in APOE, which causes lifelong changes in apoE levels, affects risk of dementia, both alone and compiled in weighted allele scores.
“Collectively, the present data suggest that rare functional genetic variation in APOE, which causes lifelong changes in apoE levels, affects risk of dementia, both alone and compiled in weighted allele scores.”
Quote in the paperSubstantial claimMay combine two claims.
InterpretationreasoningThe impact of the APOE polymorphism is well described among many ethnicities, so the study results are likely to be applicable to most humans.
“The impact of the APOE polymorphism is well described, however, among many ethnicities, so our results are likely to be applicable to most humans.”
Quote in the paperNot a substantial claimMay combine two claims.
Study design and conductown dataThe generalizability of the study results is limited because the study included white individuals only, so results may not necessarily apply to other populations.
“Second, the generalizability of our study results is limited because we studied white individuals only, and consequently our results may not necessarily apply to other populations.”
Quote in the paperNot a substantial claimMay combine two claims.
Study design and conductcitationDementia diagnoses in the Danish registries have high diagnostic validity, and any unregistered events would only lead to decreased power and bias results toward the null hypothesis.
“One potential limitation concerns the validity of the dementia diagnoses; however, the national Danish Patient Registry includes all hospital visits, and dementia diagnoses in the Danish registries have high diagnostic validity 19 , 44 ; any unregistered events would only lead to decreased power of estimates and bias results toward the null hypothesis.”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [19] Rasmussen KL, Tybjaerg‐Hansen A, Nordestgaard BG, Frikke‐Schmidt R. Plasma apolipoprotein E levels and risk of dementia: a Mendelian randomization study of 106,562 individuals. Alzheimers Dement. 2018; 14: 71‐ 80. 28774656 source
- cites [44] Phung TK, Andersen BB, Hogh P, Kessing LV, Mortensen PB, Waldemar G. Validity of dementia diagnoses in the Danish hospital registers. Dement Geriatr Cogn Disord. 2007; 24: 220‐ 228. 17690555 source
Probably not a substantial claim: may not pass S2 (checkable).
Study design and conductnone givenThe ability to adjust for and relate estimates for rare variants to the common APOE ε2/ε3/ε4 genotype is a major advantage.
“Finally, the ability to adjust for and relate estimates for rare variants to the common APOE ε2/ε3/ε4 genotype is a major advantage.”
Quote in the paperNot a substantial claimMay combine two claims.
Interpretationown dataStructural changes in apoE beyond ε2/ε3/ε4 contribute to risk of dementia, with genetically low apoE levels increasing and genetically high apoE levels decreasing risk.
“In conclusion, by resequencing the APOE gene in 10,369 individuals from the general population and genotyping selected variants in up to 105,597 individuals, we found that structural changes in apoE beyond ε2/ε3/ε4 contribute to a risk of dementia where genetically low apoE levels increase and genetically high apoE levels decrease risk.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationIn the majority of populations, the ε33 genotype is the most common, but allelic frequencies vary in different populations, which could affect the relative contribution.
“In the majority of populations, the ε33 genotype is the most common; however, interestingly allelic frequencies vary in different populations, 15 which could affect the relative contribution.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [15] Mahley RW, Jr, Rall SC. Type III hyperlipoproteinemia (dysbetalipoproteinemia): the role of apolipoprotein E in normal and abnormal lipoprotein metabolism. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The Metabolic and Molecular Bases of Inherited Disease. 8th ed. New York, NY: McGraw‐Hill; 2001: 2835‐ 2862.
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
May combine two claims.
Study design and conductnone givenThe study had a large prospective general population design with no losses to follow-up, so every individual could be followed to occurrence of event, 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 occurrence of event, end of follow‐up, death, or emigration.”
Quote in the paperSubstantial claim
The paper relies on this without support.
The exact mechanism behind the APOE ε4 association with Alzheimer's disease is not well characterized.
“Despite the impressive ɛ4 GWAS signal, the exact mechanism behind this observation is not well characterized.”
The paper relies on this without support.
The contribution from other genetic less-frequent variants in the APOE gene to risk and their contribution to apoE levels has not been studied at the population level.
“Because the APOE ɛ4 allele is both common and has a large risk effect—much higher than generally observed for common variants in common diseases—the contribution from other genetic less‐frequent variants in the APOE gene to risk and their contribution to apoE levels has not been studied at the population level.”
The paper relies on this without support.
The APOE ε4 allele is common and has a large risk effect, much higher than generally observed for common variants in common diseases.
“Because the APOE ɛ4 allele is both common and has a large risk effect—much higher than generally observed for common variants in common diseases—the contribution from other genetic less‐frequent variants in the APOE gene to risk and their contribution to apoE levels has not been studied at the population level.”
The paper relies on this without support.
Dementia diagnoses from the Danish national registries accurately identify dementia cases.
“Information on diagnoses was collected from the national Danish Patient Registry, with data on all patient contacts from all clinical hospital departments in Denmark since 1977, and from the national Danish Causes of Death Registry, with data on causes of all deaths in Denmark, as reported by hospitals and general practitioners since 1977.”
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?
To date, few studies have reported on the effect of APOECh due to limited number of carriers in the population.
“To date, few studies have reported on the effect of APOECh due to limited number of carriers in the population [5, 6, 8].”
From Characterization of APOE Christchurch carriers in 455,306 UK Biobank participants (2023) · cites this paper as [8]
The Discussion (page unavailable) describes a novel report of the APOE3 Christchurch effect in one woman, supporting that evidence on its effect was limited. It also reports low frequencies for nine rare APOE variants, but does not establish that few Christchurch studies exist because carriers are scarce in the population. (LLM, conf=0.80)
Experimental — accuracy not yet measuredIn a recent population study from Denmark of 105,597 subjects, the APOE3-Jac variant was associated with a reduced risk of developing dementia, with a hazard ratio of 0.30 and a p-value of 0.09.
“Interestingly, a recent population study from Denmark performed APOE sequencing and re-genotyping in 105,597 subjects (48). The APOE3-Jac variant was associated with a reduced risk of developing dementia, with a hazard ratio of 0.30 and a p-value of 0.09 that approaches statistical significance.”
From <i>APOE3</i> -Jacksonville (V236E) variant reduces self-aggregation and risk of dementia (2021) · cites this paper as [48]
The Results section (page unavailable) reports an all-dementia hazard ratio of 0.30 (95% CI 0.08–1.22) for carriers of Val254Glu versus non-carriers in this population study. Our copy does not identify Val254Glu as APOE3-Jac or report the cited p-value of 0.09; the Discussion says the study did not find a risk association for Val254Glu. Thus the numerical estimate is supported, but describing reduced risk as an established association overstates the result. (LLM, conf=0.86)
Experimental — accuracy not yet measuredThe Apoε4-Freiberg genotype has been previously studied with Alzheimer's disease.
“This genotype has been previously studied with Alzheimer’s disease [38,50].”
From Spectrum and Prevalence of Rare APOE Variants and Their Association with Familial Dysbetalipoproteinemia (2024) · cites this paper as [38]
The Results (Individual rare APOE variants and risk of dementia; page unavailable) examine Leu46Pro in relation to Alzheimer’s disease, and the Discussion says it is linked to ε4 and had been studied previously. Our copy does not identify Leu46Pro as the Apoε4-Freiberg genotype, so it does not establish that the specifically named genotype was studied. (LLM, conf=0.76)
Experimental — accuracy not yet measuredA Danish genetic screening of the APOE gene for an association with dementia reported 20 rare nonsynonymous APOE variants in 105,597 individuals.
“Genetic screening of the APOE gene for an association with dementia conducted in Denmark reported 20 rare nonsynonymous APOE variants in 105,597 individuals127).”
From Impact of Apolipoprotein E Variants: A Review of Naturally Occurring Variants and Clinical Features (2025) · cites this paper as [127]
The Methods > Participants section reports 105,597 Danish participants, and the Background describes screening APOE for its relationship to dementia. But the Results report 27 rare variants found by resequencing 10,369 people, with nine amino acid–changing variants subsequently genotyped in the larger cohort—not 20 rare nonsynonymous variants reported in 105,597 people. The indexed passages provide no page numbers. (LLM, conf=0.90)
Experimental — accuracy not yet measuredNine of the 20 rare nonsynonymous APOE variants reported in the Danish screening had already been reported.
“Nine of these variants had already been reported”
From Impact of Apolipoprotein E Variants: A Review of Naturally Occurring Variants and Clinical Features (2025) · cites this paper as [127]
The Results and Methods report nine rare amino acid–changing APOE variants selected for further genotyping. They do not say that nine of 20 rare nonsynonymous variants had already been reported; the searches for that count and prior reporting found no such passage. (LLM, conf=0.84)
Experimental — accuracy not yet measured
Rasmussen et al. identified 20 APOE rare missense variants in an analysis involving more than 100,000 participants and demonstrated their association with plasma APOE levels and Alzheimer's disease onset.
“Rasmussen et al. 22 identified 20 APOE RMVs in an analysis involving more than 100,000 participants and demonstrated their association with plasma APOE levels and AD onset.”
From Association of rare <i>APOE</i> missense variants with Alzheimer's disease in the Japanese population (2025) · cites this paper as [22]
The Methods and Results describe 105,597 participants, 27 rare APOE variants identified by resequencing, and nine rare amino-acid–changing variants further genotyped—not 20 rare missense variants analyzed for the stated associations. The Results link some of the nine variants to plasma apoE levels and assess their association with Alzheimer's disease risk, but do not demonstrate an association with age of onset. Page numbers are unavailable in our copy. (LLM, conf=0.89)
Experimental — accuracy not yet measuredGly145Asp and Arg154Cys, like the ε2 allele and the Christchurch mutation, seem unharmful for dementia.
“and like the ɛ2 allele and the Christchurch mutation they seem unharmful for dementia [35].”
From APOE and vascular disease: Sequencing and genotyping in general population cohorts (2023) · cites this paper as [35]
The 11 listed APOE variants (p.Thr11Ser, p.Phe12Tyr, p.Ala23Val, p.Arg33Cys, p.Ser72Phe, p.Glu114Lys, p.Lys161Asn, p.Ala210Ser, p.Ser215Phe, p.Gly218Ser, and p.Val305Met) had not been reported.
“but the following 11 variants had not (Table 5): APOE p.Thr11Ser, APOE p.Phe12Tyr, APOE p.Ala23Val (Ala5Val), APOE p.Arg33Cys (Arg15Cys), APOE p.Ser72Phe (Ser54Phe), APOE p.Glu114Lys (Glu96Lys), APOE p.Lys161Asn (Lys143Asn), APOE p.Ala210Ser (Ala192Ser), APOE p.Ser215Phe (Ser197Phe), APOE p.Gly218Ser (Gly200Ser), and APOE p.Val305Met (Val287Met) 127).”
From Impact of Apolipoprotein E Variants: A Review of Naturally Occurring Variants and Clinical Features (2025) · cites this paper as [127]
The Methods and Results list or analyze Thr11Ser, Ala23Val, and Glu114Lys, but do not say whether they had previously been reported. The retrieved passages do not address the reporting history of the other eight listed variants either, so this copy does not establish the claim about all 11. (LLM, conf=0.74)
Experimental — accuracy not yet measured
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.
Identical genotypes have different weighted allele scores
MinorTable 1B lists the same 11-variant genotype combination twice, once with a weighted allele score of −0.446060 and once with −0.881868. A fixed weighted sum cannot give different scores for identical genotypes.
“| AA | CC | GG | TT | GG | TC | GG | CC | CC | TT | CC | −0.446060 | Low | −0.45 (ε43) | 26,177 | 25 |”
“| AA | CC | GG | TT | GG | TC | GG | CC | CC | TT | CC | −0.881868 | Very low | −0.88‐(−0.55) | 80 | 0.08 |”
Hazard ratio falls outside its reported confidence interval
MinorThe reported hazard ratio of 2.48 is greater than the upper limit of its stated 95% confidence interval, 2.25.
“2.48”
“(1.44 to 2.25)”
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Self-citationSerum apolipoprotein E is associated with long-term risk of Alzheimer’s disease: The Rotterdam Study
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<i>APOE3</i> -Jacksonville (V236E) variant reduces self-aggregation and risk of dementia
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Karasakal, Ö. F., Oktay, E. Ö., & Kaman, T. (2023) · Balıkesir Üniversitesi Fen Bilimleri Enstitüsü Dergisi · doi:10.25092/baunfbed.1197932 · Cited by 2 · see citing works
Characterization of APOE Christchurch carriers in 455,306 UK Biobank participantsPreprint
He, K., Khramtsova, E. A., Cabrera‐Socorro, A., Zhang, Y., Li, S., Sarver, B. A. J., Smets, B., Li, Q. S., Muynck, L. D., Parrado, A., et al. (2022) · medRxiv · doi:10.1101/2022.12.05.22283048 · Cited by 2 · see citing works
CNS Gene Therapy for APOE4 Homozygote-Associated Alzheimer’s Disease
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- Authors
- Rasmussen, K. L., Tybjærg‐Hansen, A., Nordestgaard, B. G., & Frikke‐Schmidt, R.
- Affiliations
- Herlev Hospital (DK)
- University of Copenhagen (DK)
- Corresponding author
- Frikke‐Schmidt, Ruth
- Venue
- Alzheimer's & Dementia
- Publisher
- Wiley
- Published
- 2020-08-18
- Volume
- 16
- Issue
- 12
- Pages
- 1624-1637
- ISSN
- 1552-5260 (ISSN-L)
- 1552-5279
- PMC
- PMC7984319
- OpenAlex
- W3078410408
- Semantic Scholar
- 841c80480519417b0a168c95cf8f4221b6c795d1
- Cited by
- 64
- References
- 45
- Citations by year
- 2026: 7 · 2025: 12 · 2024: 10 · 2023: 15 · 2022: 12 · 2021: 7 · 2020: 1
- FWCI
- 5.26
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Alzheimer s & Dementia (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (publishedVersion, cc-by-nc-nd)
- Funders
- Lundbeckfonden (R278–2018-804)
- Rigshospitalet
- H. Lundbeck A/S
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Keywords
- apolipoprotein E
- MeSH terms
- Aged, Aged, 80 and over, Alzheimer Disease, Apolipoproteins E, Denmark, Female, Genotype, Humans, Male, Middle Aged, Polymorphism, Genetic, Prospective Studies, Polymerase Chain Reaction, Apolipoprotein E4, Genotyping Techniques
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.
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