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Cited by 94Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchGenetic Associations and Epidemiology

Association of Rare APOE Missense Variants V236E and R251G With Risk of Alzheimer Disease

Open access
Le Guen, Yann, Belloy, Michael E., Grenier-Boley, Benjamin, de Rojas, Itziar, Castillo-Morales, Atahualpa, Jansen, Iris, Nicolas, Aude, Bellenguez, Céline +102 more·2022·JAMA Neurology
DOI 10.1001/jamaneurol.2022.1166PMC PMC9157381
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Abstract

Importance: The APOE ε2 and APOE ε4 alleles are the strongest protective and risk-increasing, respectively, genetic variants for late-onset Alzheimer disease (AD). However, the mechanisms linking APOE to AD-particularly the apoE protein's role in AD pathogenesis and how this is affected by APOE variants-remain poorly understood. Identifying missense variants in addition to APOE ε2 and APOE ε4 could provide critical new insights, but given the low frequency of additional missense variants, AD genetic cohorts have previously been too small to interrogate this question robustly. Objective: To determine whether rare missense variants on APOE are associated with AD risk. Design, Setting, and Participants: Association with case-control status was tested in a sequenced discovery sample (stage 1) and followed up in several microarray imputed cohorts as well as the UK Biobank whole-exome sequencing resource using a proxy-AD phenotype (stages 2 and 3). This study combined case-control, family-based, population-based, and longitudinal AD-related cohorts that recruited referred and volunteer participants. Stage 1 included 37 409 nonunique participants of European or admixed European ancestry, with 11 868 individuals with AD and 11 934 controls passing analysis inclusion criteria. In stages 2 and 3, 475 473 participants were considered across 8 cohorts, of which 84 513 individuals with AD and proxy-AD and 328 372 controls passed inclusion criteria. Selection criteria were cohort specific, and this study was performed a posteriori on individuals who were genotyped. Among the available genotypes, 76 195 were excluded. All data were retrieved between September 2015 and November 2021 and analyzed between April and November 2021. Main Outcomes and Measures: In primary analyses, the AD risk associated with each missense variant was estimated, as appropriate, with either linear mixed-model regression or logistic regression. In secondary analyses, associations were estimated with age at onset using linear mixed-model regression and risk of conversion to AD using competing-risk regression. Results: A total of 544 384 participants were analyzed in the primary case-control analysis; 312 476 (57.4%) were female, and the mean (SD; range) age was 64.9 (15.2; 40-110) years. Two missense variants were associated with a 2-fold to 3-fold decreased AD risk: APOE ε4 (R251G) (odds ratio, 0.44; 95% CI, 0.33-0.59; P = 4.7 × 10-8) and APOE ε3 (V236E) (odds ratio, 0.37; 95% CI, 0.25-0.56; P = 1.9 × 10-6). Additionally, the cumulative incidence of AD in carriers of these variants was found to grow more slowly with age compared with noncarriers. Conclusions and Relevance: In this genetic association study, a novel variant associated with AD was identified: R251G always coinherited with ε4 on the APOE gene, which mitigates the ε4-associated AD risk. The protective effect of the V236E variant, which is always coinherited with ε3 on the APOE gene, was also confirmed. The location of these variants confirms that the carboxyl-terminal portion of apoE plays an important role in AD pathogenesis. The large risk reductions reported here suggest that protein chemistry and functional assays of these variants should be pursued, as they have the potential to guide drug development targeting APOE.

AI snapshot

Written from the paper’s full text.

TL;DR

In a large genetic association study, rare APOE missense variants V236E and R251G were each associated with a 2-fold to 3-fold decreased risk of Alzheimer disease. R251G, always coinherited with APOE ε4, was identified as a novel protective variant that mitigates ε4-associated AD risk.

Key findings

  • In the overall meta-analysis, V236E was associated with decreased AD risk (OR, 0.37; 95% CI, 0.25-0.56; P = 1.9 × 10⁻⁶) and R251G was associated with decreased AD risk (OR, 0.44; 95% CI, 0.33-0.59; P = 4.7 × 10⁻⁸).
  • In stage 1 discovery, V236E (OR, 0.23; 95% CI, 0.09-0.56; P = .001) and R251G (OR, 0.20; 95% CI, 0.08-0.49; P = 3.7 × 10⁻⁴) showed larger protective estimates; APOE-stratified analyses showed V236E in ε3/ε3 (OR, 0.31; 95% CI, 0.12-0.82; P = .02) and R251G in ε3/ε4 (OR, 0.17; 95% CI, 0.06-0.48; P = 7.8 × 10⁻⁴).
  • L28P was not associated with AD risk (OR, 1.12; 95% CI, 0.77-1.62; P = .56) and was not studied further.
  • Secondary analyses found V236E carriers had a mean age at AD onset 10.5 years older than noncarriers (β = 10.64; 95% CI, 1.78-19.49; P = .02) and slower AD incidence with age (HR, 0.30; 95% CI, 0.12-0.76; P = .01); R251G was not significantly associated with age at onset (β = 0.97; 95% CI, −2.96 to 4.91; P = .63) but had nominally reduced AD incidence (HR, 0.67; 95% CI, 0.46-0.97; P = .04).

Methods

  • Genetic association study using a sequenced discovery sample (stage 1: ADSP WGS/WES; 11,868 AD cases and 11,934 controls passing criteria) followed by replication in microarray imputed cohorts (stage 2: ADGC; 7,768 AD cases and 8,059 controls) and external cohorts plus UK Biobank WES proxy-AD phenotype (stage 3).
  • Primary case-control analyses used linear mixed-model regression or logistic regression adjusted for APOE ε2 and ε4 dosages, sex, and 4 genetic principal components; APOE-stratified analyses assessed V236E in ε3/ε3 and R251G in ε3/ε4.
  • Meta-analyses used fixed-effect inverse variance weighting; secondary analyses combined stages 1 and 2 to test age at onset with linear mixed-model regression and conversion to AD with competing-risk regression. Analyses were restricted to European and admixed European ancestry individuals.

Limitations

  • The paper states that the V236E association was not genome-wide significant, that UK Biobank lacks a direct clinical AD diagnosis, and that non-European ancestries were not assessed because of paucity of variant carriers.
  • Evident from the text: the variants are very rare, with low minor allele counts in several cohorts, and some replication estimates had wide confidence intervals; the UK Biobank proxy-AD phenotype relies largely on self-report of first-degree relatives’ diagnosis without age at onset.

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

Integrity signals

Registry

Crossref · 10.1001/jamaneurol.2022.1166

Cites

48 of 48 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 31 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    V236E is always coinherited with APOE ε3.

    “The V236E variant is always coinherited with APOE ε3, and the L28P and R251G are always coinherited with APOE ε4 (eTable 6 in Supple- ment 1).”
    Quote in the paperSubstantial claim
  • Findingown data

    In stages 2 and 3, V236E was significantly associated with AD risk (OR 0.42; 95% CI 0.27-0.66; P=2.0e-4).

    “In stages 2 and 3, across multiple replication cohorts, the effects of V236E and R251G in nonstratified analyses were concordant and both were significantly associated with AD risk (V236E: OR, 0.42; 95% CI, 0.27-0.66;P = 2.0 × 10 -4 ; R251G: OR, 0.48; 95% CI, 0.35-0.66;P = 5.8 × 10 -6 ).”
    Quote in the paperSubstantial claim
  • Findingown data

    Overall meta-analysis confirmed V236E association with a 2-fold to 3-fold decreased AD risk (OR 0.37; 95% CI 0.25-0.56; P=1.9e-6).

    “The overall metaanalysis (Figure 1; Table 2) provides robust effect size estimate for these 2 variants and confirmed their association with a 2-fold to 3-fold decreased AD risk (V236E: OR, 0.37; 95% CI, 0.25-0.56;P = 1.9 × 10 -6 ; R251G: OR, 0.44; 95% CI, 0.33-0.59;P = 4.7 × 10 -8 ).”
    • Also stated in: § Discussion · boosted
      “We have shown that 2 missense variants V236E and R251G are each associated with a more than 2-fold reduction in AD risk (Figure 2).”
    Quote in the paperSubstantial claim
  • Findingown data

    L28P was not associated with AD risk in nonstratified analyses (OR 1.12; 95% CI 0.77-1.62; P=.56).

    “The L28P variant (rs769452-C) was not associated with AD risk in the nonstratified analyses (OR, 1.12; 95% CI, 0.77-1.62;P = .56).”
    Quote in the paperNot a substantial claim
  • Findingown data

    V236E carriers had slower incidence of AD with age (HR 0.30; 95% CI 0.12-0.76; P=.01).

    “and slower incidence with age (hazard ratio [HR], 0.30; 95% CI, 0.12-0.76;P = .01).”
    Quote in the paperSubstantial claim
  • May combine two claims. 15
  • Classified as probably not a substantial claim. 15

  • May combine two claims.

    Findingown data

    Sensitivity analyses showed results remained unchanged when selecting individuals with admixed ancestry with at least 45% European ancestry or when restricting to individuals with European ancestry (75% cutoff).

    “Briefly, the results remained unchanged when selecting individuals with admixed ancestry with at least 45% European ancestry or when restricting the analysis to indi- viduals with European ancestry (75% cutoff).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    R251G carriers had a mean age at AD onset 6 years older than noncarriers of ε3/ε4, but this association was not significant (β=6.04; 95% CI -0.71 to 12.79; P=.08).

    “R251G carriers had a mean age at AD onset 6 years older than noncarriers of ε3/ε4, but this association was not significant (β = 6.04; 95% CI, -0.71 to 12.79; P = .08).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Compared with the reference ε3/ε3 group, the ε3/ε3 (V236E) and ε3/ε4 (R251G) groups had AD risk lower than or similar to the ε2/ε3 group.

    “Compared with the reference ε3/ε3 group, the ε3/ε3 (V236E) and ε3/ε4 (R251G) groups had AD risk lower than or similar to the ε2/ε3 group (Figure 2).”
    Quote in the paperNot a substantial claim

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

    Findingown data

    The significance of the results slightly improved when including a broader dementia category (R251G: OR 0.44; 95% CI 0.33-0.59; P=3.5e-8).

    “Overall, the significance of the results slightly improved when including a broader dementia category (R251G: OR, 0.44; 95% CI, 0.33-0.59; P = 3.5 × 10 -8 ) (eTable 9 in Supplement 1).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Removing UK Biobank proxy-AD phenotype samples reduced the significance of the results slightly, but the ORs became slightly more protective (R251G: OR 0.39; 95% CI 0.27-0.56; P=1.2e-7).

    “While removing UK Biobank proxy-AD phenotype samples reduced the significance of our results slightly, the ORs became slightly more protective (R251G: OR, 0.39; 95% CI, 0.27-0.56; P = 1.2 × 10 -7 ) (eTable 10 in Supplement 1).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    APOE ε3/ε3 (V236E) and APOE ε3/ε4 (R251G) carriers have Alzheimer disease risk equivalent to ε2/ε3 carriers.

    “Figure 2. Risk Equivalence of APOE ε3/ε3 (V236E)”
    • Also stated in: § Conclusions · plain
      “and APOE ε3/ε4 (R251G) to ε2/ε3 Carriers”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The UK Biobank proxy-AD phenotype is a valid proxy for Alzheimer disease in the association analyses.

  • May combine two claims.

    Premisecitation

    APOE ε2 and ε4 alleles are the strongest protective and risk-increasing genetic variants for late-onset Alzheimer disease, respectively.

    “The APOE ε2 and APOE ε4 alleles are the strongest protective and risk-increasing, respectively, genetic variants for late-onset Alzheimer disease (AD).”
    • Also stated in: § Abstract · plain
      “with the exception of the APOE ε2 and ε4 missense variants that are associated with substantially decreased 3 and increased AD risk, 4 respectively.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [3]

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

    • cites [4]

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

  • May combine two claims.

    Premisecitation

    Strong functional evidence supports a protective role for V236E, although this was based on an earlier case-control study with approximately 9000 participants likely underpowered to provide firm estimates of disease risk.

    “Finally, strong functional evidence has been marshalled recently to support a protective role for the Val236Glu (V236E) variant, although this was based on data from an earlier case-control study with only approximately 9000 participants, 12,13 likely underpowered to provide firm estimates of disease risk.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [12]

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

    • cites [13]

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

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

    Premisecitation

    Human studies have shown that ε4 speeds and ε2 slows the age-related misprocessing of β-amyloid.

    “Human studies have shown that ε4 speeds and ε2 slows the age-related misprocessing of β-amyloid, although how this occurs at the molecular level remains uncertain.6,7”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [6]

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

    • cites [7]

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

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

    Premisecitation

    Most common single-nucleotide variants at known AD risk loci contribute only a small amount to an individual's risk of AD.

    “Most of the common singlenucleotide variants (SNVs) at these loci only contribute a small amount to an individual's risk of AD, 2”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [2]

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

  • May combine two claims.

    Premisecitation

    R251G is located within apoE's lipid-binding region (amino acid residues 244 to 272), while V236E is adjacent to this region.

    “R251G is located within apoE's lipidbinding region (amino acid residues 244 to 272), while V236E is adjacent to this region.8”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [8]

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

  • May combine two claims.

    Interpretationreasoning

    R251G, carried on the same haplotype as ε4, is the first APOE variant found to mitigate the AD risk attributable to the ε4 isoform of the apoE protein.

    “This variant, carried on the same haplotype as ε4, is the first APOE variant found to mitigate the AD risk attributable to the ε4 isoform of the apoE protein.”
    Quote in the paperSubstantial claim

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

    Premisenone given

    The common APOE ε2 and APOE ε4 alleles are located on the N-terminal domain of the protein near the receptor-binding region.

    “The common APOE ε2 and APOE ε4 alleles are located on the N-terminal domain of the protein near the receptor-binding region.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Premisenone given

    The two variants V236E and R251G are on apoE's C-terminal domain.

    “Regarding potential mechanisms driving these associations, it is notable that these 2 variants are on apoE's C-terminal domain.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    The protective effect of V236E has already been reported in a smaller prior study focused on APOE and was suggestive in a population-based study, but this study validated the finding in a large-scale genomic study and provided an improved estimate of its effect size.

    “The protective effect of V236E has already been reported in a smaller prior study focused on APOE 13 and was suggestive in a population-based study, 15 but we validated this finding here in a large-scale genomic study and provide an improved estimate of its effect size.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [13]

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

    • cites [15]

      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 conductcitation

    Ancestry was determined with SNPWeights version 2 using reference populations from the 1000 Genomes Consortium.

    “For each cohort, we first determined the ancestry of each individual with SNPWeights version 2 (Harvard) 26 using reference populations from the 1000 Genomes Consortium.27”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [26]

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

    • cites [27]

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

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

    Study design and conductnone given

    Individuals with more than 5% genotype missingness were excluded.

    “Individuals with more than 5% genotype missingness were excluded.”
    Quote in the paperNot a substantial claim

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

    Study design and conductcitation

    Linear mixed-model analyses were additionally covaried by a sparse genetic association matrix.

    “Linear mixed-model analyses were additionally covaried by a sparse genetic association matrix estimated with the PC-Relate method 32 implemented in GENESIS.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [32]

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

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

    Premisecitation

    V236E also appears to increase dimerization, which may affect apoE's ability to bind to its receptors.

    “It is worth noting, however, that V236E also appears to increase dimerization (see Figure S10 12 ), which may affect apoE's ability to bind to its receptors.[42][43][44]”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [12]

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

    • cites [42]

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

    • cites [43]

      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 conductreasoning

    An association was considered significant in stage 1 if it reached a Bonferroni-corrected P value threshold of .017.

    “An association was considered significant in stage 1 if it reached a Bonferronicorrected P value threshold of .017(.05/3) in the model adjusted for ε2 and ε4 dosages; all P values were 2-tailed.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductcitation

    All statistical analyses were adjusted for sex and 4 genetic principal components.

    “All statistical analyses were adjusted for sex and 4 genetic principal components estimated with the PC-AiR method 31 implemented in GENESIS.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [31]

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

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

    Premisecitation

    Some compelling functional data suggest that V236E confers protection by reducing oligomerization of apoE.

    “While some compelling functional data suggest that V236E confers protection by reducing oligomerization of apoE, there are alternative mechanisms that merit consideration (increasing dimerization, for one).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [12]

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

  • May combine two claims.

    Premisecitation

    In 5×FAD mice, APOE ε3 (V236E) reduced Aβ deposition, plaque-associated immune response, and neuritic dystrophy around amyloid plaques.

    “In 5×FAD mice, they observed that APOE ε3 (V236E) reduced Aβ deposition, plaque-associated immune response, and neuritic dystrophy around amyloid plaques.12”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [12]

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

  • May combine two claims.

    Study design and conductcitation

    Case-control analyses were not adjusted for age because correcting for age when individuals with AD are younger than controls leads to the model incorrectly inferring the age effect on AD risk, resulting in statistical power loss.

    “Case-control analyses were not adjusted for age given that correcting for age when individuals with AD are younger than controls leads to the model incorrectly inferring the age effect on AD risk, resulting in statistical power loss.23”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [23]

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

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

    Study design and conductcitation

    Duplicate individuals were identified with KING.

    “Duplicate individuals were identified with KING (Kinship-based Inference for GWAS) 25 and their clinical, diagnostic, and pathological data (including”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [25]

      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 conductcitation

    Only missense variants with a minor allele count greater than 10 in any APOE main genotype groups in stage 1 were considered.

    “In our analysis, we only considered missense variants with a minor allele count greater than 10 in any APOE main genotype groups in our next-generation sequencing discovery (stage 1) to avoid outlier-confounded effect size estimates.28”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [28]

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

  • May combine two claims.

    Premisecitation

    APOE ε3 (V236E) primarily remains as a monomer and is less likely to form oligomers compared with the canonical APOE ε3 allele.

    “Chemically, they noted that APOE ε3 (V236E) primarily remains as a monomer and is less likely to form oligomers compared with the canonical APOE ε3 allele. 12”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [12]

      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 conductnone given

    Cohorts with imputation quality R2 greater than 0.70 at rs199768005 for V236E and at rs267606661 for R251G were retained.

    “We retained cohorts with R 2 greater than 0.70 at rs199768005 for the V236E analyses and at rs267606661 for the R251G analyses.”
    Quote in the paperSubstantial claim
28 of 28

  • The paper relies on this without support.

    The UK Biobank proxy-AD phenotype is a valid proxy for Alzheimer disease in the association analyses.

    “We included the UK Biobank data set that does not include a direct clinical diagnosis of AD.”
1 of 1

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • APOE4-R251G decreases the risk of ApoE4 to be similar to that of ApoE3.

    “ApoE4-R251G has been shown to decrease the risk of ApoE4 to be similar to that of ApoE3 37,38”

    From Utilizing a cell culture based novel cellular thermal shift assay to understand the isoform-dependent thermal stability of ApoE variants (2026) · cites this paper as [37]

    The Discussion reports that R251G mitigates the Alzheimer disease risk associated with APOE ε4. But it says the resulting risk estimate is similar to APOE ε2, specifically ε2/ε3—not ε3 as the citing sentence states. The Results likewise compare the ε3/ε4 (R251G) group with ε2/ε3. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • APOE3-Christchurch and APOE3-Jacksonville are protective compared with ApoE3.

    “ApoE3-Christchurch and ApoE3-Jacksonville have both been shown to be protective when compared with ApoE3 [35][36][37]”

    From Utilizing a cell culture based novel cellular thermal shift assay to understand the isoform-dependent thermal stability of ApoE variants (2026) · cites this paper as [37]

    The Results (page unavailable) compare V236E, the APOE3-Jacksonville variant, with ε3/ε3 noncarriers and find lower Alzheimer disease risk. The Abstract (page unavailable) says APOE3-Christchurch was only posited to be protective in PSEN1-related early-onset disease, based on one patient without statistical genetic support. It does not establish the broader claim that Christchurch is protective compared with ApoE3. (LLM, conf=0.90)

    Experimental — accuracy not yet measured

  • Rare APOE missense variants impact protein function and modify disease risk.

    “This includes the important discoveries about rare APOE missense variants that impact protein function and modify disease risk.”

    From Discovery of a Missense Mutation (Q222K) of the <i>APOE</i> Gene from the Australian Imaging, Biomarker and Lifestyle Study (2023) · cites this paper as [20]

    The Abstract reports that the rare variants V236E and R251G are associated with substantially reduced Alzheimer disease risk. The Conclusions describe functional evidence suggesting that V236E reduces apoE oligomerization, but say that R251G’s protective mechanism remains unexplored. The paper therefore supports the risk claim, but not an established effect on protein function for both variants. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • Carriers of the APOE3-backbone Jacksonville variant (V236E) have AD risk equivalent to APOE-ε2 homozygotes.

    “The APOE3-backbone Jacksonville variant (V236E), located in the C-terminal coiled-coil interface, reduces ApoE self-aggregation and enhances lipidation, and carriers have AD risk equivalent to APOE-ε2 homozygotes (15,19).”

    From APOE Isoform-Dependent Self-Association Measured by a Split-Luciferase Complementation Assay: Differential Effects of Disease-Risk and Protective Variants (2026) · cites this paper as [19]

    The Results (page unavailable) report reduced AD risk in V236E carriers and say the ε3/ε3 (V236E) group had risk lower than or similar to the ε2/ε3 group. They do not establish equivalent risk to ε2/ε2 homozygotes, the comparator specified in the claim. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • The APOE3-backbone Jacksonville variant (V236E) reduces ApoE self-aggregation and enhances lipidation.

    “The APOE3-backbone Jacksonville variant (V236E), located in the C-terminal coiled-coil interface, reduces ApoE self-aggregation and enhances lipidation, and carriers have AD risk equivalent to APOE-ε2 homozygotes (15,19).”

    From APOE Isoform-Dependent Self-Association Measured by a Split-Luciferase Complementation Assay: Differential Effects of Disease-Risk and Protective Variants (2026) · cites this paper as [19]

    The Discussion reports that APOE ε3 (V236E) is less likely to form oligomers than canonical APOE ε3, supporting reduced self-aggregation. Neither the Discussion nor the other passages found report enhanced lipidation of V236E; the discussion of potentially improved lipid binding concerns R251G and is speculative. No page numbers are available in our copy. (LLM, conf=0.88)

    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.

  • R251G confidence interval differs between Figure 1 and Table 2

    Minor

    For CCHS and CGPS, Figure 1 gives an upper 95% confidence limit of 1.72, while Table 2 gives 2.72 for the same odds ratio.

  • Female percentage does not match the Table 1 count

    Minor

    The table lists 14 female participants among 16 in this APOE ε2/ε2 group, which is 87.5%, rather than the printed 84.6%.

    Reported 84.6 · recomputed 87.5

2 of 2

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Authors
Le Guen, Y., Belloy, M. E., Grenier-Boley, B., de Rojas, I., Castillo-Morales, A., Jansen, I., Nicolas, A., Bellenguez, C., Dalmasso, C., Küçükali, F., Eger, S. J., Rasmussen, K. L., Thomassen, J. Q., Deleuze, J.-F., He, Z., Napolioni, V., Amouyel, P., Jessen, F., Kehoe, P. G., van Duijn, C., Tsolaki, M., Sánchez-Juan, P., Sleegers, K., Ingelsson, M., Rossi, G., Hiltunen, M., Sims, R., van der Flier, W. M., Ramirez, A., Andreassen, O. A., Frikke-Schmidt, R., Williams, J., Ruiz, A., Lambert, J.-C., Greicius, M. D., Members of the EADB, G., Arosio, B., Benussi, L., Boland, A., Borroni, B., Caffarra, P., Daian, D., Daniele, A., Debette, S., Dufouil, C., Düzel, E., Galimberti, D., Giedraitis, V., Grimmer, T., Graff, C., Grünblatt, E., Hanon, O., Hausner, L., Heilmann-Heimbach, S., Holstege, H., Hort, J., Jürgen, D., Kuulasmaa, T., van der Lugt, A., Masullo, C., Mecocci, P., Mehrabian, S., de Mendonça, A., Moebus, S., Nacmias, B., Nicolas, G., Olaso, R., Papenberg, G., Parnetti, L., Pasquier, F., Peters, O., Pijnenburg, Y. A. L., Popp, J., Rainero, I., Ramakers, I., Riedel-Heller, S., Scarmeas, N., Scheltens, P., Scherbaum, N., Schneider, A., Seripa, D., Soininen, H., Solfrizzi, V., Spalletta, G., Squassina, A., van Swieten, J., Tegos, T. J., Tremolizzo, L., Verhey, F., Vyhnalek, M., Wiltfang, J., Boada, M., García-González, P., Puerta, R., Real, L. M., Álvarez, V., Bullido, M. J., Clarimon, J., García-Alberca, J. M., Mir, P., Moreno, F., Pastor, P., Piñol-Ripoll, G., Molina-Porcel, L., Pérez-Tur, J., Rodríguez-Rodríguez, E., Royo, J. L., Sánchez-Valle, R., Dichgans, M., & Rujescu, D.
Affiliations
  • Department of Neurology and Neurological Sciences, Stanford University, Palo Alto, California
  • University of Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1167-RID-AGE Facteurs de risque et déterminants moléculaires des maladies liées au vieillissement, Lille, France
  • Research Center and Memory Clinic Fundació ACE, Institut Català de Neurociències Aplicades, Universitat Internacional de Catalunya, Barcelona, Spain
  • Cardiff University (GB)
  • Amsterdam Neuroscience (NL)
  • Inserm (FR)
  • Consejo Nacional de Investigaciones Científicas y Técnicas (AR)
  • University of Antwerp (BE)
  • Stanford University (US)
  • University of Copenhagen (DK)
  • Copenhagen University Hospital (DK)
  • Commissariat à l'Énergie Atomique et aux Énergies Alternatives (FR)
  • Università di Camerino (IT)
  • University of Cologne (DE)
  • University of Bristol (GB)
  • Department of Epidemiology, ErasmusMC, Rotterdam, the Netherlands
  • Aristotle University of Thessaloniki (GR)
  • Networking Research Center on Neurodegenerative Diseases (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain
  • Uppsala University (SE)
  • Fondazione IRCCS Istituto Neurologico Carlo Besta (IT)
  • University of Eastern Finland (FI)
  • Alzheimer Center Amsterdam, Department of Neurology, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC, Amsterdam, the Netherlands
  • Department of Psychiatry and Psychotherapy, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
  • Oslo University Hospital (NO)
  • Department of Clinical Biochemistry, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
  • University of Milan (IT)
  • University of Parma (IT)
  • Università Cattolica del Sacro Cuore (IT)
  • Université de Bordeaux (FR)
  • Karolinska University Hospital (SE)
  • University of Zurich (CH)
  • Université Paris Cité (FR)
  • University of Bonn (DE)
  • Institute of Human Genetics, University of Bonn, School of Medicine, University Hospital Bonn, Bonn, Germany
  • Charles University (CZ)
  • Department of Psychiatry, Psychosomatics and Psychotherapy, Center of Mental Health, University Hospital of Würzburg, Würzburg, Germany
  • Department of Radiology and Nuclear Medicine, ErasmusMC, Rotterdam, the Netherlands
  • University of Perugia (IT)
  • University of Lisbon (PT)
  • Faculty of Medicine, University of Lisbon, Lisbon, Portugal
  • Don Carlo Gnocchi Foundation (IT)
  • Normandie Université, UNIROUEN, Inserm U1245 and CHU Rouen, Department of Genetics and CNR-MAJ, Rouen, France
  • Stockholm University (SE)
  • German Center for Neurodegenerative Diseases (DE)
  • Maastricht University (NL)
  • National and Kapodistrian University of Athens (GR)
  • University Hospital Bonn (DE)
  • Baylor College of Medicine (US)
  • University of Cagliari (IT)
  • Department of Neurology, ErasmusMC, Rotterdam, the Netherlands
  • Memory Clinic, Department of Neurology, Charles University, 2nd Faculty of Medicine and Motol University Hospital, Prague, Czech Republic
  • Instituto de Salud Carlos III (ES)
  • Universitat Internacional de Catalunya (ES)
  • Unidad Clínica de Enfermedades Infecciosas y Microbiología, Hospital Universitario de Valme, Sevilla, Spain
  • Consejo Superior de Investigaciones Científicas (ES)
  • Fundació Docència i Recerca MútuaTerrassa, Terrassa, Spain
  • Unitat Trastorns Cognitius, Hospital Universitari Santa Maria de Lleida, Lleida, Spain
  • Neurological Tissue Bank (Biobanc), Hospital Clinic IDIBAPS, Barcelona, Spain
  • Depatamento de Especialidades Quirúrgicas, Bioquímica e Inmunología, Facultad de Medicina, Universidad de Málaga, Málaga, Spain
  • Alzheimer’s Disease and Other Cognitive Disorders Unit, Service of Neurology, Hospital Clínic of Barcelona, Institut d’Investigacions Biomèdiques August Pi i Sunyer, University of Barcelona, Barcelona, Spain
  • Medical University of Vienna (AT)
ORCID
Venue
JAMA Neurology
Publisher
American Medical Association (AMA)
Published
2022-07-01
Volume
79
Issue
7
Pages
652
ISSN
2168-6149 (ISSN-L)
DOI
10.1001/jamaneurol.2022.1166
PMC
PMC9157381
OpenAlex
W4281716488
Cited by
93
References
52
Citations by year
2026: 18 · 2025: 24 · 2024: 29 · 2023: 13 · 2022: 9
FWCI
11.61
Type
journal article
Language
en
Open access
Locations
  • JAMA Neurology (publishedVersion)
  • PubMed Central (publishedVersion)
  • Research at the University of Copenhagen (University of Copenhagen) (publishedVersion, other-oa)
  • EUR Research Repository (Erasmus University Rotterdam) (publishedVersion, other-oa)
  • PubMed (publishedVersion)
  • Kölner Universitäts PublikationsServer (Universität zu Köln) (publishedVersion)
  • Research Publications (Maastricht University) (publishedVersion, other-oa)
  • Amsterdam UMC (VU Amsterdam) - Institutional Repository (publishedVersion)
  • Bristol Research (University of Bristol) (acceptedVersion, cc-by)
  • Explore Bristol Research (acceptedVersion, cc-by)
  • Florence Research (University of Florence) (submittedVersion, other-oa)
  • Institutional Research Information System University of Turin (University of Turin) (submittedVersion, other-oa)
  • Digital Commons-TMC (Texas Medical Center) (submittedVersion)
  • Data Archiving and Networked Services (DANS) (submittedVersion)
  • EUR Research Repository (Erasmus University Rotterdam) (submittedVersion)
  • HAL (submittedVersion)
  • Archivio Istituzionale della Ricerca (Universita Degli Studi Di Milano) (submittedVersion, other-oa)
  • Universitätsbibliographie, Universität Duisburg-Essen (submittedVersion)
  • BOA (University of Milano-Bicocca) (submittedVersion)
  • DIGITAL.CSIC (Spanish National Research Council (CSIC)) (submittedVersion, cc-by)
  • Open access LMU (Ludwid Maxmilian's Universitat Munchen) (submittedVersion)
  • ORCA Online Research @Cardiff (Cardiff University) (submittedVersion)
  • Institutional Research Information System (Università degli Studi di Brescia) (submittedVersion)
  • UNICA IRIS Institutional Research Information System (University of Cagliari) (submittedVersion)
  • IRIS (submittedVersion)
  • LillOA (Université de Lille (University Of Lille)) (submittedVersion, other-oa)
  • mediaTUM (Technical University of Munich) (submittedVersion)
  • Oskar-Bordeaux (Universite de Bordeaux) (submittedVersion)
  • DZNE Pub (submittedVersion)
  • Unicam Scientific Publications (University of Camerino) (submittedVersion, other-oa)
  • Pure Amsterdam UMC (submittedVersion)
  • Portuguese National Funding Agency for Science, Research and Technology (RCAAP Project by FCT) (submittedVersion)
  • SERVAL (Université de Lausanne) (submittedVersion)
  • RISalud Institutional Health Repository of Andalucía (submittedVersion, other-oa)
  • Research Publications (Maastricht University) (submittedVersion)
Funders
  • Alzheimer's Association (AARF-20-683984, UMR1167)
  • Univerzita Karlova v Praze
  • Universidade de Aveiro
  • Itä-Suomen Yliopisto
  • Universidad de Sevilla
  • Medical University Sofia
  • Universidad de Málaga
  • Università degli Studi di Milano
  • Università degli Studi di Cagliari
  • EU Joint Programme – Neurodegenerative Disease Research
  • Development of Innovative Strategies for a Transdisciplinary approach to ALZheimer's disease
  • Université de Lille
  • Centro de Biología Molecular Severo Ochoa
  • Amsterdam University Medical Centers
  • University of Oxford
  • European Commission (890650)
  • Cardiff University
  • University of Bristol
  • Universität Heidelberg
  • Agence Nationale de la Recherche (ANR-11-LABX-0009)
  • Institut National de la Santé et de la Recherche Médicale (U1245, UMR 1219)
  • Vrije Universiteit Amsterdam
  • Universiteit Maastricht
  • Università degli Studi di Milano-Bicocca
  • Eidgenössische Technische Hochschule Zürich
  • Universität Wien
  • Lundbeckfonden (R278–2018-804)
  • University of Toronto
  • Karolinska Institutet
  • Università degli Studi di Firenze
  • Universidad Autónoma de Madrid
  • Università degli Studi di Parma
  • National and Kapodistrian University of Athens
  • Deutsches Zentrum für Neurodegenerative Erkrankungen
  • Universita degli Studi di Bari Aldo Moro
  • Universitetet i Oslo
  • Technische Universität München
  • Università Cattolica del Sacro Cuore
  • Universidade de Lisboa
  • Universitat de Barcelona
  • Medizinische Universität Wien
  • Humboldt-Universität zu Berlin
  • Université de Bordeaux
  • Universidad de Cantabria
  • Centre Hospitalier Universitaire Vaudois
  • Universität Zürich
  • Aristotle University of Thessaloniki
  • Uppsala Universitet
  • Université Paris-Saclay
  • Università degli Studi di Brescia (03/2023)
  • Freie Universität Berlin
  • Universität zu Köln
  • Fondazione I.R.C.C.S. Istituto Neurologico Carlo Besta
  • Rheinische Friedrich-Wilhelms-Universität Bonn
  • Universität Duisburg-Essen
  • Stockholms Universitet
  • Universitätsspital Zürich
  • Assistance publique-Hôpitaux de Paris
  • Centre Hospitalier Universitaire de Bordeaux
  • Università degli Studi di Perugia
  • Università degli Studi di Camerino
  • Universitat Autònoma de Barcelona
  • Normandie Université
  • Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas
  • Berlin Institute of Health
  • Région Normandie
  • Instituto de Investigación Marqués de Valdecilla
  • Amsterdam Neuroscience
  • Université de Paris
  • Instituto de Investigación Sanitaria del Principado de Asturias
  • National Institutes of Health
  • University of Texas Health Science Center at San Antonio
  • Medical Research Council (MC_PC_17228, MR/L010305/1, MR/L023784/1)
  • Economic and Social Research Council (ES/L008238/1)
  • Instituto de Salud Carlos III
  • Neuroscience Center Zurich, University of Zurich
  • National Institute on Aging
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, missense mutations, Alzheimer's disease, APOE ε2, APOE ε4, rare variants, Alzheimer's disease risk, age of onset, UK Biobank, European ancestry, competing risk analysis, linear mixed models
MeSH terms
Alleles, Alzheimer Disease, Apolipoproteins E, Female, Genotype, Humans, Male, Age of Onset, Apolipoprotein E4, Apolipoprotein E2

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