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PreprintCited by 1Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchGenetic Associations and Epidemiology

Association of Rare APOE Missense Variants R189C and W276C With Risk of Alzheimer Disease

Open access
Le Guen, Yann, Reil, Dylan, Jackson, Rosemary J., Peña-Tauber, Andrés, Khosla, Chaitan, Greicius, Michael D.·2026·medRxiv
DOI 10.64898/2026.05.08.26352778
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Abstract

Rare APOE missense variants in admixed populations can clarify mechanisms of Alzheimer disease (AD) risk beyond ε2 and ε4. We analyzed APOE coding variation in the Alzheimer disease Sequencing Project and AllofUs and meta-analyzed ancestry-adjusted case-control associations. Two ε3-linked variants enriched in Native American ancestry among Admixed American individuals were associated with AD: R189C increased risk (odds ratio (OR), 3.35; 95% confidence interval (CI), 1.25–9.00; P = 0.016), whereas W276C was protective (OR, 0.28; 95% CI, 0.10–0.82; P = 0.020). In a nascent ApoE secretion assay that resolves high molecular weight lipid-bound species from lipid-poor species, R189C showed an APOE- ε4-like shift toward the lipid-bound fraction. In an orthogonal self-association assay, W276C reduced ApoE self-association to the protective APOE -Jacksonville variant level. These findings expand the spectrum of APOE missense variants that are associated with AD and implicate C-terminal ApoE conformation and lipidation states as tractable mechanisms for pathogenesis and therapeutic targeting.

AI snapshot

Written from the paper’s full text.

TL;DR

In Admixed American participants from ADSP and All of Us, two rare ε3-linked APOE missense variants showed opposite associations with Alzheimer disease: R189C increased risk and W276C was protective. Functional assays linked R189C to an ApoE4-like lipid-bound secretion profile and W276C to reduced ApoE self-association resembling the protective Jacksonville variant.

Key findings

  • R189C was associated with increased AD risk in meta-analysis (OR = 3.35, 95% CI = 1.25–9.00, P = 0.016), with directionally consistent signals in ADSP (OR = 2.36) and All of Us (OR = 5.63).
  • W276C was associated with reduced AD risk (OR = 0.28, 95% CI = 0.10–0.82, P = 0.020), with concordant protective point estimates in ADSP (OR = 0.31) and All of Us (OR = 0.03).
  • R136S (Christchurch) showed no evidence of protection in this Admixed American meta-analysis (OR = 1.42, 95% CI = 0.18–11.25, P = 0.740).
  • In functional assays, ApoE3-R189C showed an ApoE4-like shift toward the high molecular weight lipid-bound fraction (Tukey-adjusted P = 0.0012 for ApoE3 vs ApoE4 and for ApoE3 vs ApoE3-R189C; ApoE3-R189C vs ApoE4 P = 0.9995), while ApoE3-W276C reduced self-association to the level of protective ApoE3-V236E (Holm-adjusted P = 1.65 × 10⁻⁵ vs ApoE3; ApoE3-V236E vs ApoE3-W276C P = 0.93).

Methods

  • Two-cohort genetic association study of seven non-synonymous APOE variants in Admixed American participants from the Alzheimer’s Disease Sequencing Project (ADSP) and All of Us whole-genome sequencing.
  • ADSP used SNPWeights ancestry assignment, AMR ancestry proportion >15%, and a generalized linear mixed-effects model adjusted for sex, APOE-ε2 dosage, APOE-ε4 dosage, and 3 ancestry principal components, with relatedness accounted for by a sparse genetic relationship matrix. All of Us used the published genetic-ancestry framework, a proxy AD/dementia phenotype, and PLINK Firth residualized logistic regression adjusted for age, sex, APOE-ε2 dosage, APOE-ε4 dosage, and 16 genetic principal components; proxy effect sizes and standard errors were doubled before meta-analysis.
  • ADSP and All of Us estimates were combined by inverse-variance weighted fixed-effect meta-analysis on the log-odds-ratio scale. Functional characterization used an ApoE secretion assay in Expi293F cells resolving high molecular weight lipid-bound versus lipid-poor ApoE by size-exclusion chromatography, and a split-luciferase ApoE self-association assay in HEK293 cells normalized to ApoE3.

Limitations

  • The paper states that the variants are very rare, confidence intervals remain wide, and the All of Us analysis relied in part on a proxy phenotype.
  • The paper states that the functional experiments were designed to test directionally informative biochemical states rather than establish a full causal chain from variant to disease.
  • Evident from the text: allele counts were very low, and the self-association assay provides a relative readout because absolute ApoE concentrations were not determined.

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

Integrity signals

Registry

Crossref · 10.64898/2026.05.08.26352778

Cites

23 of 23 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

17 of 20 cited sources checked · 14 supported · 0 flagged · accuracy not yet measured

  • Premisecitation

    In predominantly European datasets, the C-terminal variants V236E (Jacksonville) on ε3 and R251G on ε4 are associated with substantially lower AD risk.

    “In predominantly European datasets, the C-terminal variants V236E (Jacksonville) on ε3 and R251G on ε4 are associated with substantially lower AD risk 5”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [5] 2022, Association of Rare APOE Missense Variants V236E and R251G With Risk of Alzheimer Disease, JAMA Neurol source
  • Findingown data

    In the ApoE secretion assay, ApoE3-R189C was not detectably different from ApoE4 (P=0.9995).

    “ApoE3-R189C was not detectably different from ApoE4 (P = 0.9995)”
    Quote in the paperSubstantial claim
  • Findingown data

    In the split-luciferase self-association assay, ApoE3-V236E showed less self-association than ApoE3 (Holm-adjusted P=1.35 × 10^-6).

    “Both ApoE3-V236E and ApoE3-W276C showed less self-association than ApoE3 (Holm-adjusted P = 1.35 × 10 -6 and P = 1.65 × 10 -5 , respectively)”
    Quote in the paperSubstantial claim
  • Findingown data

    ApoE3-V236E and ApoE3-W276C were not detectably different from one another in self-association (two-sided Mann-Whitney P=0.93).

    “ApoE3-V236E and ApoE3-W276C were not detectably different from one another (two-sided Mann-Whitney P = 0.93).”
    Quote in the paperSubstantial claim
  • Findingown data

    W276C is associated with reduced risk of Alzheimer disease in the combined Admixed American meta-analysis (OR=0.28, 95% CI 0.10-0.82, P=0.020).

    “W276C was protective (OR, 0.28; 95% CI, 0.10-0.82;P = 0.020)”
    Quote in the paperSubstantial claim
  • Classified as probably not a substantial claim. 23
  • May combine two claims. 15

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

    Premisecitation

    In African ancestry populations, the ε3-linked R145C variant increases AD risk in a genotype-specific manner.

    “In African ancestry populations, the ε3-linked R145C variant increases AD risk in a genotype-specific manner 4 .”
    Quote in the paperNot a substantial claim1 of 1 sources checked

  • Classified as probably not a substantial claim.

    Premisecitation

    The Jacksonville variant V236E reduces ApoE self-aggregation.

    “In prior work 14 , the Jacksonville variant V236E was shown to reduce ApoE self-aggregation, providing a plausible biochemical basis for protection.”
    Quote in the paperSubstantial claim1 of 1 sources checked

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

    Premisecitation

    Secreted ApoE resolves into a high molecular weight, lipid-bound lipoprotein particle (Peak 1) and a lower molecular weight, lipid-poor species (Peak 2).

    “secreted ApoE resolves into a high molecular weight, lipid-bound lipoprotein particle (previously termed Peak 1) and a lower molecular weight, lipid-poor species (previously termed Peak 2) 12 .”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [12] 2025, ApoE is Secreted as a Lipid Nanoparticle by Mammalian Cells: Implications for Alzheimer’s Disease Pathogenesis, Biochemistry source

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

    Premisecitation

    The split-luciferase assay measures ApoE self-association.

    “The second assay, developed independently, measured ApoE self-association using a cell-based association readout 13 .”
    Quote in the paperNot a substantial claim1 of 1 sources checked

  • Classified as probably not a substantial claim.

    Premisecitation

    The high molecular weight ApoE fraction elicits cholesterol efflux at a higher rate from cells with ATP-dependent lipid pump activity than the lipid-poor species.

    “The former particle not only elicits cholesterol efflux at a higher rate from cells with ATP-dependent lipid pump activity but it also undergoes more effective receptor mediated endocytosis.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [12] 2025, ApoE is Secreted as a Lipid Nanoparticle by Mammalian Cells: Implications for Alzheimer’s Disease Pathogenesis, Biochemistry source

  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing). May combine two claims.

    Premisecitation

    APOE is increasingly viewed not only as a risk locus, but also as a mechanistically actionable therapeutic axis in AD.

    “as APOE is increasingly viewed not only as a risk locus, but also as a mechanistically actionable therapeutic axis in AD 2 .”
    Quote in the paperNot a substantial claim1 of 1 sources checked

  • Classified as probably not a substantial claim.

    Study design and conductown data

    In All of Us, association testing adjusted for age, sex, APOE-ε2 dosage, APOE-ε4 dosage and 16 genetic principal components.

    “adjusting for age, sex, APOE-ε2 dosage, APOE-ε4 dosage and 16 genetic principal components precomputed by All of Us 11 .”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [11] source

      The Methods section on genetic ancestry inference says All of Us generated 16 principal components, supporting the reference to precomputed genetic PCs. It does not say that its association tests adjusted for all 16: the genotype-by-phenotype replication Methods specify age, sex and the first three PCs, while the LDL-C GWAS Methods specify the first five PCs. Neither passage reports adjustment for APOE-ε2 or APOE-ε4 dosage. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

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

    Premisecitation

    APOE remains the strongest common genetic determinant of late-onset Alzheimer disease.

    “APOE remains the strongest common genetic determinant of late-onset Alzheimer disease (AD) 1 , but the molecular basis of its effect is still unresolved.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [1] 2023, APOE Genotype and Alzheimer Disease Risk Across Age, Sex, and Population Ancestry, JAMA Neurol source

  • Classified as probably not a substantial claim.

    Premisecitation

    The high molecular weight ApoE fraction undergoes more effective receptor-mediated endocytosis than the lipid-poor species.

    “The former particle not only elicits cholesterol efflux at a higher rate from cells with ATP-dependent lipid pump activity but it also undergoes more effective receptor mediated endocytosis.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [12] 2025, ApoE is Secreted as a Lipid Nanoparticle by Mammalian Cells: Implications for Alzheimer’s Disease Pathogenesis, Biochemistry source

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

    Premisecitation

    A subsequent report suggested delayed onset even in heterozygotes in that kindred.

    “and a subsequent report suggested delayed onset even in heterozygotes in that kindred 7 .”
    Quote in the paperNot a substantial claim1 of 1 sources checked

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

    Premisecitation

    The Christchurch variant R136S drew broad attention after a homozygous carrier in a PSEN1 E280A kindred showed a striking delay in age-at-onset of symptoms.

    “The Christchurch variant R136S drew broad attention after a homozygous carrier in a PSEN1 E280A kindred showed a striking delay in age-at-onset of symptoms 6”
    Quote in the paperNot a substantial claim1 of 1 sources checked

  • May combine two claims.

    Premisecitation

    The interpretation that residue position and its impact on intermolecular interactions are critical is consistent with prior human genetics, with biochemical data mapping lipid binding and oligomerization properties of ApoE to its C-terminal domain, and with other data linking the physical state of ApoE to its role in amyloid handling, tau-mediated neurodegeneration and receptor-dependent Traffick

    “That interpretation is consistent with prior human genetics 5 , with biochemical data mapping lipid binding and oligomerization properties of ApoE to its C-terminal domain and with other data linking the physical state of ApoE to its role in amyloid handling, tau-mediated neurodegeneration 15 and receptor-dependent trafficking 16 .”
    Quote in the paperSubstantial claim3 of 3 sources checked
    • cites [5] 2022, Association of Rare APOE Missense Variants V236E and R251G With Risk of Alzheimer Disease, JAMA Neurol source
    • cites [15] source

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

      Experimental — accuracy not yet measured
    • cites [16] 2025, Decreased lipidated ApoE-receptor interactions confer protection against pathogenicity of ApoE and its lipid cargoes in lysosomes, Cell source

  • May combine two claims.

    Interpretationcitation

    C-terminal ApoE biology, including lipidation and self-association, is not merely correlative but is closely tied to pathogenesis and may inform future APOE-directed therapeutic strategies.

    “Together, these data support a model in which C-terminal ApoE biology, including lipidation and self-association, is not merely correlative but is closely tied to pathogenesis and may inform future APOE-directed therapeutic strategies 2,17 .”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [2] source
    • cites [17] 2024, Report of the APOE4 National Institute on Aging/Alzheimer Disease Sequencing Project Consortium Working Group: Reducing APOE4 in Carriers is a Therapeutic Goal for Alzheimer’s Disease, Ann. Neurol source

      The sections on cellular and animal studies and endolysosomal pathways link APOE4-related lipid dysregulation and altered protein solubility to Alzheimer’s pathology. The Discussion also proposes APOE-directed therapeutic approaches. However, the cited paper does not establish the claim’s specific link between C-terminal lipidation or self-association and pathogenesis; searches for those terms found no such passage. Page numbers were not available in our copy. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

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

    Findingown data

    One ApoE4-R251G measurement and one ApoE3-R145C measurement met the prespecified outlier criterion.

    “One ApoE4-R251G measurement and one ApoE3-R145C measurement met this criterion.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    R189C was associated with increased risk in ADSP (OR=2.36) and All of Us (OR=5.63), with directionally consistent signals.

    “with a directionally consistent signal in both ADSP (OR = 2.36) and All of Us (OR = 5.63).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In this Admixed American meta-analysis, R136S (Christchurch) showed no evidence of protection and had a non-significant point estimate above the null (OR=1.42, 95% CI 0.18-11.25, P=0.740).

    “R136S (Christchurch) showed no evidence of protection and instead had a non-significant point estimate above the null (OR = 1.42, 95% CI 0.18-11.25,P = 0.740).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Both R189C and W276C introduce cysteine residues onto an ε3 background, yet they associate with opposite clinical effects.

    “it is notable that both R189C and W276C introduce cysteine residues onto an ε3 background, yet they associate with opposite clinical effects.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: R189C and W276C are ε3-linked variants.

  • May combine two claims.

    Findingown data

    W276C was associated with reduced risk in ADSP (OR=0.31) and All of Us (OR=0.03), with concordant protective point estimates.

    “again with concordant protective point estimates in ADSP (OR = 0.31) and All of Us (OR = 0.03).”
    Quote in the paperSubstantial claim

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

    Study design and conductnone given

    The 48-h serum-free condition was used because longer incubations increased apoE cleavage and serum reduced isoform-specific differences.

    “This 48-h serum-free condition was used because longer incubations increased apoE cleavage and serum reduced isoform-specific differences.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    A simple model in which Cys addition uniformly confers protection or risk is argued against; instead, residue position and its impact on intermolecular interactions with lipids and/or proteins are critical.

    “This argues against a simple model in which Cys addition uniformly confers protection or risk, and instead suggests that residue position and its impact on intermolecular interactions with lipids and/or proteins are critical.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    APOE loss-of-function variants are compatible with longevity and may be associated with resistance to AD-related pathology.

    “recent human genetic evidence indicates that APOE loss-of-function variants are compatible with longevity and may be associated with resistance to AD-related pathology 3”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [3] source

  • May combine two claims.

    Study design and conductown data

    Analyses were robust to inclusion of all data points, and sensitivity analyses with and without excluded points did not alter the interpretation of the prespecified biological comparisons.

    “Analyses were robust to inclusion of all data points, and sensitivity analyses with and without the excluded points did not alter the interpretation of the prespecified biological comparisons.”
    Quote in the paperNot a substantial claim

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

    Study design and conductown data

    The ApoE4-R251G point corresponded to a documented technical artifact during the assay.

    “The ApoE4-R251G point also corresponded to a documented technical artifact during the assay.”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    The All of Us analysis relied in part on a proxy phenotype.

    “The variants described here are very rare, confidence intervals remain wide, and the All of Us analysis relied in part on a proxy phenotype.”
    Quote in the paperNot a substantial claim

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

    Study design and conductreasoning

    Confidence intervals remain wide in this study.

    “The variants described here are very rare, confidence intervals remain wide, and the All of Us analysis relied in part on a proxy phenotype.”
    Quote in the paperNot a substantial claim

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

    Study design and conductreasoning

    Absolute ApoE concentrations were not determined; the assay provides a relative self-association readout across matched conditions.

    “Absolute ApoE concentrations were not determined; accordingly, the assay provides a relative self-association readout across matched conditions.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    The two newly implicated Admixed American variants have distinct intermolecular interaction characteristics than ApoE3: R189C has an ApoE4-like preference for lipidation, and W276C has a Jacksonville-like reduction in self-association.

    “Thus, the two newly implicated Admixed American variants have distinct intermolecular interaction characteristics than ApoE3: R189C has an ApoE4-like preference for lipidation, and W276C has a Jacksonville-like reduction in self-association.”
    Quote in the paperSubstantial claim

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

    Study design and conductnone given

    In ADSP, relatedness was accounted for using a sparse genetic relationship matrix.

    “Relatedness was accounted for using a sparse genetic relationship matrix.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductown data

    In ADSP, association models were adjusted for sex, APOE-ε2 dosage, APOE-ε4 dosage and 3 ancestry principal components.

    “Models were adjusted for sex, APOE-ε2 dosage, APOE-ε4 dosage and 3 ancestry principal components.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    The heterozygote finding has been contended.

    “The heterozygote finding has been contended 8 , however”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [8] 2024, APOE3 Christchurch Heterozygosity and Autosomal Dominant Alzheimer’s Disease, N. Engl. J. Med source

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    The functional experiments were designed to test directionally informative biochemical states rather than establish a full causal chain from variant to disease.

    “The functional experiments were designed to test directionally informative biochemical states rather than establish a full causal chain from variant to disease.”
    Quote in the paperSubstantial claim

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

    Study design and conductnone given

    For the split-luciferase assay, outlier exclusion was prespecified at the construct level using a robust modified z-score based on the median absolute deviation, with |modified z| > 3.5 considered outlying.

    “For the split-luciferase assay, outlier exclusion was prespecified at the construct level using a robust modified z-score based on the median absolute deviation, with |modified z| > 3.5 considered outlying.”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    The comparisons emphasized in Fig. 2a were prespecified on biological grounds.

    “The comparisons emphasized in Fig. 2a were prespecified on biological grounds”
    Quote in the paperNot a substantial claim
33 of 33

  • The paper relies on this without support.

    Rare APOE missense variants in admixed populations can clarify mechanisms of Alzheimer disease risk beyond ε2 and ε4.

    “Rare APOE missense variants in admixed populations can clarify mechanisms of Alzheimer disease (AD) risk beyond ε2 and ε4.”

  • The paper relies on this without support.

    The molecular basis of APOE's effect on Alzheimer disease is still unresolved.

    “but the molecular basis of its effect is still unresolved.”

  • The paper relies on this without support.

    R189C and W276C are ε3-linked variants.

    “Two ε3-linked C-terminal variants showed evidence of association with AD across both datasets.”

  • The paper relies on this without support.

    APOE-ε2 introduces a cysteine residue at position 158 and APOE-ε4 lacks the Cys present at residue 112 in APOE-ε3.

    “with APOE-ε2 introducing a cysteine residue at position 158 and APOE-ε4 lacking the Cys present at residue 112 in APOE-ε3.”

  • The paper relies on this without support.

    The ancestry assignments in ADSP and All of Us are comparable enough to combine in meta-analysis.

    “In ADSP, ancestry was assigned with SNPWeights 9 using 1000 Genomes reference populations 10 ; in All of Us, we used the published genetic-ancestry framework based on projection into a reference principal-component space and classifier-based assignment 11 .”
5 of 5

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Authors
Le Guen, Y., Reil, D., Jackson, R. J., Peña-Tauber, A., Khosla, C., & Greicius, M. D.
Affiliations
  • Quantitative Sciences Unit, Division of Computational Medicine, Department of Medicine Stanford University, Stanford, California 94305, United States
  • Stanford University (US)
  • University of Dundee (GB)
  • Department of Neurology and Neurological Sciences, Stanford University, Stanford, California 94305, United States
ORCID
Venue
medRxiv
Publisher
openRxiv
Published
2026-05-12
DOI
10.64898/2026.05.08.26352778
OpenAlex
W7160899590
Semantic Scholar
d8d59f9230a2c41c702d09c2db9e526cddec27d6
Cited by
0
References
21
Type
posted content
Language
en
Open access
Licence
Locations
medRxiv (acceptedVersion, cc-by-nc)
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
Alzheimer's disease, apolipoprotein E, missense mutations, APOE ε3, Native American ancestry, admixed populations, apoE secretion, C-terminal conformation, genetic risk

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