APOE C130R - GET-Evidence


(See latest approved version)


(APOE Cys130Arg)

Short summary

This is generally known as the ApoE4 allele of ApoE and is associated with increased risk of Alzheimer’s. 20-25% of individuals are heterozygous for this variant, and 1-2% are homozygous. Data from Khachaturian et al. suggests an average 7% of all individuals developed Alzheimer’s by the age of 80; when this is split by ApoE4 status: 10% of ApoE4 heterozygotes (3% increased attributable risk), 40% of ApoE4 homozygotes (33% increased attributable risk), and 5% of non-carriers (2% decreased attributable risk). Notably, their model suggests 70-75% of people would eventually develop Alzheimer’s by the age of 100 regardless of ApoE4 genotype (and 25-30% are resistant, regardless of genotype), but that ApoE4 variants shift the disease onset to occur significantly earlier (4 years earlier for heterozygous carriers, 13 years for homozygotes).

Variant evidence

Other variants in this gene are associated with Alzheimer’s, but Polyphen 2 & SIFT predict nonpathogenic

Functional 3

Compared to E2 & E3, ApoE4 has lower rate of delaying plaque formation in transgenic mice & triggers more amyloid-beta production

See 11950276, 17428983.

Case/Control 5

Very high significance findings in many studies

See 9343467, 15123497.

Familial -
Clinical importance
Severity 4

Alzheimer’s disease

Treatability 2

Treatment is largely palliative; there is research seeking treatments for the disease or prevention of it but no conclusively effective treatments have been found so far.

Penetrance 4

3% increased attributable risk for Alzheimer’s by age 80 for heterozygotes, 33% increased attributable risk for homozygotes.

See 15123497.



High clinical importance, pathogenic

(The "high clinical importance, " qualifier is assigned automatically based on the above evidence and importance scores.)

Inheritance pattern


Summary of published research, and additional commentary

Other sources & evaluations covering ApoE4: (1) ApoE on OMIM (this variant is listed rs429358 and CYS112ARG due to alternative amino acid numbering) http://www.omim.org/entry/107741 (2) Alzheimer’s Disease on 23andMe: https://www.23andme.com/health/alzheimers/techreport/ (3) GeneReviews Alzheimer Disease Overview: http://www.ncbi.nlm.nih.gov/books/NBK1161/

Allele frequency

  • C @ chr19:45411941: 13.5% (1381/10200) in EVS
  • C @ chr19:50103780: 12.8% (10/78) in GET-Evidence
  • Frequency shown in summary reports: 13.5% (1381/10200)


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PubMed PMID: 9343467

This paper is the one typically cited regarding the effects of ApoE E2 and E4 on the risk of Alzheimer’s disease. Because translating odds ratios to attributable risks is complicated (requiring assumptions regarding allele frequencies and disease frequencies) and because Khachaturian et al. was able to follow a particularly long-lived population, data from Khachaturian et al. is what is used by GET-Evidence for estimating the effect of ApoE4 on Alzheimer’s risk.

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PubMed PMID: 11950276

ApoE4 delayed plaque formation in transgenic mice the least, in three ApoE variants (E2 > E3 > E4) tested in a mouse model of Alzheimer’s.

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PubMed PMID: 15123497

The population analyzed in this study notably contains some very old individuals, allowing the authors to carefully study the lifetime influence of ApoE4 on Alzheimer’s disease. They find that, in general, Alzheimer’s disease is best described by a model where a fraction of the population is resistant to the disease and will never develop it no longer how long they live. In this model, 25-30% of individuals appear to be in this “resistant” group.

When individuals are segregated according to ApoE4 carrier status (homozygous, heterozygous, and non-carrier), they find that the age of onset is shifted earlier for carriers of ApoE4 (Figure 3). For non-carriers, ~50% are diagnosed with Alzheimer’s disease by the age of ~95 years. This shifts to ~91 years of age for individuals heterozygous for ApoE4 (~4 years earlier onset) and ~82 years for ApoE4 homozygotes (~13 years earlier onset).

Investigating the incidence of Alzheimer’s by age 80 in their model, 7% of all individuals on average have developed it by this age (Figure 2). Non-carriers have an average rate of ~5%, heterozygotes a rate of ~10% (2x), and homozygotes a rate of ~40% (8x) (from Figure 3). Penetrance in GET-Evidence is evaluated according to these numbers, with 3% increased attributable risk for heterozygotes (from 7%) and 33% increased attributable risk for homozygotes.

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PubMed PMID: 17428983

Functional Evidence (variant shows increased risk of production of Abeta in neuroblastoma cells)


hu025CEA - CGI sample GS01669-DNA_D02 from PGP sample 27316983
het C @ chr19:45411941


hu241DEA - CGI sample GS01175-DNA_D05 from PGP sample 1205491
het C @ chr19:45411941


hu2D6140 - CGI sample GS01173-DNA_F06 from PGP sample 64191565
het C @ chr19:45411941


hu38168C - CGI sample GS01173-DNA_H06 from PGP sample 91708424
hom C @ chr19:45411941


hu3CAB43 - CGI sample GS01175-DNA_D03 from PGP sample 27486199
het C @ chr19:45411941


hu4040B8 - CGI sample GS01175-DNA_D01 from PGP sample 31286272
het C @ chr19:45411941


hu44DCFF - CGI sample GS01669-DNA_C07 from PGP sample 74521372
het C @ chr19:45411941


huA0E089 - CGI sample GS01175-DNA_B04 from PGP sample 88590671
het C @ chr19:45411941



huCA017E - CGI sample GS01175-DNA_B01 from PGP sample 86206034
het C @ chr19:45411941


huFAF983 - CGI sample GS01175-DNA_F02 from PGP sample 95788191
hom C @ chr19:45411941


GS18502 - var-GS18502-1100-36-ASM
het C @ chr19:50103781


GS18504 - var-GS18504-1100-36-ASM
hom C @ chr19:50103781


GS18517 - var-GS18517-1100-36-ASM
het C @ chr19:50103781


GS19129 - var-GS19129-1100-36-ASM
het C @ chr19:50103781


GS21767 - var-GS21767-1100-36-ASM
het C @ chr19:50103781




Other external references

  • rs429358
  • GeneTests records for the APOE gene
    Alzheimer Disease Risk Factor (APOE Genotype)
    Alzheimer Disease Type 2
    Cardiovascular Disease Risk Factor (Apolipoprotein E)
  • [Psoriasis]
    Risk or phenotype-associated allele: ApoE E4 allele (rs429358 C, rs7412 C) (130Arg, 176Arg). Phenotype: Increased incidence of chronic plaque psoriasis and guttate psoriasis, but no difference in response of psoriasis to the drug acitretin. Study size: 306 cases, 137 controls. Study population/ethnicity: Patients with chronic plaque psoriasis (n = 212), guttate psoriasis (n = 94). Significance metric(s): p =0.008 Type of association: CO; GN
  • [Neurodegenerative Diseases; Posterior Cortical Atrophy]
    Risk or phenotype-associated allele: APOE: epsilon3/epsilon3 (defined as rs429358 T/T 130Cys/Cys + rs7412 C/C 176Arg/Arg). Phenotype: Neurodegenerative disease characterized by asymmetric parietal atrophy, visuospatial dysfunction, incomplete Balint's syndrome, environmental agnosia, left-sided motor symptoms including dystonic postures and myoclonus in the left hand, without significant dementia (as in posterior cortical atrophy) was observed in a woman with early-onset neurodegenerative disease progressing 10 years from onset at age 52 to death. Study size: 1. Study population/ethnicity: Right-handed female/Japanese. Significance metric(s): non significant case report. Type of association: CO; GN
  • [Infarction; Myocardial Infarction]
    Risk or phenotype-associated allele: The ApoE E4 allele is a combination of rs429358 C (130Arg) and rs7412 C (176Arg). Phenotype: The Apo E4 allele is associated with 80 percent increased risk of dying (mortality risk ratio = 1.8) compared with other patients upon evaluation at 5.5 years following survival of myocardial infarction. ApoE E4 carriers who had high Lp(a) levels had a risk ratio of 3.7 of coronary death. Simvastatin treatment reduced the mortality risk to 0.33 in Apoe E4 carriers and to 0.66 in other patients (p = 0.23 for treatment by genotype interaction). Study size: 966 survivors of myocardial infarction enrolled in the Scandinavian Simvastatin Survival Study. Study population/ethnicity: Danish and Finnish. Significance metric(s): mortality risk ratio = 1.8. Type of association: CO; PD; GN
  • [Alzheimer Disease]
    Risk or phenotype-associated allele: The APOE E4 allele is a combination of rs429358 C (130Arg) and rs7412 C (176Arg). Phenotype: The APOE E4 allele (130Arg, 176Arg) was studied relative to the E3 (130Cys, 176Arg) and E2 (130Cys, 176Cys) alleles. Relative to the homozygous E3/E3 diplotype, Caucasians showed increased risk of Alzheimer Disease (AD): OR = 2.6 for E4/E2, OR = 3.2 for E4/E3, OR = 14.9 for E4/E4. The E2 allele was protective against risk of AD: OR = 0.6 for E2/E2, OR = 0.6 for E3/E2. Japanese showed greater increased risk of AD than Caucasians: OR=5.6 for E3/E4, OR = 33.1 for E4/E4. Study size: 5930 patients who met criteria for probable or definite AD, and 8607 controls without dementia. Study population/ethnicity: A clinic-/autopsy-based case-control study of patients between 40 and 90 years old recruited from clinical, community, and brain bank sources./Caucasian, African American, Hispanic, Japanese. Significance metric(s): OR. Type of association: CO; GN
  • [Cataract; Macular Degeneration]
    Risk or phenotype-associated allele: The E3 and E4 alleles of APOE, defined by the combined genotype at rs429358T>C (Cys130Arg) and rs7412C>T (Arg176Cys). Phenotype: The APOE E3 allele (130Cys, 176Arg) and E4 (130Arg, 176Arg) alleles were protective. Carriers of the E3 allele had significantly higher average macular thickness in both eyes (p = 0.012), and significantly better visual acuity (p = 0.041) than non-E3 carriers. E4 carriers showed reduced incidence of cataract than non-APOE4 carriers (p = 0.039). Study size: 32 patients who underwent cataract surgery in both eyes, and 56 controls. Study population/ethnicity: Patients from London, England aged 50-75 years old. Significance metric(s): p-value. Type of association: CO; GN
  • [Arteriosclerosis; Hyperlipoproteinemia Type III; Hyperlipoproteinemias; Vascular Diseases]
    Risk or phenotype-associated allele: The ApoE E2 allele is a combination of rs429358 T (130Cys) and rs7412 T (176Cys). Phenotype: The Apo E2 allele contributes to increased risk of type III hyperlipoproteinemia, characterized by increased cholesterol and triglyceride levels, the presence of beta-VLDL (cholesterol-enriched remnants of intestinal chylomicrons and hepatic VLDL), xanthomas, and premature vascular disease, both coronary heart disease and peripheral artery disease. Study size: Three multiplex, multigenerational pedigrees, and case control study of 5 probands versus 94 controls. Study population/ethnicity: Germans. Significance metric(s): N/A. Type of association: CO; GN
  • Score: 0.002 (benign)
    Web search results (34 hits -- see all)
    HAPLOTYPES OF THE APOE GENE RELATED APPLICATIONS This application ... APOE is a plasma protein that mediates the transport and uptake of cholesterol ...
  • BioPortfolio - ENTPD7
    ENPP3 antibodies (1) · ENTPD7 antibodies (1) · FXYD1 antibodies (1) · FXYD3 antibodies (1) · Hydrogen ... The rs429358 (APOE:c.388T>C; p.C130R) and rs7412 (APOE:c.526C>T; p. ...
    the human and chimpanzee species diverged from our common ancestor, constituting ... single-nucleotide changes, five million insertion/deletion events, and ...
    cmm.ucsd.edu/varki/varkilab/A144 copy.pdf
  • Controlling Linkage Disequilibrium in Association Tests ...
    genetic effect of the studied APOE variants was re-evaluated ... variants than rs429358 in APOE, which has been doubtful. for associations with Alzheimer's ...
  • RealGene - Biotech Company Italiana
    ApoE C112R (C130R) - Novità. Saggio dedicato allo studio del polimorfismo ApoE C112R ... Saggio dedicato allo studio del polimorfismo ApoE R158C (R176C) ...
  • r02_2004_b07.pdf
    APOE. apolipoprotein E. C/T C/T. C130R C176R. Glaucoma (녹내장) OPTN ... 수송에 관여하는 것으로 보이며 특히 ε4 allele을 가지는 apoE는 다른 형태의 apoE. 에 비해서 Aβ에 더 잘 결합하며 amyloid 섬유의 생성을 ...
  • RealGene - A Unique Activating Mutation in JAK2 (V617F) Is at ...
    Myeloproliferative disorders (MPDs) are heterogeneous diseases that ... ApoE C112R (C130R) - Novità. Saggio dedicato allo studio del polimorfismo ApoE C112R (C130R). ApoE R158C ...
  • Gene SNP (alias) MAF WARG R2 P Pilot R2 P ABCB1 rs3842 0.137 ...
    APOE. rs429358 (C130R or C112R) 0.173 0. 9.68 × 10. 1. 1.9. 1.67 × 10. 1. APOE. rs7412 (R176C or R158C) 0.07. 0. 9.93 × 10. 1. 1.2. 3.59 × 10. 1. CALU. rs339057. 0.438 0.3. 1.27 × 10. 1 ...
  • Parkinson Disease Knowledgebase
    APOE. Variant (mutation/polymorphism) information mined from UniProt : ... C130R (Disease) [ VAR_000652 ] C130R (Disease) G145D (Polymorphism) ...

Other in silico analyses

  • NBLOSUM100 score = 8
  • GET-Evidence autoscore = 3

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Gene search

"GENE" or "GENE A123C":

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