The apolipoprotein E (ApoE) gene makes a protein which, when combined with fat, becomes a lipoprotein. The lipoprotein ApoE is a very low-density lipoprotein, responsible in part for removing cholesterol from the bloodstream. Variations in ApoE affect cholesterol metabolism, which in turn alter your chances of having heart disease and in particular a heart attack or a stroke. Variations in ApoE are also associated with altered odds of having Alzheimer's disease and other diseases.
There are three relatively common allelic variants of ApoE, as defined by two SNPs, rs429358 and rs7412 known as ApoE-ε2, ApoE-ε3, and ApoE-ε4. The proteins produced by these genes are called ApoE2, ApoE3, and ApoE4. The most common variant overall is the "standard" ApoE-ε3, and therefore more people inherited one ApoE-ε3 from each parent than any other of the possible pairs of variants. Note that each of these types can actually have additional changes too, so there are different subtypes as well.
|Apo-ε1/ε1||gs267||6||(C;C)||(T;T)||the rare missing allele|
|Apo-ε1/ε3||gs270||2.6||(C;T)||(C;T)||ambiguous ε2/ε4 or ε1/ε3|
|Apo-ε2/ε4||gs270||2.6||(C;T)||(C;T)||ambiguous ε2/ε4 or ε1/ε3|
|Apo-ε2/ε2||gs268||4||(T;T)||(T;T)||good; lowest risk|
|Apo-ε3/ε3||gs246||2||(T;T)||(C;C)||the most common|
|Apo-ε4/ε4||gs216||6||(C;C)||(C;C)||~11x increased Alzheimer's risk|
Word of caution to those with data from Ancestry.com: in our experience, based on data in OpenSNP and from Promethease users since 2006, Ancestry data always reports rs429358 as (T;T), even for people who's data from other sources indicates they are (C;T). Therefore, until Ancestry corrects this false negative problem, be aware that the ApoE genosets defined by the genotypes listed above (and therefore assigned by Promethease) will be inaccurate if they are based on (inaccurate) Ancestry data. Specifically, some percentage of Ancestry users who are supposedly gs246 positive (Apo-ε3/ε3) are actually either gs141 (Apo-ε3/ε4) or gs216 (Apo-ε4/ε4).
A rare form of the ApoE3 allele, rs121918393, also known as the Christchurch (R136S) mutation, appears to convey a significant amount of resistance to PSEN1-based form of autosomal dominant Alzheimer’s, according to a 2019 study.
Note: Although ApoE status is technically defined by these two SNPs, rs429358 and rs7412, a SNP in the adjacent ApoC1 gene, rs4420638, is co-inherited with ApoE and thus predictive of it, as published in the following report:
- [PMID 17192785] The researchers found that on testing DNA samples from 1,086 well-characterized Alzheimer's disease cases, a single SNP (rs4420638) lying 14 kb distal to the ApoE locus has a powerful association with late-onset AD (corrected p value was 5.3 x 10 e-34). No other SNP showed as robust an association. The authors estimated that people with two ApoE-ε4 copies (i.e. presumably indicated by having either the rs4420638(G;G) or rs429358(C;C) genotypes) have a 25-fold increased risk for developing the disease compared to Apo-ε3/Apo-ε3 carriers.
- rs2373115, a SNP in the GAB2 gene
- Inheritance of the rs1799724(T) allele appears to synergistically increase the risk of Alzheimer's in ApoE-ε4 carriers and is associated with altered CSF Abeta42 levels [PMID 15895461]
- A haplotype of 3 SNPs in the POLD1 gene; the combined presence of this POLD1 I-G-T haplotype and the ApoE-ε4 allele almost doubles the risk of AD (odds ratio: 10.09, CI: 3.88-26.25, =<0.0001) compared to ApoE-ε4 carriers alone.[PMID 17498878]
A study of 2,000+ individuals living in Costa Rica found a gene-diet interaction involving the ApoE alleles. Specifically, high fat diets cause a greater LDL cholesterol response and higher heart attack risk in ApoE-ε2 and ApoE-ε4 carriers compared with ApoE-ε3 homozygotes.[PMID 18494374]
abstract ApoE-ε4 and herpes simplex virus type 1 appear related to the development of Alzheimer's disease.