Name: apolipoprotein E
Entrez gene ID: 348
Ensembl gene ID: ENSG00000130203
Chylomicron remnants and very low density lipoprotein (VLDL) remnants are rapidly removed from the circulation by receptor-mediated endocytosis in the liver. Apolipoprotein E, a main apoprotein of the chylomicron, binds to a specific receptor on liver cells and peripheral cells. ApoE is essential for the normal catabolism of triglyceride-rich lipoprotein constituents.; Mediates the binding, internalization, and catabolism of lipoprotein particles. It can serve as a ligand for the LDL (apo B/E) receptor and for the specific apo-E receptor (chylomicron remnant) of hepatic tissues. [UniProt]
In humans APOE is located on chromosome 19. There are three common allelic variants of APOE (ε2 to ε4).
The resulting proteins are referred to as ApoE2, ApoE3 and ApoE4.
The respective proteins differ only in single amino acid, but have a dramatic influence on the life of affected humans.
The frequency of the epsilon 2 allele of ApoE is significantly increased in centenarians relative the overall control population, while the epsilon 4 allele is significantly decreased in centenarians . Among individuals 85 years or older how had good cognition, the mortality of those that had the 2/3 genotype was half that in those who carried the epsilon 3/3 genotype and the mortality in subjects with the epsilon 3/4 genotype is twice that of those who carry the epsilon 3/3 genotype. This 4-fold variation results in 2-year difference in survival .
The epsilon 4 allele is also associated with higher cholesterol levels and cardiovascolar disease [10818513; 8624216] as well as risk factor for cognitive impariment under age 85 . However the APOE polymorphism is not a risk factor for cognitive impairment in individuals older than 85 years .
The Polymorphism (E2, E3, and E4) was examined in a sample of 228 healthy Italian subjects (124 men and 104 women) aged 18-93, with the result that the frequency of E4 decreased with age and was not found in subjects aged 75 and older .
By Examining the common polymorphism was in 182 women and 100 men aged > 84 years and in 100 boys and 100 girls younger than 17 years (English, Cambridge) a difference between genotypes in the elderly women and the young sample was observed. However, this did not retain significance when the genotype frequencies of the young sample were adjusted to values expected from the allele frequencies on the basis of Hardy-Weinberg equilibrium and compared to observed genotypes in elderly men and women .
In a Braxiallian population the common polymorphism was examined in 70 elderly patients aged 80 years or more. No association was observed between the genotypes and longevity, though individuals with the E3E4 genotype had a mean age greater than those with the E3E3 genotype .
In a Korean population the common polymorphism examination of 103 centenarians (13 men and 90 women, mean age 102.4 +/- 2.6 years) and 6435 adults (5008 men and 1427 women) of mean age 50.7 +/- 7.9 years found that the frequencies of genotypes and alleles of the centenarians were not significantly different from those of the control groups. The frequency of the E4 allele was significantly higher in centenarians with dementia than in centenarians without definitive dementia .
Examination of the common polymorphism in 224 older (75 years) Jewish Jerusalem residents of Ashkenazi ethnicity (150 males and 74 females) and a group of 441 younger subjects (22 years) revealed that the Ashkenazi older subjects were characterized by an increased percentage of the E2 allele and a decreased percentage of the E4 allele .
A study of APOE polymorphisms in a samples of 538 Colombian subjects (aged 18-106 years) did not find any differences between young and old subjects .
APOE correlated highly with longevity in a plethora of genetic signatures and has been associated with Alzheimer's disease .
ε3 and *ε4 are much more efficient binding lipoprotein receptors .
The various APOE isoforms interact differently with specific lipoprotein receptors, ultimately altering circulating levels of cholesterol. APOE from VLDL, chylomirons and chylomicron remnants binds to specific receptor cells in the liver. Carriers of the ε2 allele are less efficient at making and transferring VLDLs and chylomicrons from the blood plasma to the liver because of its binding properties. By contrast, carriers of the ε3 are much more efficient in these processes. While APOE4 and APOE3 bind with approximately equal affinity to lipoprotein receptors, APOE2 binds with less than 2% of this strength . Thus, compared with carriers of the ε3 or ε4 allele, carriers of the ε2 allele are slower to clear dietary fat from their blood . The difference lipoprotein particles results in differences in regulating hepatic low density lipoprotein (LDL) receptors which in turn contribute to genotypic differences in total and LDL cholesterol levels [1998654; 3277611; 8696954; 8018666; 1867194; 3698268].
While APOE was not found to be associated with longevity in some studies [16799145; 21703254], APOE was found to be associated with longevity in many others [11780357; 11213279; 16487435; [23286790; 15621215; 8018664; 21418511; 8136829; 9792194; 22445811; 12185856; 10069711; 21703254; 17934638; 17234815; 11788960; 17934638; 10643896; 11280044; 14615589; 23040522; 18034366]. APOE was found to be associated with longevity . APOE was not found to be associated with longevity . APOE was found to be associated with longevity . APOE was found to be associated with longevity . APOE was found to be associated with longevity . APOE was found to be associated with longevity . APOE was found to be associated with longevity .
Longevity Associated Variants:
APOE e2/e3/e4 0.02 
APOE e2,e3,e4 0.05 
rs429358 + rs7412 0.04 
APOE e2/e4 0.001 
APOE haplotype None 
APOE polymorphism 0.02 
- None 
APOE genotype None 
- None 
rs429358, rs7412 None 
rs429358, rs7412 None 
rs769449 0.018 
APOE polymorphism 0.437 
rs429358, rs7412 0.001 
APOE e2/e3/e4 None 
E4 0.013 
apoE haplotypes 0.013 
apoE haplotypes 0.013 
apoE haplotypes 0.013 
APOE None 
APOE polymorphism 0.002 
HP1/2 common polymorphism 0.05 
APOE polymorphism - HP1/2 common polymorphism 0.013 
- None 
APOE e2,e3,e4 0.01 
rs4420638 9.6e-08 
epsilon2/3/4 0.05 
APOE polymorphism 0.001 
rs429358, rs7412 0.025 
APOE polymorphism 0.0001 
rs2075650 3.39e-17 
APOE4 0.71 
rs429358, rs7412 0.0006 
rs429358, rs7412 0.005 
rs429358, rs7412 0.009 
APOE haplotype - rs1346044 0.0001 
rs429358, rs7412 0.0212 
rs2075650 0.000527 
E2 / E3 / E4 1.2e-08 
rs429358, rs7412 0.0005 
rs449647 0.767 
rs405509 0.027 
rs440446 0.509 
rs769448 0.66 
rs769449 0.62 
rs7412 0.405 
rs429538 0.2821 
rs4420638 3.4e-36 
e4 0.03 
e4 0.05 
e4 0.001 
rs2075650 4.44e-16 
e4 0.04 
No Age Effect
8136829: Genetic associations with human longevity at the APOE and ACE loci.
10818513: Severity of cardiovascular disease, apolipoprotein E genotype, and brain pathology in aging and dementia.
8624216: Apolipoprotein E genotype determines survival in the oldest old (85 years or older) who have good cognition.
8541369: Apolipoprotein E allele frequencies in an Italian population: relation to age and lipid profile.
9105559: Analysis of the apo E/apo C-I, angiotensin converting enzyme and methylenetetrahydrofolate reductase genes as candidates affecting human longevity.
12185856: Analysis of the association between apolipoprotein E polymorphism and cardiovascular risk factors in an elderly population with longevity.
15621215: Candidate genes associated with ageing and life expectancy in the Jerusalem longitudinal study.
16971231: Analysis of common polymorphisms in angiotensin-converting enzyme and apolipoprotein e genes and human longevity in Colombia.
22279548: Genetic signatures of exceptional longevity in humans.
23286790: Genome-wide linkage analysis for human longevity: Genetics of Healthy Ageing Study.
12634288: Distributions of ACE and APOE polymorphisms and their relations with dementia status in Korean centenarians.
11780357: Apolipoprotein E gene polymorphism and its association with human longevity in the Uygur nationality in Xinjiang.
8018664: Aging and genetic variation of plasma apolipoproteins. Relative loss of the apolipoprotein E4 phenotype in centenarians.
7628082: Apolipoprotein E: an important gene and protein to follow in laboratory medicine.
3479440: Dietary fat clearance in normal subjects is regulated by genetic variation in apolipoprotein E.
1998654: Effects of the apolipoprotein E polymorphism on levels of lipids, lipoproteins, and apolipoproteins among Mexican-Americans in Starr County, Texas.
3277611: Apolipoprotein E polymorphism and atherosclerosis.
8696954: Apolipoprotein E polymorphism in American Indians and its relation to plasma lipoproteins and diabetes. The Strong Heart Study.
8018666: Effects of gender and menopausal status on the association of apolipoprotein E phenotype with plasma lipoprotein levels. Results from the Framingham Offspring Study.
1867194: The apolipoprotein E polymorphism: a comparison of allele frequencies and effects in nine populations.
3698268: Association of apolipoprotein E polymorphism, low-density lipoprotein cholesterol, and coronary artery disease.
11882522: Apolipoprotein E polymorphism and cardiovascular disease: a HuGE review.
16799145: Association between serum beta-carotene levels and decline of cognitive function in high-functioning older persons with or without apolipoprotein E 4 alleles: MacArthur studies of successful aging.
20569235: HRAS1 and LASS1 with APOE are associated with human longevity and healthy aging.
17934638: Apolipoprotein E polymorphism distribution in an elderly Brazilian population: the Bambuí Health and Aging Study.
11788960: Mortality differences by APOE genotype estimated from demographic synthesis.
21703254: APOE haplotypes are associated with human longevity in a Central Italy population: evidence for epistasis with HP 1/2 polymorphism.
21418511: Genome-wide association study identifies a single major locus contributing to survival into old age; the APOE locus revisited.
16960022: Sex differences in the association of apolipoprotein E and angiotensin-converting enzyme gene polymorphisms with healthy aging and longevity: a population-based study from Southern Italy.
10069711: Polymorphisms at the Werner locus: I. Newly identified polymorphisms, ethnic variability of 1367Cys/Arg, and its stability in a population of Finnish centenarians.
17234815: Lower prevalence of epsilon 4 allele of apolipoprotein E gene in healthy, longer-lived individuals of Hellenic origin.
11213279: Longevity and the epsilon2 allele of apolipoprotein E: the Finnish Centenarians Study.
16487435: Apolipoprotein E genotype is related to plasma levels of C-reactive protein and lipids and to longevity in nonagenarians.
11470126: Apolipoprotein E alleles in nonagenarian subjects in the Belfast Elderly Longitudinal Free-living Ageing Study (BELFAST).
9792194: Apolipoprotein E and longevity among Han Chinese population.
22445811: Genetic variants influencing human aging from late-onset Alzheimer's disease (LOAD) genome-wide association studies (GWAS).
10643896: Decreased frequency of apolipoprotein E epsilon4 allele from Northern to Southern Europe in Alzheimer's disease patients and centenarians.
11280044: A study of French centenarians: are ACE and APOE associated with longevity?
14615589: Haplotype-based identification of a microsomal transfer protein marker associated with the human lifespan.
23040522: Apolipoprotein E and familial longevity.
18034366: Lack of replication of genetic associations with human longevity.
Aging Relevance Analysis/Source: