DNA HealthLipid Metabolism

Apolipoprotein E


Allele frequency in population:

The human APOE gene exists as three polymorphic alleles—ε2, ε3 and ε4—which have a worldwide frequency of 8.4%, 77.9% and 13.7%, respectively.

Gene and SNP Summary

Apolipoprotein E is encoded by the APOE gene, which plays a key role in lipid transport and metabolism and is essential in cholesterol homeostasis. Two SNPs lead to the formation of three APOE isoforms, E2, E3 and E4. The SNP has been linked to cardiovascular disease (CVD), immunoregulation, cognitive decline and Alzheimer’s disease (AD), as well as infectious diseases. Carriers of the E4 allele tend to exhibit an increased risk for the above-mentioned chronic diseases. APOE E4 carriers may be more responsive to their external environment, where focusing on decreasing environmental stressors and pollution, ensuring quantity and quality of dietary fat is addressed, and increasing intake of phytonutrient rich foods, as well as including sufficient exercise, may prove beneficial in negating the effects of the SNP.



Gene Detail

APOE encodes the major apoprotein, apolipoprotein E, which mainly functions in lipoprotein-mediated lipid transport between organs via the plasma and interstitial fluids. APOE plays a critical role in plasma and tissue lipid and cholesterol homeostasis as well as in lipid transport in the central nervous system, regulating neuron survival and sprouting.


ApoE has been associated with alterations in lipid metabolism and risk for CVD, immunoregulation, and possibly also infectious diseases. It is the most significant known genetic contributor to the development of late onset Alzheimer’s disease (LOAD), and is also a strong predictor of mild cognitive impairment (MCI).




At least three isoforms of the gene exist, where two single nucleotide polymorphisms (SNPs) form three major alleles; E2, E3 and E4. Apo E 130 cys>arg alters the key structural elements of the protein. The replacement of Cys (apoE3) with Arg (apoE4) on position 130 of the protein facilitates the interaction between Arg61 and Glu 255, which mediates closer contact between the amino-terminal and carboxyl-terminal domains. This thus impairs the protein structure, function and metabolism ability; causing the E4 isoform to bind preferentially to VLDL.

It can be said that the APOE E2 allele confers the lowest risk for cardiovascular disease (CVD), the APOE E3/E3 genotype is considered to be neutral, and the E4 allele exhibits an increased risk for CVD. It must however be noted that homozygous E2 carriers do present with increased risk for hypertriglyceridemia.

Part of the mechanism behind the varying CVD risk is due to the structure of the different ApoE isoforms, which influences their ability to bind lipids, receptors and Aβ. APOE E4 carriers are associated with having altered lipid metabolism. Due to increased LDL receptor binding & VLDL preference, E4 carriers have increased risk for higher levels of total cholesterol, LDL cholesterol & VLDL cholesterol.

APOE E4 carriers also have altered polyunsaturated fatty acid (PUFA) metabolism, where the E4 allele is associated with an inhibition in lipid metabolism, inducing inefficient delivery of PUFA, in particular DHA, to neurons, leading to altered lipid membrane homeostasis. Another mechanism to consider in CVD development is inflammation as an underlying factor, where APOE E4 carriers show increased levels of plasma inflammatory markers compared to non-carriers.

Depending on the APOE isoform, the level of antioxidant capacity also differs in a dose-dependent manner, such that E2 carriers have the highest antioxidant capacity, and E4 carriers have the lowest antioxidant capacity. The APOE E4 genotype has been found to be associated with increased membrane oxidation and nitric oxide (NO) and superoxide anion radical production thereby increasing risk for atherosclerosis. ApoE E4 carriers had significantly lower activities of GSH-Px and CAT, and lower serum total antioxidant status compared to non ApoE4 carriers.



As E4 carriers show a decreased ability to transport certain fatty acids, leading to decreased plasticity of cell membranes, prevention and intervention strategies against development of CVD and AD include increasing intake of omega 3 fatty acids, especially docosahexaenoic acid (DHA) in cognitive decline cases. Therefore, manipulation of dietary fat content and reducing total quantity of fat may serve as a means of reducing the increased CVD burden associated with an apoE4 genotype.

In terms of antioxidant use, retinoic acid has been suggested as a possible intervention as it modulates APOE expression. Also, a diet high in sources of B carotene may also be protective for E4 carriers as higher serum beta-carotene was associated with lower risk of cognitive decline only in ApoE4 carriers among high-functioning older persons.


A dietary pattern showing a higher intake of vegetables, fruit, whole grains, fish and legumes, and lower intake of high-fat dairies, meat and sweets, was associated with increased levels of vitamin B12, vitamin D and ω-3 polyunsaturated fatty acid (PUFA), as well as  higher intake of β-carotene and folate. This, in turn, was associated with decreased risk for CVD and AD, especially in E4 carriers. Similarly, a nutrient pattern higher in fresh fruit and vegetables, whole grains, fish and low-fat dairies, and lower in sweets, fried potatoes, high-fat dairies, processed meat and butter offered protection. More recent studies have also suggested moderate intensity exercise on a regular basis as an important intervention strategy in APOE E4 carriers.



Apolipoprotein E: structure determines function, from atherosclerosis to Alzheimerʼs disease to AIDS

Mahley et al, 2009.