In the circulation, it is present as part of several classes of lipoprotein particles, including chylomicron remnants, VLDL, IDL, and some HDL.

[14] About 220,000 years ago, a cysteine to arginine substitution took place at amino acid 112 (Cys112Arg) of the APOE4 gene, and this resulted in the E3 allele.

Finally, 80,000 years ago, another arginine to cysteine substitution at amino acid 158 (Arg158Cys) of the APOE3 gene created the E2 allele.

The N-terminal region (residues 1–167) forms an anti-parallel four-helix bundle such that the non-polar sides face inside the protein.

[53] However, E4 has also been associated with enhanced vitamin D and calcium status,[54] higher fecundity,[55] protection against early childhood infection and malnutrition,[56] and decreased fetal, perinatal, and infant mortality.

As of 2007, there was no evidence that APOE polymorphisms influence cognition in younger age groups (other than possible increased episodic memory ability and neural efficiency in younger APOE4 age groups), nor that the APOE4 isoform places individuals at increased risk for any infectious disease.

[59] However, the association between the APOE4 allele and Alzheimer's disease has been shown to be weaker in minority groups differently compared to their Caucasian counterparts.

[64][7] More recently, it has been studied for its role in several biological processes not directly related to lipoprotein transport, including Alzheimer's disease (AD), immunoregulation, and cognition.

[65] In the field of immune regulation, a growing number of studies point to APOE's interaction with many immunological processes, including suppressing T cell proliferation, macrophage functioning regulation, lipid antigen presentation facilitation (by CD1)[66] to natural killer T cell as well as modulation of inflammation and oxidation.

[68] As of 2012, the E4 variant was the largest known genetic risk factor for late-onset sporadic Alzheimer's disease (AD) in a variety of ethnic groups.

The isoform APOE-ε4 is not as effective as the others at promoting these reactions, resulting in increased vulnerability to AD in individuals with that gene variation.

[80] While ApoE4 has been found to greatly increase the odds that an individual will develop Alzheimer's, a 2002 study concluded, that in persons with any combination of APOE alleles, high serum total cholesterol and high blood pressure in mid-life are independent risk factors which together can nearly triple the risk that the individual will later develop AD.

[82] The influence of APOE-ε4 on hippocampal atrophy was suggested to be more predominant early in the course of AD at milder stages prior to more widespread neurodegeneration.

In November 2024, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency recommended the marketing authorisation of lecanemab (anti-beta-amyloid antibody; trade name: Leqembi® from Eisai and Biogen) in Europe for the treatment of adult patients diagnosed with early-stage AD (mild cognitive impairment and mild dementia) who have no or only one copy of the APOE-ε4 allele.

[84] Therefore, detection of the APOE gene variant is recommended prior to starting anti-beta-amyloid therapy to assess the patient’s risk of adverse effects.

[85] The APOE genotyping of AD patients for risk assessment in the context of an anti-beta-amyloid therapy can be performed with the help of commercially available PCR-based assays.

[86] Knockout mice that lack the apolipoprotein-E gene (APOE−/−) develop extreme hypercholesterolemia when fed a high-fat diet.

[87] APOE−/− knockout mice show marked attenuation of cerebral malaria and increased survival, as well as decreased sequestration of parasites and T cells within the brain, likely due to protection of the blood–brain barrier.

[89] Borrelia burgdorferi, the causative agent of Lyme disease, is a host-adapted pathogen that acquires environmental cholesterol to form glycolipids for use in cell membrane maintenance.

This study suggests that apoE deficiency (and potentially other hyperlipidemias) may be a risk factor in the pathogenicity of Lyme disease.