Clinical Information

Apolipoproteins are structural constituents of lipoprotein particles that participate in lipoprotein synthesis, secretion, processing, and metabolism. Apolipoproteins have critical roles in blood lipid metabolism. Disease-causing variants in apolipoprotein E (APOE) are responsible for familial dysbetalipoproteinemia, or type III hyperlipoproteinemia, in which increased plasma cholesterol and triglycerides result from impaired clearance of chylomicron and very-low-density lipoprotein remnants. Additionally, specific APOE alleles are associated with risk for late-onset Alzheimer disease.

The human APOE gene is located on chromosome 19. The 3 common APOE alleles are designated e2, e3, and e4, which encode the ApoE isoforms E2, E3, and E4, respectively. E3, considered the reference allele, shows cysteine (Cys) at amino acid position 130 and arginine (Arg) at position 176 on the NP_0032 transcript. E2 and E4 differ from E3 by single amino acid substitutions at positions 176 and 130, respectively. E2 shows cysteine (Cys) at position 176 and has an estimated global minor allele frequency of 2% to 12%, depending on ancestral population. E4 shows arginine (Arg) at position 130 and has an estimated global minor allele frequency of 7% to 15%, depending on ancestral population.

E2 and E4 are both associated with higher plasma triglyceride concentrations. Over 90% of individuals with type III hyperlipoproteinemia are homozygous for the e2 allele. However, less than 10% of individuals homozygous for the e2 allele have overt type III hyperlipoproteinemia. This suggests that other genetic, hormonal, or environmental factors must contribute to the phenotypic expression of the disease. The e4 allele has been linked to pure elevations of low-density lipoproteins. Patients with a lipid profile consistent with type III hyperlipidemia are candidates for analysis of their APOE genotype.

The APOE gene is also a known susceptibility gene for Alzheimer disease. The e4 allele is associated with an increased risk for Alzheimer disease, particularly late-onset disease, in a dose-dependent manner. This risk is also influenced by other factors, including age and ancestral population/genetic background. It is estimated that individuals with the APOE e3/e4 genotype have a 3-fold to 4-fold relative risk for Alzheimer disease, while homozygotes for e4 allele have a 10-fold to 15-fold relative risk. Several studies have suggested a protective effect of the APOE e2 allele.

The APOE e4 allele, however, is neither sufficient nor necessary for the development of Alzheimer disease.

Approximately 50% of individuals with Alzheimer disease carry an e4 allele, and many individuals who have an e4 allele will never develop Alzheimer disease. The use of APOE analysis for predictive testing for Alzheimer disease in asymptomatic individuals is not currently recommended by the American College of Medical Genetics and Genomics due to limited predictive value.

Additionally, according to the US Food and Drug Administration (FDA) label, the APOE e4 allele has been associated with a higher incidence of amyloid-related imaging abnormalities (ARIA) in the context of amyloid-targeting antibody treatments for Alzheimer disease, including lecanemab and donanemab. For this reason, the FDA recommends genotyping for APOE e4 status prior to treatment in order to allow for better understanding of an individual’s ARIA risk.