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. Defects 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.

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, the most common isoform in the White population, shows cysteine (Cys) at amino acid position 112 and arginine (Arg) at position 158. E2 and E4 differ from E3 by single amino acid substitutions at positions 158 and 112, respectively (E2: Arg158->Cys; E4: Cys112->Arg). The allele frequencies for most White populations are as follows:

-e2=8% to 12%

-e3=74% to 78%

-e4=14% to 15%

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. It is estimated that individuals with the APOE e3/e4 genotype have a 4-fold relative risk for Alzheimer disease, while homozygotes for e4 allele have a 12-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 is not currently recommended by the American College of Medical Genetics and Genomics due to limited clinical utility and poor predictive value.

Additionally, according to the US Food and Drug Administration label, the APOE e4 allele in the context of amyloid-targeting antibody treatments for Alzheimer disease has been associated with a higher incidence of amyloid related imaging abnormalities.