Apolipoprotein E

Overview
Apolipoprotein E (APOE) is an apoprotein found in the chylomicron that binds to a specific receptor on liver cells and peripheral cells.

Function
APOE is essential for the normal catabolism of triglyceride-rich lipoprotein constituents. APOE was initially recognized for its importance in lipoprotein metabolism and cardiovascular disease. 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. Neonates with brain injuries and/or defects who also have abnormalities in the APOE gene may have an increased risk for cerebral palsy, according to researchers at the Northwestern University Feinberg School of Medicine. Defects in APOE result in familial dysbetalipoproteinemia, or type III hyperlipoproteinemia (HLP III), in which increased plasma cholesterol and triglycerides are the consequence of impaired clearance of chylomicron, VLDL and LDL remnants.

APOE is 299 amino acids long and transports lipoproteins, fat-soluble vitamins, and cholesterol into the lymph system and then into the blood. It is synthesized principally in the liver, but has also been found in other tissues such as the brain, kidneys, and spleen. In the nervous system, non-neuronal cell types, most notably astroglia and microglia, are the primary producers of APOE, while neurons preferentially express the receptors for APOE. There are seven currently identified mammalian receptors for APOE which belong to the evolutionarily conserved low density lipoprotein receptor gene family.

Gene
The APOE gene, ApoE, is mapped to chromosome 19 in a cluster with Apolipoprotein C1 and Apolipoprotein C2. ApoE consists of four exons and three introns, totaling 3597 base pairs.

The gene is polymorphic, with three major alleles, ApoE2, ApoE3, ApoE4, which translate into three isoforms of the protein: normal - ApoE-ε3; dysfunctional - ApoE-ε2 and ApoE-ε4. These isoforms differ from each other only by single amino acid substitutions at positions 112 and 158, but have profound physiological consequences.


 * E2 is associated with the genetic disorder type III hyperlipoproteinemia and with both increased and decreased risk for atherosclerosis.


 * E4 has been implicated in atherosclerosis and Alzheimer's disease, impaired cognitive function, and reduced neurite outgrowth.

ApoE is a target gene of liver X receptor, a nuclear receptor member that play role in metabolism regulation of cholesterol, fatty acid, and glucose homeostasis.

Alzheimer's Disease
APOE-ε4 has been shown to cause an increased susceptibility to Alzheimer's disease (AD). The pivotal role of ApoE in AD was first identified through linkage analysis by Margaret Pericak-Vance while working in the Roses lab at Duke University. Linkage studies were followed by association analysis confirming the role of the APOE-ε4 allele.

Although 40-65% of AD patients have at least one copy of the 4 allele, ApoE4 is not a determinant of the disease - at least a third of patients with AD are ApoE4 negative and some ApoE4 homozygotes never develop the disease.

Among ApoE4 carriers, another gene, GAB2, is thought to further influence the risk of getting AD.

A confirmatory cohort study conducted by the Dutch in rotterdam, examining a total of 6,713 elderly people at risk of developing dementia found that there was an increased risk of developing Alzheimers, and with it dementia, when ApoE4 gene was present however this was not significant.

There is also evidence that the 2 allele may serve a protective role in AD.

Thus, the genotype most at risk for Alzheimer's disease and at earlier age is ApoE 4,4. The ApoE 3,4 genotype is at increased risk, though not to the degree that those homozygous for ApoE 4 are. The genotype ApoE 3,3 is considered at normal risk for Alzheimer's disease. The genotype ApoE 2,3 is considered at less risk for Alzheimer's disease. Interestingly, people with both a copy of the 2 allele and the 4 allele, ApoE 2,4, are at normal risk similar to the ApoE 3,3 genotype.