Apolipoprotein E (ApoE) is a lipoprotein that is found in Chylomicrons and Intermediate Density Lipoproteins (IDLs) and transports fat-soluble vitamins, cholesterol, and lipoproteins into the blood via the lymphatic system. The receptors for ApoE are in the LDL receptor family.
ApoE defects are associated with Type III hyperlipoproteinemia (familial dysbetalipoproteinemia) where an increase in serum cholesterol & triglycerides are caused by decreased clearance of chylomicron, VLDL, and LDL remnants.
Alzheimer’s Disease – The exact mechanism of how E4 causes such dramatic effects on Alzheimer’s Disease risk remains to be fully determined. However, evidence has been presented suggesting an interaction with amyloid. Alzheimer’s Disease is characterized by build-ups of aggregates of the peptide beta-amyloid. Apolipoprotein E enhances the break-down of this peptide, both within and between cells. E4 is not as efficient at catalyzing this proteolytic break-down which causes an increase in risk to Alzheimer’s Disease.
Although 40-65% of AD patients have at least one copy of the 4 allele, ApoE4 is not a determinant of Alzheimer’s Disease – at least a third of patients with AD are E4 negative and some E4 homozygotes never develop the disease. Yet those with two E4 alleles have up to 20 times the risk of developing AD.
There is evidence that E2 may protect against AD. Thus, the genotype most at risk for Alzheimer’s disease and at earlier age is ApoE 4,4. The E3/E4 genotype is at increased risk, though not to the degree that those homozygous for E 4 are. E3/E3 is considered at normal risk for Alzheimer’s disease. The genotype E2/E3 is considered at less risk for Alzheimer’s disease. Interestingly, people with E2/E4 are at normal risk similar to the E3/E3 genotype.
There is evidence that ApoE may suppress T cell proliferation, macrophage function regulation, lipid antigen presentation facilitation to NK T cells and modulate oxidation & inflammation.
There are 3 different forms of Apo E:
- E2 – found in approximately 7% of the population. Type 3 hyperlipidemia is associated with E2 and shows and increased risk and decreased risk for atherosclerosis. Homozygotes for E2 (E2/E2) have difficulty clearing dietary fat and may be at an increased risk of Type 3 hyperlipidemia. 94.4% of individuals with Type III hyperlipidemia are E2/E2 but only 2% of patients who are E2/E2 develop Type III hyperlipidemia.
- E3 – found in 78% of the population and is considered ‘normal risk’.
- E4 – found in 14% of the population and is associated with atherosclerosis and alzheimer’s disease. It is the largest known genetic risk factor for late-onset sporadic Alzheimer’s Disease (AD). Caucasian and Japanese carriers of 2 E4 alleles have a 10-30x risk of developing AD by 75 years of age, as compared to those not carrying any E4 alleles.