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What is being tested?

Apoliprotein E (Apo E) is a protein that helps transport lipids (fats and cholesterol) in the blood. It is recognised by specific cell surface receptors that allow it to deliver lipids to cells for use or storage and to deliver excess lipids to the liver for excretion.

Apo E is produced under the direction of the APOE gene and is one of five main types of blood lipoproteins (A-E), it is produced primarily in the liver and brain.

The APOE genotype test looks at a person's DNA to determine what combination of APOE forms (genotype) are present. The APOE gene exists in three different forms (alleles) – e2, e3, and e4 – with e3 being the most common allele, found in 60 per cent of the general population. Everyone inherits two APOE genes, one from each parent, that is some combination of these three forms, e.g. e2/e2, e2/e4, e3/e4 etc.

APOE e3/e3 is the most common genotype. APOE e3 is associated with "normal" lipid metabolism, thus may not have any genetic impact on risk of developing cardiovascular disease. APOE e4 (e4/e4 and e4/e3) is found in 25 per cent of the population and is associated with higher LDL-C ("bad cholesterol") and an increased risk of atherosclerosis.

People with the APOE e2 allele tend to have lower LDL-C levels but elevated triglycerides. APOE e2 is less able to clear lipids from the blood compared to the other forms. This means that if someone has an e2/e2 combination, they may clear dietary fat from their body at a slower rate. APOE e2/e2 is also associated with type III hyperlipoproteinaemia/hyperlipidaemia (HPL III or familial dysbetalipoproteinaemia), a rare inherited disorder that causes fatty yellowish deposits on the skin called xanthomas, increased triglycerides in the blood, and atherosclerosis that develops at an early age. Less than 20 per cent of people with e2/e2 develop type III hyperlipoproteinaemia, and usually requires other factors such as obesity or diabetes in order to develop.

APOE e4 has been associated with an increased risk of late onset Alzheimer's disease (AD), that is AD that develops after the age of 65. People who have one copy of e4 (e2/e4 or e3/e4) carry some increased risk and people with two copies of e4 (e4/e4) are associated with even more of a risk of developing AD. However, it is important to note, that this risk is relative to other people at the same age with fewer copies of e4, in terms of lifetime risk, most individuals with APOE e4 will never develop AD and there are many people with AD who are e4 negative.

How is it used?

Apo E genotype is sometimes used as part of follow-up testing if high cholesterol and triglyceride concentrations are found, to check if a particular lipid abnormality has been genetically inherited. It is not widely used, but when it is requested, it may be in combination with other tests, such as lipoprotein electrophoresis.

When is it requested?

Apo E genotyping is sometimes requested when a patient has significantly elevated cholesterol and triglyceride levels that do not respond to changes in the patient's lifestyle (dietary and exercise patterns); when a patient presents with xanthomas (yellowish raised patches) on their skin and the doctor suspects Type III hyperlipoproteinaemia; or when family members have ApoE e2/e2 and a doctor wants to see if the patient may be at a higher risk for early heart disease.

What does the result mean?

Patients with Apo E e2/e2 genotype are at a higher risk of premature vascular disease, but they may never develop disease. Likewise, they may have the disease and not have e2/e2 alleles because it is only one of the factors involved. In fact only 1 in 50 people with e2/e2 will ever manifest the disease. Apo E genotyping adds additional information and, if symptoms are present, e2/e2 is diagnostic of Type III hyperlipoproteinaemia (although the diagnosis must be made in conjunction with other test results and the patient’s clinical history). Therefore, this test is limited and used solely by lipid specialists on rare occasions.

Is there anything else I should know?

Although Apo E genotyping is being used clinically by Alzheimer's experts, the most it can provide at this time is additional information about a patient with dementia. A definite diagnosis of Alzheimer's disease can only be made by examining a patient's brain tissue after their death.

Apo E genotyping is not available in many laboratories. If your doctor recommends this test, your specimen may need to be sent to a reference laboratory and results may take longer to return than they would from local laboratories.

Alterations in lipid concentrations are only one risk factor for, and do not lead directly to, vascular disease or atherosclerosis. Other factors, such as obesity, diabetes, smoking, high blood pressure and hypothyroidism, may also play a role in whether a person actually develops disease.

Common questions

  • My father has been diagnosed with probable late onset Alzheimer's disease (AD) and his APOE test is negative for e4 alleles. Should his doctor be doing other genetic testing?

No, not at this time. Forty percent of those who do have late onset AD are negative for APOE e4 alleles.

Currently there are only three unknown genes that associated with AD.
Mutations of these genes (PSEN1, PSEN2 and APP) are associated with AD in a very small number of specific family lines, they tend to be associated with early onset AD, rather than late onset. If your father did not show signs of AD until after the age of 65, then these other genetic tests are not indicated. (If you have a very strong family history of AD, several family members over several generations have had AD, you may want to talk to your father's doctor about family risk factors).

  • I have a 50-year-old brother with Down syndrome who has been diagnosed with probable Alzheimer's disease (AD). Does this put me at a higher family risk for AD?

Not necessarily. Most people who have Down syndrome will eventually have some degree of Alzheimer's disease symptoms. Down syndrome is associated with a lifelong overproduction of amyloid precursor protein; a portion of this protein, called amyloid beta 42 peptide (Aß42), is associated with the formation of senile plaques (areas of dead nerve cells and protein deposits in the brain) that are characteristic of AD.

  • I have type III hyperlipoproteinaemia and am APO e2/e2. Does this put my children at risk of my condition?

The inheritance of APOE e2/2 in a person does not mean that they will develop type III hyperlipoproteinaemia. Only 1 in 50 people with APOE e2/2 will develop it; basically of 50 people with that combination of genes, 49 will be fine and 1 person will develop the condition. For your child to also be APOE e2/2 then they would have to inherit an e2 from the other parent. 

Pre-natal genetics and testing is not done, however as one percent of the population has the genetic pattern (APOE e2/e2) but the vast majority will never see ill effects from it. Other factors appear to determine whether the genes ever cause a problem including medical conditions such as hypothyroidism or diabetes mellitus. Therefore, the fact that you have have type III hyperlipoproteinaemia migh raise the risk to your child very slightly above that of a randomly selected member of the general population but it is only slight and depends on too many unpredictable factors making routine testing of family members unnecessary.

  • Should everyone have their APOE genotype tested?

No, the test is not intended to be used to screen the general population. It is intended to be used in very specific situations to give a doctor additional information. The majority of people have APOE e3 and so will tend to have normal lipid metabolism. Most of the people with other APOE combinations will either; never develop significant problems associated with their lipid metabolism, have type III hyperlipoproteinaemia, or develop APOE associated late onset AD.

  • Is there a reason to test for APOE genotype more than once?

No, not unless your doctor suspects that the first test was in error. A person inherits one copy of the gene from each parent and genotype does not change.

Last Updated: Thursday, 1st June 2023

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