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ApoE Genotyping

Also known as: ApoE cardiac risk; ApoE 2 mutations; APOE4 genotype
Formal name: Apolipoprotein E genotyping
Related tests: Cardiac Risk Assessment; HDL Cholesterol; LDL Cholesterol; Lipid Profile; Triglycerides; Tau/Aß42

At a Glance

Why Get Tested?

Apo E genotyping is not widely used. The clinical usefulness of this test is still being researched. However, it may be used in two different conditions:

  • For cardiovascular risk assessment, to help make treatment decisions for individuals with cardiovascular disease or to help confirm a diagnosis of Type III hyperlipoproteinemia (also known as familial dysbetalipoproteinemia)
  • As an aid in the diagnosis of probable late onset Alzheimer's disease in a symptomatic adult

When to Get Tested?

  • When your doctor suspects that you have an inherited component to your high cholesterol and triglyceride levels or if you have yellowish lesions called xanthomas on your skin
  • When you have progressive symptoms of dementia and your doctor wants to determine the likelihood that this is due to Alzheimer’s disease

Sample Required?

A blood sample drawn from a vein in your arm

Test Preparation Needed?

None

The Test Sample

What is being tested?

Apolipoprotein (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 and has two primary metabolic roles:

  1. The transport of lipids from where they are made or absorbed to the tissues where they are stored.
  2. The transport of cholesterol and other lipids from the body's organs to the liver for excretion. ApoE also plays a role in lipoprotein metabolism. It helps clear very low-density lipoprotein (VLDL) and chylomicrons, the large lipoproteins that are responsible for the initial transport of dietary lipids to the liver, from the bloodstream.

This test looks at a person's DNA to determine what combination of ApoE forms (genotype) is present. The ApoE gene exists in three different forms (alleles) – e2, e3, and e4 – with e3 being the most common allele, found in 60% of the general population. Everyone inherits a pair of ApoE genes that is some combination of these three.

ApoE e3/e3 is the most common genotype. ApoE e4 (e4/e4 and e4/e3) is found in 25% of the population and is associated with an increased risk of atherosclerosis. People with these genotypes could be predisposed to an exaggerated elevation of LDL-C ("bad cholesterol") and triglycerides when their diet is high in saturated fat.

ApoE e4 has also been associated with an increased risk of late onset Alzheimer's disease (AD) – AD that develops after the age of 65. This effect is additive in that one copy of e4 (e2/e4 or e3/e4) carries some increased risk and two copies of e4 (e4/e4) are associated with an even greater risk of developing AD. It is important to note, however, that this risk is only relative. Most individuals with ApoE e4 will never develop AD and there are many AD patients who are e4 negative.

People with the ApoE e2 allele tend to have lower LDL-C levels but elevated triglycerides. ApoE e2 is also associated with type III hyperlipoproteinemia/hyperlipidemia (HPL III or familial dysbetalipoproteinemia), 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.

How is the sample collected for testing?

A blood sample is obtained by inserting a needle into a vein in your arm.

NOTE: If undergoing medical tests makes you or someone you care for anxious, embarrassed, or even difficult to manage, you might consider reading one or more of the following articles: Coping with Test Pain, Discomfort, and Anxiety, Tips on Blood Testing, Tips to Help Children through Their Medical Tests, and Tips to Help the Elderly through Their Medical Tests.

Another article, Follow That Sample, provides a glimpse at the collection and processing of a blood sample and throat culture.

Is any test preparation needed to ensure the quality of the sample?

No test preparation is needed.

The Test

How is it used?

In Cardiovascular Disease (CVD)
The test for ApoE is not widely used and it's clinical usefulness is still being researched. When it is ordered, it may be used in combination with other lipid tests that evaluate risk for CVD, such as cholesterol levels and lipoprotein electrophoresis. It may sometimes be used to check for and help diagnose a genetic component to a lipid abnormality.

Testing for ApoE may sometimes be ordered to help guide lipid treatment. In cases of high cholesterol and triglyceride levels, statins are usually considered the treatment of choice to decrease the risk of developing CVD. However, there is a wide variability in the response to these lipid-lowering drugs that is in part influenced by the Apo E genotype. Though appropriately responsive to a low fat diet, people with ApoE e4 may be less likely than those with ApoE e2 to respond to statins by decreasing their levels of LDL-C and may require adjustments to their treatment plans. At present, the clinical utility of this type of information is yet to be totally understood. Dietary adjustment and statin drugs are the preferred agents for lipid-lowering therapy. Apo E genotyping may be used to provide supplemental information.

ApoE testing may also be ordered occasionally to help diagnose type III hyperlipoproteinemia in a person with symptoms that suggest the disorder and to evaluate the potential for the condition in other family members.

In Alzheimer's Disease
ApoE genotyping is also sometimes used as an adjunct test to help in the diagnosis of probable late onset Alzheimer's disease (AD) in symptomatic adults. It is called susceptibility or risk factor testing because it indicates whether there is an increased risk of AD but is not specifically diagnostic of AD. If a patient has dementia, the presence of ApoE4 may increase the likelihood that the dementia is due to AD, but does not prove that it is. There are no clear-cut tests to diagnose Alzheimer's disease during life. Physicians can, however, make a reasonably accurate clinical diagnosis of AD by ruling out other potential causes of dementia and checking for a genetic predisposition to AD with ApoE genotyping as supplemental information in conjunction with Tau/Aß42 testing.

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When is it ordered?

  • ApoE genotyping is sometimes ordered when a patient has significantly elevated cholesterol and triglyceride levels that do not respond to dietary and exercise lifestyle changes.
  • When family members have ApoE e2/e2 and a doctor wants to see if the person might be at a higher risk for early heart disease.
  • When someone has yellowish skin lesions called xanthomas and the doctor suspects Type III hyperlipoproteinemia.

ApoE genotyping is also sometimes ordered as an adjunct test when patients have symptoms of progressive dementia, such as decreasing intellectual ability and language and speech skills, memory loss, and personality and behavioral changes that are starting to interfere with daily living. After non-AD causes, such as overmedication, vascular dementia (caused by strokes), and thyroid disease, have been ruled out, ApoE genotyping may help determine the probability that dementia is due to Alzheimer’s disease.

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What does the test result mean?

People with ApoE e2/e2 alleles 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. ApoE genotyping adds additional information and, if symptoms are present, e2/e2 can help confirm type III hyperlipoproteinemia.

Those who have ApoE e4/e4 are more likely to have atherosclerosis. People who have symptoms of late onset Alzheimer's disease (AD) AND have one or more ApoE e4 copies of the e4 gene are more likely to have AD. However, it is not diagnostic of AD and should NOT be used to screen asymptomatic people or their family members. Many of those who have e4 alleles will never develop AD. Even in symptomatic people, only about 60% of those with late onset AD will have ApoE e4 alleles.

ApoE e3 has "normal" lipid metabolism, thus may not have any genotype impact.

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Is there anything else I should know?

Although ApoE 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.

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

Alterations in lipid concentrations do not lead directly to vascular disease or atherosclerosis. Other factors, such as obesity, diabetes, and hypothyroidism, also play a role in whether a person actually develops disease.

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Common Questions

1.  My father has been diagnosed with probable late onset 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 have late onset AD are negative for ApoE e4 alleles. While genetic mutations of the PSEN1, PSEN2, and APP genes are associated with AD in a very small number of specific family lines, they are associated with early onset AD, not late onset. If your father did not show signs of AD until after the age of 65, then this other genetic testing is 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.

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2.  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 never develop significant problems associated with their lipid metabolism, have type III hyperlipoproteinemia, or develop ApoE associated late onset AD.

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3.  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.

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Article Sources

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NOTE: This article is based on research that utilizes the sources cited here as well as the collective experience of the Lab Tests Online Editorial Review Board. This article is periodically reviewed by the Editorial Board and may be updated as a result of the review. Any new sources cited will be added to the list and distinguished from the original sources used.

Sources Used in Current Review

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Stephen P. Day, Ph.D. Director, Medical Affairs, Third Wave Molecular Diagnostics.

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Ian R.A. Mackenzie, MD FRCPC. Department of Pathology, Vancouver General Hospital, British Columbia, Canada.