To help confirm a diagnosis of Type III hyperlipoproteinaemia (also known as dysbetalipoproteinaemia, remnant disease or broad beta disease). Outside of routine clinic practice e.g. for research purposes, it can be used to help confirm a diagnosis of late onset Alzheimer’s Disease (AD) in a symptomatic adult
Apolipoprotein E (Apo E) Genotyping
This is a non-standard test currently limited mostly to hospital specialists. It can be measured if your doctor suspects that your high cholesterol and triglyceride concentrations may be due to a genetically inherited disorder, or if you have specific types of xanthomas (yellowish raised patches) on your skin (particularly palms, knees and elbows).
A blood sample taken from a vein in your arm
No test preparation is needed
There are two methods to determine your apolipoprotein E (apo E) type. The test can look at a patient's DNA to determine what combination of apo E gene alleles (copies) he or she has. The apo E gene exists in three different forms – e2, e3, and e4 – with e3 being the most common form and considered to be 'neutral'. Everyone has a pair of apo E genes that is some combination of these three, for example e3/e3, e2/e2, e2/e4 etc.
An alternative method is based on electrophoresis as the proteins have different charges. Due to analytical limitations and the presence of rarer types/mutations one test may find abnormalities that the other misses.
Apo E is made in the liver and brain and helps transport lipids (fats) from one place to another thus helping to clear dietary fats, such as triglycerides, from the blood.
The e2 form of apo E 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 and be at a higher risk for early vascular disease because of the increased likelihood that the fats will be deposited in the blood vessel walls. It is not a straightforward diagnosis, however, as other factors, such as obesity, diabetes, and hypothyroidism, may play a role in whether a patient actually develops disease.
The apo e4 allele has been shown to be associated with an increased risk of late onset Alzheimer's Disease (developing after the age of 65). While one copy of e4 constitutes a risk (e2/e4 or e3/e4) and two copies of e4 (e4/e4) indicate a greater risk of developing AD, the actual amount of risk involved has not been fully established, likely varies between individuals and has no role in routine clinical testing.
How is it used?
Apo E genotyping 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 concentrations or when a patient presents with xanthomas (yellowish raised patches) on their skin and the doctor suspects Type III hyperlipoproteinaemia.
What does the test result mean?
Patients with apo E e2/e2 alleles are at a higher risk of premature vascular disease, but they may never develop hyperlipidaemia. 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 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?
The diagnosis of Alzheimer’s disease is based on clinical (cognitive) criteria proposed by the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association (now the Alzheimer's Association), known as the NINCDS-ADRDA Alzheimer's Criteria. The only way to diagnose Alzheimer’s definitively is by examining a patient’s brain tissue after their death. Patients who have symptoms of late onset Alzheimer’s Disease (older than 65 years old) AND have one or more e4 copies of the apo E gene are more likely to have Alzheimer’s but it is not diagnostic, therefore has NO place in screening patients or family members. Many people will have e4 alleles and never develop Alzheimer’s and only about 60% of those with late onset Alzheimer’s Disease will have apo E e4 alleles. Apo E e4/e4 is also associated with atherosclerosis.
Apo E genotyping is not available in many laboratories. If your doctor recommends this test, your specimen will need to be sent to a reference laboratory (provides specialist testing and interpretation) and results may take longer to return.
My father has been diagnosed with probable late onset Alzheimer’s Disease 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 Alzheimer’s Disease are negative for apo E 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 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’s Syndrome who has been diagnosed with probable Alzheimer’s. Does this put me at a higher family risk for Alzheimer’s Disease?
Not necessarily. Most people who have Down’s Syndrome will eventually present with varying degrees of the symptoms of Alzheimer’s Disease. Down’s 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 Alzheimer’s Disease.
I have type III hyperlipidaemia and am apo E e2/e2. Does this put my children at risk of my condition?
The inheritance of apo E e2/e2 in a person does not mean that they will develop type III hyperlipidaemia. Only 1 in 50 people with apo e2/e2 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 apo e2/e2 then they would have to inherit an e2 from the other parent. Pre-natal genetics and testing is not done however as 1% (1 in 100) of the population has the genetic pattern (apo 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 type III hyperlipidaemia might 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 redundant.