At a Glance

Why Get Tested?

APOE genotype tests are most often done as part of research protocols to help understand the role of genetic factors in cardiovascular disease. However, the testing is sometimes used in clinical settings to help confirm a diagnosis of type III hyperlipoproteinemia (also known as familial dysbetalipoproteinemia).

Were you looking instead for APOE genotyping used in Alzheimer disease?

When To Get Tested?

When your healthcare provider 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

Sample Required?

A blood sample drawn from a vein in your arm

Test Preparation Needed?

None

What is being tested?

Apolipoprotein E (Apo E) is a protein that helps transport lipids (fats and cholesterol) in the blood. It is recognized 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.

The ApoE protein has three genetic forms that have slightly different compositions. They are called ApoE2, ApoE3, and ApoE 4. ApoE3 is the most common form. Compared to ApoeE3, ApoE2 is poorly recognized by cell surface receptors whereas ApoE4 binds more tightly to those receptors. People with ApoE2 tend to have higher amounts of lipids in their blood since delivery from blood to cells is impaired by poor binding of ApoE2 to receptors.

Three different genes (termed alleles) are designated as e2, e3, and e4 and code respectively for ApoE2, ApoE3, and ApoE4. Each person inherits one allele from each parent. A person who has the same allele from each parent is termed homozygous: e2/e2 or e3/e3 or e4/e4. One who has different alleles is termed heterozygous: e2/e3 or e2/e4 or e3/e4.

The APOE genotype test evaluates a person’s DNA to determine what APOE forms (alleles) are present. APOE e3/e3 is the most common genotype (seen in well over half of the population) and is considered “neutral.” Risks of disease are made relative to the e3/e3 population. APOE e4 (as e4/e4 and e4/e3) is found in nearly a quarter of the population and is associated with an increased risk of atherosclerosis. People with these genotypes could be predisposed to a significantly elevated level of LDL-C (“bad cholesterol”) and triglycerides when their diet is high in saturated fat. The various APOE allele frequencies differ between ethnic populations.

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. Importantly, while a large majority of patients with type III hyperlipoproteinemia are homozygous for the e2 allele (e2/e2), less than 10% of people with the e2/e2 genotype develop type III hyperlipoproteinemia/hyperlipidemia.

Common Questions

How is it used?

While APOE genotyping is mostly done in research settings, it can be used clinically to help in diagnosis and treatment of elevated lipid levels.

APOE testing may be used to help diagnose type III hyperlipoproteinemia (HPL III or familial dysbetalipoproteinemia) in a person with symptoms that suggest the disorder and to evaluate the potential for the condition in other family members. This is a rare inherited disorder that causes fatty, yellowish deposits on the skin called xanthomas, a high level of triglycerides in the blood, and atherosclerosis that develops at an early age.

APOE genotyping has potential 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 cardiovascular disease (CVD). However, there is a wide variability in the response to these lipid-lowering drugs that is in part influenced by the APOE genotype. At present, the clinical utility of this type of information is yet to be totally understood.

When is it ordered?

As a test to evaluate lipid metabolism or cardiovascular risk, APOE genotyping is ordered when someone has:

Significantly elevated cholesterol and triglyceride levels that do not respond to dietary and exercise lifestyle changes
Family members known to have abnormal APOE alleles and a healthcare practitioner wants to see if the person might be at a higher risk for early heart disease
Yellowish skin lesions called xanthomas and the health care practitioner suspects type III hyperlipoproteinemia

What does the test result mean?

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 (genotype e4/e4 or e4/e3) is found in nearly a quarter of the population and is associated with an increased risk of atherosclerosis. People with these genotypes could be predisposed to significantly elevated levels of LDL-C (“bad cholesterol”) and triglycerides when their diet is high in saturated fat.

People with the APOE e2/e2 alleles tend to have lower LDL-C levels but elevated triglycerides. APOE e2 is also associated with type III hyperlipoproteinemia/hyperlipidemia. People with APOE e2/e2 alleles are at a higher risk of premature vascular disease, but they may never develop disease. APOE genotyping adds additional information and, if symptoms are present, e2/e2 can help confirm type III hyperlipoproteinemia.

Most cases of apoE-influenced type III hyperlipoproteinemia occur in an autosomal recessive manner, meaning that individuals with an e2/e3 genotype may be carriers of disease but may not show signs of lipid dysfunction.

Is there anything else I should know?

APOE genotyping is not available in every laboratory. If a healthcare practitioner recommends this test, the specimen will likely be sent to a reference laboratory 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. Additionally, APOE genetic tests cannot detect all mutations that may cause type III hyperlipoproteinemia or other lipid-related diseases. Therefore, the absence of a mutation cannot rule out the possibility of disease or carrier status.

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 healthcare practitioner additional information about a possible genetic cause for observed lipid abnormalities.

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

No. A person inherits one copy of the gene from each parent and genotype does not change.

View Sources

Sources Used in Current Review

2017 review performed by Allison B. Chambliss, PhD, DABCC, FACB, Scientific Director, LAC+USC Medical Center Core Laboratory.

Mahley RW, Weisgraber KH, and Huang Y. Apolipoprotein E: structure determines function, from atherosclerosis to Alzheimer’s disease to AIDS. J Lipid Res. 2009 Apr; 50(Suppl): S183–S188. Available online at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2674716/. Accessed Sept 2017.

Bays HE, Jones PH, Orringer CE, Brown WV, Jacobson TA. National Lipid Association Annual Summary of Clinical Lipidology 2016. J Clin Lipidol. 2016 Jan-Feb;10(1 Suppl):S1-43. doi: 10.1016/j.jacl.2015.08.002. Available online at https://www.ncbi.nlm.nih.gov/pubmed/26891998 http://nlaresourcecenter.lipidjournal.com/Content/PDFs/Appendix-Final.pdf. Accessed Sept 2017.

Rosenson RS. Lipoprotein classification, metabolism, and role in atherosclerosis. UpToDate. Last updated May 05, 2017. Available online at https://www.uptodate.com/contents/lipoprotein-classification-metabolism-and-role-in-atherosclerosis?source=search_result&search=apolipoprotein%20e&selectedTitle=4~53. Accessed Sept 2017.

Sources Used in Previous Reviews

Thomas, Clayton L., Editor (1997). Taber’s Cyclopedic Medical Dictionary. F.A. Davis Company, Philadelphia, PA [18th Edition].

Pagana, Kathleen D. & Pagana, Timothy J. (2001). Mosby’s Diagnostic and Laboratory Test Reference 5th Edition: Mosby, Inc., Saint Louis, MO.

Sloane, P. (1998, November 1). Advances in the Treatment of Alzheimer’s Disease. American Family Physician by the American Academy of Family Physicians [On-line journal]. Available online at http://www.aafp.org/afp/981101ap/sloane.html.

Eastman, P. (2002 March). Keeping Alzheimer’s at Bay, Early Diagnosis Keeps Patients Functioning Longer. AARP Bulletin Online [On-line serial]. Available online at http://www.aarp.org/bulletin/departments/2002/health/0310_health_1.html.

McConnell, S., et. al. Unraveling the Mysteries of Alzheimer’s Disease: Exciting New Developments in Research. From panel sponsored by the Alzheimer’s Association [On-line information]. Available online at http://www.asaging.org/am/cia2/alzheimer.html.

Galasko, D., et. al. (1998). High Cerebrospinal Fluid Tau and Low Amyloid b42 Levels in the Clinical Diagnosis of Alzheimer Disease and Relation to Apolipoprotein E Genotype. Arch Neurol [On-line journal], vol (55) pages (937-945). Available online at http://archneur.ama-assn.org/issues/v55n7/abs/noc7433.html.

ARF (1996-2002). Standard Medical Workup for Alzheimer’s Disease. Alzheimer Research Forum [On-line information]. Available online at http://www.alzforum.org/members/research/treatment_guide/workup.html.

Family Caregiver Alliance. Fact Sheet: Alzheimer’s Disease [On-line information]. Available online at http://www.caregiver.org/factsheets/diagnoses/alzheimersC.html.

Bird, T. (2001 June 22 last update). Alzheimer Overview. GeneReviews [On-line information]. Available online through http://www.genetests.org.

Gottlieb, F. and Lambert, J. G. (2002, January 2, last update). Alzheimer’s Disease. MEDLINEplus [On-line information]. Available online at http://www.nlm.nih.gov/medlineplus/ency/article/000760.htm.

Miller, M. (1998 February 18). 26 national Alzheimer’s Disease Centers Collaborate on Study of the Utility of Genetic Testing for Alzheimer’s. National Institutes of Health News Release [On-line press release]. Available online at http://www.nia.nih.gov/news/pr/1998/02%2D18.htm.

NIH (2000). Progress report on Alzheimer’s disease, taking the next steps. NIH Publication No. 00-4859 [On-line report]. Available online at http://www.alzheimers.org/pubs/prog00.htm#Introduction.

UniSci (2002, April 08). New Approaches Seen For Early Alzheimer’s Diagnosis. Daily University Science News [On-line Article]. Review of two studies found in Neuropsychology, Vol 16 (2). Available online at http://unisci.com/stories/20022/0408025.htm.

Eldercare (2002 February 28, last update). Is it Alzheimer’s … or Just Forgetfulness? Sponsored by Nebraska’s Area Agencies on Aging [On-line information]. Available online at http://nncf.unl.edu/eldercare/info/lifeline/LLforget.html.

Hain, T. (2000 February 13). Alzheimer’s Disease. Neurology, Northwestern University Medical School [3rd year neurology medical student curriculum material]. Available online at http://www.neuro.nwu.edu/meded/behavioral/alzheimers.html.

Kleiner-Fisman, G., Updated by (2002 January 2, last update). CSF Collection. MedlinePlus [On-line information]. Available online at http://www.nlm.nih.gov/medlineplus/ency/article/003428.htm.

MedlinePlus, (2001 November 20). Familial dysbetalipoproteinemia. MedlinePlus [On-line information]. Available online at http://www.nlm.nih.gov/medlineplus/ency/article/000402.htm.

Eichner, J., et. al. (2002, March 15). Apolipoprotein E Polymorphism and Cardiovascular Disease. HuGE Review, appeared in Am J Epidemiol 2002 [On-line journal], 155(6): 487-95. Available online at http://www.cdc.gov/genomics/hugenet/reviews/APOEcardio.htm through http://www.cdc.gov.

MedlinePlus, (2001 October 29). Familial hypercholesterolemia. MedlinePlus [On-line information]. Available online at http://www.nlm.nih.gov/medlineplus/ency/article/000392.htm.

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

Robert C. Green, M.D., M.P.H. Professor of Neurology, Genetics and Epidemiology. Director, Alzheimer’s Disease Clinical and Research Program. Boston University Schools of Medicine and Public Health, Boston, MA.

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

(Updated 2009 May 9). Alzheimer’s Disease Genetics Fact Sheet. Alzheimer’s Disease Education & Referral Center [On-line information]. Available online at http://www.nia.nih.gov/Alzheimers/Publications/geneticsfs.htm. Accessed May 2009.

Bird, T. (Revised 2008 July 24). Alzheimer Disease Overview. GeneReviews [On-line information]. Available online at http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene∂=alzheimer. Accessed May 2009.

Rogaeva, E. (2009 February 5). The Genetic Profile of Alzheimer’s Disease: Updates and Considerations. Medscape from Geriatrics and Aging [On-line information]. Available online at http://www.medscape.com/viewarticle/586756. Accessed May 2009.

Gandelman, G. (Updated 2008 January 23). Familial dysbetalipoproteinemia. MedlinePlus Medical Encyclopedia [On-line information]. Available online at http://www.nlm.nih.gov/medlineplus/ency/article/000402.htm. Accessed May 2009.

Mayo Clinic Staff (2008 September 17). Alzheimer’s: Is it in your genes? MayoClinic.com [On-line information]. Available online at http://www.mayoclinic.com/print/alzheimers-genes/AZ00047/METHOD=print. Accessed May 2009.

(Updated 2008 December). Cardiovascular Disease (Non-traditional Risk Markers) – Risk Markers – CVD (Non-traditional). ARUP Consult [On-line information]. Available online at http://www.arupconsult.com/Topics/CardiacDz/CVDRiskMarkerNontrad.html. Accessed May 2009.

(September 18, 2007) Riordan M. Linear association among apoE genotypes with LDL levels and coronary risk. Available online at http://www.theheart.org/article/813529.do. Accessed July 2009.

(August 10, 2009) Ward H, et. al. APOE Genotype, Lipids, and Coronary Heart Disease Risk, A Prospective Population. Arch Intern Med. 2009;169(15):1424-1429. Available online at http://archinte.jamanetwork.com/article.aspx?articleid=1108512. Accessed October 2013.

(2013) Yan-Wei Yin, et al. Association between Apolipoprotein E Gene Polymorphism and the Risk of Coronary Artery Disease in Chinese Population: Evidence from a Meta-Analysis of 40 Studies. PLoS ONE 8(6): e66924. doi:10.1371/journal.pone.0066924. Available online at http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0066924. Accessed October 2013.

Henry’s Clinical Diagnosis and Management by Laboratory Methods. 22nd ed. McPherson R, Pincus M, eds. Philadelphia, PA: Saunders Elsevier: 2011, 230-231.

(December 2, 2010) Citkowitz E. Dysbetalipoproteinemia Workup. Medscape Reference. Available online at http://emedicine.medscape.com/article/118466-workup. Accessed October 2013.

(2007) Bennet A, et al. Association of apolipoprotein E genotypes with lipid levels and coronary risk. JAMA 2007; 298(11):1300. Abstract available online at http://www.ncbi.nlm.nih.gov/pubmed/17878422. Accessed October 2013.

(2008) Donnelly L, et al. Apolipoprotein E genotypes are associated with lipid lowering responses to statin treatment in diabetes: a Go-DARTS study. Pharmacogenet Genomics 2008; 18(4):279. Abstract available online at http://www.ncbi.nlm.nih.gov/pubmed/18334912. Accessed October 2013.

(2012) Ciftdogan D et al. The association of apolipoprotein E polymorphism and lipid levels in children with a family history of premature coronary artery disease. J Clin Lipidol 2012; 6(1):81. Abstract available online at http://www.ncbi.nlm.nih.gov/pubmed/22264578. Accessed October 2013.

Tietz Textbook of Clinical Chemistry and Molecular Diagnostics. Burtis CA, Ashwood ER, Bruns DE, eds. 4th edition, St. Louis: Elsevier Saunders; 2006, Pp 930-931.

Ask a Laboratory Scientist

This form enables patients to ask specific questions about lab tests. Your questions will be answered by a laboratory scientist as part of a voluntary service provided by one of our partners, American Society for Clinical Laboratory Science. Please allow 2-3 business days for an email response from one of the volunteers on the Consumer Information Response Team.

APOE Genotyping, Cardiovascular Disease