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APOE

apolipoprotein E

The APOE gene provides instructions for producing apolipoprotein E, a protein crucial for transporting fats like cholesterol throughout the body. Apolipoprotein E, encoded by the APOE gene, is a key component of lipoproteins, which carry lipids through the bloodstream.

Chromosome 19q13.32 Polygenic HGNC:613
APOE 19q13.32 p arm q arm 19

APOE is located on the long (q) arm of chromosome 19, at band 19q13.32. Arm ratio per GRCh38 - banding schematic.

Explore chromosome 19 in the library →

Overview

The APOE gene, or apolipoprotein E, is fundamental to lipid metabolism within the body. It provides the genetic blueprint for apolipoprotein E, a protein that combines with lipids to form lipoproteins. These lipoproteins are responsible for the vital transport of cholesterol and other fats via the bloodstream to various tissues. Proper regulation of cholesterol levels is essential for preventing cardiovascular diseases, such as heart attacks and strokes.

There are several versions (alleles) of the APOE gene, with e2, e3, and e4 being the primary forms. The e3 allele is the most prevalent in the general population, accounting for over half of all APOE alleles.

What the gene does

Apolipoprotein E, the protein product of the APOE gene, is integral to the processing and clearance of lipoproteins. It acts as a ligand for various receptors, including the low-density lipoprotein (LDL) receptor, facilitating the uptake of lipoproteins into cells. This mechanism is critical for the redistribution of lipids to cells for energy, membrane synthesis, and steroid hormone production.

Specifically, the protein features a region from amino acids 158-168 that is responsible for binding to LDL and other lipoprotein receptors. Furthermore, a lipid-binding and lipoprotein association region, spanning amino acids 210-290, enables apolipoprotein E to interact with and stabilise lipoprotein particles. The protein's ability to homooligomerise, mediated by a region from amino acids 266-317, may also influence its function and interactions with other molecules. A distinct region for specificity with very low-density lipoprotein (VLDL) is found between amino acids 278-290, highlighting its role in VLDL metabolism. Through these specific interaction domains, apolipoprotein E plays a central role in maintaining lipid balance and overall metabolic health.

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Chromosome location

The APOE gene is situated on chromosome 19 at position 13.32 (19q13.32). This particular chromosomal location places it within a region that is significant for various metabolic and neurological functions. The gene codes for a protein that is 317 amino acids in length.

Protein structure

The apolipoprotein E protein, encoded by the APOE gene, displays a multi-domain structure crucial for its function in lipid transport and receptor binding. The protein contains a series of approximate tandem repeats, spanning from amino acids 80-255. Within this larger region, several smaller repeat units are identified: - Repeat 1: amino acids 80-101 - Repeat 2: amino acids 102-123 - Repeat 3: amino acids 124-145 - Repeat 4: amino acids 146-167 - Repeat 5: amino acids 168-189 - Repeat 6: amino acids 190-211 - Repeat 7: amino acids 212-233 - Repeat 8: amino acids 234-255

Beyond these repeat regions, specific functional domains are present. The LDL and other lipoprotein receptors binding region is located between amino acids 158-168, critical for cellular lipid uptake. A broader lipid-binding and lipoprotein association region spans from amino acids 210-290. The protein also possesses a homooligomerization region (amino acids 266-317) and a specificity region for association with VLDL (amino acids 278-290).

Domain map · 317 amino acids
1 (80–101)2 (102–123)3 (124–145)4 (146–167)5 (168–189)6 (190–211)7 (212–233)8 (234–255)180–1012102–1233124–1451~159317
Repeat - repeating structural motif
🧬 Explore 3D structure on AlphaFold
UniProt:P02649Length:317 aaStructure:AlphaFold

Key variants

Genetic variations within the APOE gene can influence its function, potentially affecting lipid metabolism and disease risk. These variations, particularly the e2, e3, and e4 alleles, represent slight differences in the gene sequence which lead to distinct forms of the apolipoprotein E protein. The presence of specific APOE alleles can contribute to an individual's genetic predisposition for various health conditions, including neurodegenerative and cardiovascular disorders. Understanding these genetic differences is important for assessing risk profiles.

253
Total variants catalogued in ClinVar
View all on ClinVar →
20 Pathogenic / Likely pathogenic 114 Uncertain significance 108 Benign / Likely benign 11 Conflicting or other

Sample of pathogenic variants

10 pathogenic / likely-pathogenic variants from ClinVar, ranked by review status (expert-panel-reviewed first). This is a sample; recurrent founder variants in a specific population may not appear here - see the full ClinVar listing via the link above.

Variant (HGVS) Protein change Classification Evidence Associated condition
c.127C>T
single nucleotide variant
 p.Arg43Cys Pathogenic/Likely pathogenic ★★☆☆ Cardiovascular phenotype
c.460C>A
single nucleotide variant
 p.Arg154Ser Pathogenic/Likely pathogenic ★★☆☆ Familial hypercholesterolemia
c.497TCC[1]
Microsatellite
 p.Leu167del Pathogenic ★★☆☆ APOE-related disorder
c.146del
Deletion
 p.Gly49fs Pathogenic - Familial type 3 hyperlipoproteinemia
c.415_435dup
Duplication
 p.Glu139_Gly145dup Pathogenic - Familial type 3 hyperlipoproteinemia
c.455G>A
single nucleotide variant
 p.Arg152Gln Pathogenic - APOE2 VARIANT
c.488G>C
single nucleotide variant
 p.Arg163Pro Pathogenic - Lipoprotein glomerulopathy
c.490A>C
single nucleotide variant
 p.Lys164Gln Pathogenic - Hyperlipoproteinemia, type III, due to APOE2
c.490A>G
single nucleotide variant
 p.Lys164Glu Pathogenic - Familial type 3 hyperlipoproteinemia
c.736C>T
single nucleotide variant
 p.Arg246Cys Pathogenic - APOE2-DUNEDIN

Evidence stars indicate ClinVar review status. Individual variant interpretation should always be performed by a qualified clinical laboratory - many variants remain classified as Variants of Uncertain Significance (VUS) pending more research.

Associated conditions

Variations in the APOE gene, specifically the e4 allele, have been linked to an increased risk of developing late-onset Alzheimer's disease, a type of dementia typically affecting individuals over 65 years old. This allele can also raise the risk for other forms of dementia, such as dementia with Lewy bodies, although not all with this allele will develop the condition. Further research indicates that APOE alleles can influence the risk of cardiovascular diseases, including atherosclerosis, where fatty deposits accumulate in arterial linings. Additionally, APOE variants have been studied in relation to age-related hearing loss and age-related macular degeneration. The gene is also associated with conditions featured in Jeen's Hyperlipidaemia (polygenic) panel.

UK clinical status

In the UK, the APOE gene is part of several NHS Genomic Medicine Service (GMS) panels, highlighting its clinical relevance for various conditions. It is included in panels for Familial chylomicronaemia syndrome (FCS), Familial hypercholesterolaemia (GMS), Proteinuric renal disease, and Undiagnosed metabolic disorders. Its inclusion underlines the gene's importance in diagnosing and understanding a range of inherited metabolic and renal conditions within the national healthcare system.

Green-listed
High evidence · clinically actionable in NHS testing
Included in NHS GMS signed-off panels
Familial Chylomicronaemia Syndrome · R324 NHS GMS → Familial hypercholesterolaemia (GMS) · R134 NHS GMS → Likely inborn error of metabolism · R98 NHS GMS → Proteinuric renal disease · R195 NHS GMS →
NHS Genomic Medicine Service Jeen carrier screening

Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory

Diet & lifestyle considerations

Research suggests that certain lifestyle factors may interact with APOE genotype to influence health outcomes. For instance, maintaining a heart-healthy diet, regular physical activity, and a healthy weight are generally recommended for cardiovascular health in the general population. For individuals carrying the APOE e4 allele, some studies indicate that lifestyle choices might be particularly relevant in modifying risk for conditions like Alzheimer's disease, though this is an area of ongoing research. Avoiding smoking and excessive alcohol consumption are also widely recommended for general health.

Supplement considerations

While the APOE gene is involved in lipid metabolism and neurodegenerative conditions, there is no conclusive evidence to suggest that specific supplements can prevent or treat conditions associated with APOE variants. Some research has explored the effects of omega-3 fatty acids, B vitamins, and antioxidants on cognitive health; however, these studies are not specific to APOE genotypes, and robust clinical recommendations are not established. Individuals considering any supplements should discuss this with a healthcare professional to ensure safety and appropriateness.

Frequently asked questions

What is the primary function of the APOE gene?

The APOE gene provides instructions for making apolipoprotein E, a protein essential for transporting lipids like cholesterol throughout the bloodstream as part of lipoproteins.

How many main versions (alleles) of the APOE gene are there?

There are three main alleles of the APOE gene: e2, e3, and e4. The e3 allele is the most common among the general population.

Is the APOE gene linked to Alzheimer's disease?

Yes, specifically the APOE e4 allele is associated with an increased risk of developing late-onset Alzheimer's disease. However, inheriting this allele does not mean an individual will definitely develop the condition.

What other health conditions are associated with APOE gene variations?

Variations in the APOE gene have been linked to cardiovascular diseases like atherosclerosis, dementia with Lewy bodies, age-related hearing loss, and age-related macular degeneration.

Can lifestyle changes affect the impact of APOE gene variations?

Research suggests that healthy lifestyle factors such as diet, exercise, and maintaining a healthy weight may influence health outcomes, especially for individuals with certain APOE genotypes, but further research is ongoing.

References

  1. Dickson DW, Heckman MG, Murray ME. APOE ε4 is associated with severity of Lewy body pathology independent of Alzheimer pathology. Neurology. 2018. PMID: 30143564
  2. Hill JM, Bhattacharjee PS, Neumann DM. Apolipoprotein E alleles can contribute to the pathogenesis of numerous clinical conditions including HSV-1 corneal disease. Experimental eye research. 2007. PMID: 17007837
  3. Tikellis G, Sun C, Gorin MB. Apolipoprotein e gene and age-related maculopathy in older individuals: the cardiovascular health study. Archives of ophthalmology (Chicago, Ill. : 1960). 2007. PMID: 17210854
  4. Heeren J, Beisiegel U, Grewal T. Apolipoprotein E recycling: implications for dyslipidemia and atherosclerosis. Arteriosclerosis, thrombosis, and vascular biology. 2006. PMID: 16373604
  5. Huang Y. Apolipoprotein E and Alzheimer disease. Neurology. 2006. PMID: 16432152
  6. Baird PN, Richardson AJ, Robman LD. Apolipoprotein (APOE) gene is associated with progression of age-related macular degeneration (AMD). Human mutation. 2006. PMID: 16453339
  7. Mahley RW, Weisgraber KH, Huang Y. Apolipoprotein E4: a causative factor and therapeutic target in neuropathology, including Alzheimer's disease. Proceedings of the National Academy of Sciences of the United States of America. 2006. PMID: 16567625
  8. Bojanowski CM, Shen D, Chew EY. An apolipoprotein E variant may protect against age-related macular degeneration through cytokine regulation. Environmental and molecular mutagenesis. 2006. PMID: 16823865
  9. van der Flier WM, Schoonenboom SN, Pijnenburg YA. The effect of APOE genotype on clinical phenotype in Alzheimer disease. Neurology. 2006. PMID: 16894123
  10. Raber J, Huang Y, Ashford JW. ApoE genotype accounts for the vast majority of AD risk and AD pathology. Neurobiology of aging. 2004. PMID: 15172743
  11. Ashford JW. APOE genotype effects on Alzheimer's disease onset and epidemiology. Journal of molecular neuroscience : MN. 2004. PMID: 15181244
  12. Song Y, Stampfer MJ, Liu S. Meta-analysis: apolipoprotein E genotypes and risk for coronary heart disease. Annals of internal medicine. 2004. PMID: 15262670
  13. Rocchi A, Pellegrini S, Siciliano G. Causative and susceptibility genes for Alzheimer's disease: a review. Brain research bulletin. 2003. PMID: 12788204
  14. Eichner JE, Dunn ST, Perveen G. Apolipoprotein E polymorphism and cardiovascular disease: a HuGE review. American journal of epidemiology. 2002. PMID: 11882522
  15. Deary IJ, Whiteman MC, Pattie A. Cognitive change and the APOE epsilon 4 allele. Nature. 2002. PMID: 12198535
  16. Selkoe DJ. Alzheimer's disease: genes, proteins, and therapy. Physiological reviews. 2001. PMID: 11274343
  17. Feussner G, Piesch S, Dobmeyer J. Genetics of type III hyperlipoproteinemia. Genetic epidemiology. 1997. PMID: 9181357
Educational content. This page is not medical or genetic advice, is not individually reviewed by a clinician for each reader, and should not replace a consultation with a qualified healthcare professional or genetic counsellor. If you are considering genetic testing or acting on a test result, book a consultation.
Data sources Last updated 17 July 2026. Content compiled from HGNC · MedlinePlus Genetics · ClinGen · Genomics England PanelApp · NHS National Genomic Test Directory · ClinVar · UniProt · AlphaFold .