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The need for an advanced understanding of lipidology structure and function in healthcare is growing.  Lipoprotein testing provides valuable insights into an individual's lipid profile, aiding in the assessment of cardiovascular risk and guiding interventions above and beyond the standard lipid panel.  

Apolipoprotein E (ApoE) is a lipoprotein that exerts multifaceted roles extending beyond its traditional function in lipid transportation. 

Widely recognized for its involvement in cholesterol metabolism and atherosclerosis, ApoE's significance also spans neurological health and disease. 

This article delves into the diverse functions of ApoE including its intricate mechanisms of action, clinical implications, and natural strategies to optimize lipoprotein levels. From its pivotal role in modulating lipoprotein metabolism to its implications in Alzheimer's disease and other neurological disorders, understanding ApoE provides insights into various aspects of human health and disease.

Understanding ApoE

What is ApoE?

Apolipoprotein E (ApoE) is a protein synthesized by the liver, the brain and macrophages.  It is also found in abundance in lymph and interstitial fluid.  [4., 5.] 

Apolipoprotein E (ApoE) exists in three major isoforms that each exert distinct effects on lipid metabolism and neuronal function: ApoE2, ApoE3, and ApoE4.  Each isoform differs by only a single amino acid.  [6.]

Of these three isoforms, ApoE3 is the “normal” form, as ApoE2 and ApoE4 are associated with altered lipid metabolism and ApoE4 is also associated with the pathogenesis of Alzheimer’s Disease.  [4.]

Its primary role in lipid metabolism is facilitating the transport and clearance of cholesterol and triglycerides from circulation, primarily through interactions with lipoprotein receptors.  

Function of ApoE in Lipid Metabolism and Cardiovascular Health

Apolipoprotein E (ApoE) regulates lipid metabolism and aids in the clearance of lipoproteins from circulation.  However, the three variants, ApoE2, ApoE3, and ApoE4 may confer different levels of risk vs. protection.  The positive health benefits typically attributed to ApoE are likely due to the effects of the isoform ApoE3.  [6.] 

ApoE acts as a key mediator in the uptake of triglyceride-rich lipoproteins, including chylomicrons and very low-density lipoproteins (VLDL), by the liver through interaction with cell surface receptors such as the LDL receptor (LDLR) and LDL receptor-related protein 1 (LRP1).  This effect may specifically apply to ApoE3. 

In contrast, the ApoE2 and ApoE4 variants are associated with an elevated risk of heart disease.  [6.]

While ApoE2 raises the levels of atherogenic lipoproteins due to its reduced binding affinity to LDL receptors, ApoE4 contributes to increased LDL levels by favoring binding to triglyceride-rich VLDLs, consequently downregulating LDL receptors.

ApoE2's defective binding to LDL receptors can lead to type III hyperlipoproteinemia, particularly when coupled with conditions like diabetes or hypothyroidism, causing the accumulation of atherogenic β-VLDL and increasing the risk of atherosclerosis.  [6.] 

In contrast, ApoE4's preference for large, triglyceride-rich VLDL particles leads to elevated plasma LDL levels and heightened susceptibility to atherosclerosis. However, a structural alteration in domain binding site may alter ApoE4's binding preference from VLDL to smaller, phospholipid-rich HDL, potentially mitigating its atherogenic effects.  [6.]

ApoE4 has also been established as an independent risk factor for metabolic syndrome.  [11.]

Function of ApoE in Neurological Health

ApoE4 is a significant genetic risk factor for Alzheimer's disease (AD) and other neurological disorders, including frontotemporal dementia and certain types of Parkinson's disease.  Carriers of the ApoE4 allele have a substantially increased risk of developing AD, with each allele lowering the age of onset by about 8 years.  [6.] 

Mechanisms underlying ApoE4's involvement in AD include its impact on the amyloid pathway, where it accelerates amyloid beta (Aβ) deposition or impairs Aβ clearance. Additionally, ApoE4 has direct neurotoxic effects including mitochondrial dysfunction, increased tau phosphorylation, and impaired neuronal function, which contribute to neurodegeneration.  [6.] 

Small-molecule structure correctors that block ApoE4 domain interaction show promise in slowing ApoE4-associated neuropathology in preclinical studies, suggesting that targeting ApoE4 could be a potential therapeutic strategy for AD and related disorders.  [6.] 

Clinical Significance of ApoE

ApoE holds much potential clinical relevance in the realm of cardiometabolic and neurodegenerative disease risk.  

ApoE and Cardiometabolic Disease Risk

ApoE plays a complex role in cardiometabolic disease risk with both positive and negative associations observed. 

ApoE2 has been linked to increased risk for type III hyperlipoproteinemia due to its defective binding to LDL receptors which can exacerbate hyperlipidemia, particularly in individuals with other metabolic conditions such as diabetes or obesity.  [4.] 

Conversely, ApoE4 is associated with elevated plasma LDL levels, increasing the risk for atherosclerosis.  [6.]  It may also be an independent risk factor for metabolic disease.  [11.]

However, individuals carrying the ApoE3 allele may also have reduced levels of atherogenic lipoproteins due to their enhanced clearance, potentially conferring protection against cardiovascular disease. 

Certain variants of ApoE have been linked to differential responses to dietary fat intake, influencing plasma lipid profiles and cardiovascular risk.  [7.]

For these reasons, understanding one’s ApoE genotype may be helpful in creating an appropriate and personalized risk management strategy.  

ApoE and Neurodegenerative Disease Risk

The APOE 4 allele is a significant risk factor for Alzheimer's disease (AD) and other neurodegenerative conditions. Studies have consistently shown that individuals carrying the ApoE4 allele face an elevated risk of both early-onset and late-onset AD, with the risk increasing significantly in ε4 homozygotes.  [5.]

Conversely, the ApoE2 allele of APOE appears to offer protective effects against AD, with individuals carrying this allele exhibiting a lower risk compared to those with the more common ApoE3/ApoE3 genotype.  [5.] 

APOE4 carriers are prone to earlier onset of AD, with a substantial increase in the prevalence of the disease and a decrease in the mean age of clinical onset compared to non-carriers.  [5.]

Furthermore, APOE4 has been associated with increased deposition of amyloid-beta (Aβ) plaques, a hallmark of AD pathology, particularly among individuals aged 50-59 years. The presence of APOE4 also correlates with a higher risk of cerebral amyloid angiopathy (CAA) and CAA-related hemorrhages, highlighting its broad impact on neurodegenerative disease risk.  [5.] 

APOE4 also interacts synergistically with cardiovascular risk factors such as atherosclerosis, peripheral vascular disease, and diabetes, compounding the risk of cognitive decline and neurodegeneration.  [5.] 

ApoE Testing Options

Overview of ApoE Testing

ApoE testing is most commonly done as a genotype test to assess the presence of specific alleles in an individual’s genome, which may provide increased or decreased risk of certain diseases.  This test may be done with whole blood which requires a venipuncture, or as a cheek swab.

In some cases, often in research scenarios, ApoE blood tests are done to assess the levels of apolipoprotein E (ApoE) in the bloodstream.  Venipuncture is commonly required for this test.

Interpretation of ApoE Test Results

ApoE Genotyping Results

Humans have two copies of each gene, including ApoE.  An individual may be heterozygous, meaning he or she has two different copies of one particular gene, or homozygous, meaning he or she has 2 identical copies of the gene.  Heterozygosity and homozygosity may cause different levels of functionality.  

Homozygous ApoE genotype results are E2/E2, E3/E3, and E4/E4.  

Heterozygous ApoE genotype results E2/E3, E2/E4,and E3,E4.

It is important to discuss results with a healthcare provider within the context of an individual’s full health history to understand the implications of results and create a management strategy.  

Natural Ways to Optimize ApoE Levels

Diet and lifestyle strategies to optimize lipid metabolism and cardiometabolic health are foundational.  Supplements and medications should be used under the guidance of a licensed healthcare professional.  

Dietary Strategies

Diets Containing Fermented Dairy Products: diets containing fermented dairy products have been shown to increase ApoA1 levels and promote healthy lipid metabolism.  [3., 8.]  

Foods Rich in Omega-3 Fatty Acids: Fatty fish (salmon, mackerel, sardines), flaxseeds, chia seeds, walnuts all have scientific evidence of efficacy in improving lipoprotein biomarkers and reducing cardiovascular disease risk.  [3., 8.]

Fiber-Rich Foods: Whole grains (oats, barley, quinoa), fruits (apples, berries, oranges), vegetables (broccoli, Brussels sprouts, carrots), legumes (beans, lentils) are all Mediterranean diet staples that have shown effectiveness in reducing cardiovascular disease risk.  [8.]

Avoid excess sugar: diets high in sugar have negative effects on lipid and glucose metabolism, as well as on lipoprotein levels.  [3.]

Lifestyle Modifications

Regular Exercise: Aerobic activities (walking, jogging, swimming), strength training, yoga, tai chi may all promote cardiovascular health.  [3., 12.]

Smoking Cessation: Quitting smoking reduces oxidative stress and inflammation, contributing to improved lipid profiles including improvements in lipoprotein levels.  [3.]

Stress Management: Techniques such as meditation, deep breathing exercises, yoga, and mindfulness may help lower stress levels and improve overall cardiovascular health,and in some cases may also have a positive effect on lipid profiles.  [10.]

Niacin (Vitamin B3): Niacin supplementation has been shown to improve lipoprotein and HDL cholesterol levels.  [1.]

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APOE is a gene that produces proteins involved in cholesterol metabolism. Detecting the APOE genotype can help identify risk factors for cardiovascular disease and other conditions related to altered lipid transport.
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See References

[1.] Brown WM, Chiacchia FS. Therapies to Increase ApoA-I and HDL-Cholesterol Levels. Drug Target Insights. 2008;3. doi:10.4137/DTI.S447

[2.] Endres K. Apolipoprotein A1, the neglected relative of Apolipoprotein E and its potential role in Alzheimer's disease. Neural Regen Res. 2021 Nov;16(11):2141-2148. doi: 10.4103/1673-5374.310669. PMID: 33818485; PMCID: PMC8354123. 

[3.] Frondelius K, Borg M, Ericson U, Borné Y, Melander O, Sonestedt E. Lifestyle and Dietary Determinants of Serum Apolipoprotein A1 and Apolipoprotein B Concentrations: Cross-Sectional Analyses within a Swedish Cohort of 24,984 Individuals. Nutrients. 2017 Feb 28;9(3):211. doi: 10.3390/nu9030211. PMID: 28264492; PMCID: PMC5372874. 

[4.] Huang Y, Mahley RW. Apolipoprotein E: structure and function in lipid metabolism, neurobiology, and Alzheimer's diseases. Neurobiol Dis. 2014 Dec;72 Pt A:3-12. doi: 10.1016/j.nbd.2014.08.025. Epub 2014 Aug 27. PMID: 25173806; PMCID: PMC4253862.

[5.] Liu CC, Liu CC, Kanekiyo T, Xu H, Bu G. Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy. Nat Rev Neurol. 2013 Feb;9(2):106-18. doi: 10.1038/nrneurol.2012.263. Epub 2013 Jan 8. Erratum in: Nat Rev Neurol. 2013. doi: 10.1038/nmeurol.2013.32. Liu, Chia-Chan [corrected to Liu, Chia-Chen]. PMID: 23296339; PMCID: PMC3726719.

[6.] Mahley RW. Apolipoprotein E: from cardiovascular disease to neurodegenerative disorders. J Mol Med (Berl). 2016 Jul;94(7):739-46. doi: 10.1007/s00109-016-1427-y. Epub 2016 Jun 9. PMID: 27277824; PMCID: PMC4921111.

[7.] Mokhtar FBA, Plat J, Mensink RP. Genetic variation and intestinal cholesterol absorption in humans: A systematic review and a gene network analysis. Progress in Lipid Research. 2022;86:101164. doi:‌

[8.] Nacarelli GS, Fasolino T, Davis S. Dietary, macronutrient, micronutrient, and nutrigenetic factors impacting cardiovascular risk markers apolipoprotein B and apolipoprotein A1: a narrative review. Nutrition Reviews. Published online August 23, 2023:nuad102. doi: 

[9.] Nazir S, Jankowski V, Bender G, Zewinger S, Rye KA, van der Vorst EPC. Interaction between high-density lipoproteins and inflammation: Function matters more than concentration! Advanced Drug Delivery Reviews. 2020;159:94-119. doi:

[10.] Papp ME, Lindfors P, Nygren-Bonnier M, Gullstrand L, Wändell PE. Effects of High-Intensity Hatha Yoga on Cardiovascular Fitness, Adipocytokines, and Apolipoproteins in Healthy Students: A Randomized Controlled Study. J Altern Complement Med. 2016 Jan;22(1):81-7. doi: 10.1089/acm.2015.0082. Epub 2015 Nov 13. Erratum in: J Altern Complement Med. 2017 May;23(5):396. PMID: 26565690; PMCID: PMC4739349.

[11.] Sima A, Iordan A, Stancu C. Apolipoprotein E polymorphism – a risk factor for metabolic syndrome. Clinical Chemical Laboratory Medicine. 2007;45(9). doi: 

[12.] Yazdani R, Marefati H, Shahesmaeili A, Nakhaei S, Bagheri A, Dastoorpoor M. Effect of Aerobic Exercises on Serum Levels of Apolipoprotein A1 and Apolipoprotein B, and Their Ratio in Patients with Chronic Obstructive Pulmonary Disease. Tanaffos. 2018 Feb;17(2):82-89. PMID: 30627178; PMCID: PMC6320561.

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