By Dave Larson, MD

ApoE Genetics: As the prices of genetic testing have fallen, more and more data is being generated about the interplay between our genetic code, our lifestyle choices, and the burden of disease. For example, every baby born in the US is tested for Phenylketonuria (commonly known as PKU), a genetic disease that determines how the body handles a certain food ingredient called phenylalanine. The link between phenylalanine (found in artificial sweeteners) in the diet and symptoms of the disease is clear, and so important that food manufacturers are required to place warnings on foods that contain it.

Another important gene that interacts with our diet is Apolipoprotein E (commonly called ApoE). ApoE is produced primarily in the brain and the liver, and acts like a taxi for fats and cholesterol in our body, delivering vital nutrients that are essential to create new cell membranes (including neuronal cell membranes), hormones, and much more. In fact, ApoE is the PRINCIPAL cholesterol carrier in the brain.  It was first discovered at UCSF in 1973, but became famous in 1995 with its link with Alzheimer’s disease.

We all have the ApoE gene on chromosome 19, the important question is which types (called isoforms) we have. There are 3 different variants of the ApoE gene (ϵ2, ϵ3, and ϵ4) which code for the 3 isoforms of the ApoE protein, ApoE2, E3, and E4. We inherit one allele of the gene from each parent, giving us 6 possible “genotypes.” These genotypes (and their associated frequency in the population) are 2/2 (1%), 2/3 (10%), 3/3 (64%), 3/4 (18%), 2/4 (2%), and 4/4 (5%).  There are no good or bad genotypes, and each type has certain risks, benefits, and personalized lifestyle recommendations that I want you to know about. Understanding the complex interplay between your genotype and your lifestyle can greatly help in the assessment of your unique lipid metabolism, and guide personalized treatment to lower your risk of cardiovascular disease and neurodegenerative diseases such as Alzheimer’s disease.
You can find your genotype on page 2 of your annual physical labs.

Here are the bullet points of what you need to know.

ApoE2. Compared with ApoE3, those with ApoE2 alleles tend to have reduced cardiovascular risk, but a propensity for increased triglyceride levels, insulin resistance, and obesity.  Personalized Recommendations for you are to:

• Limit Sugar: If you have a 2 in your ApoE genotype, you should work to drastically limit the amount of sugar in your diet, choose low glycemic carbohydrates, and place your focus on healthy fats, non-starchy vegetables, and lean protein.
• Healthy fats are good for you: People with ApoE2 may respond better than those with ApoE4 or ApoE3 to a diet higher in heart-healthy fats.  Aim for a moderate-fat diet (<35% fat), choosing health fats, limiting saturated fats.
• Moderate alcohol intake (1 drink/day for women, 1-2 drinks/day for men) may be healthy for you (increases HDL-C and decreases LDL-C).

ApoE3.  ApoE3 is considered the “normal” form of this lipoprotein, so there are no specific
associated conditions. Instead the other ApoE isoforms are compared to ApoE3 to determine their relative risk. Like ApoE2, those with the ApoE3 genotype tend to do well with healthy fats in their diet. They also tend to respond more favorably to statin medications.

ApoE4. Of all the isoforms, ApoE4 has the greatest interaction with our diet and lifestyle. Think of ApoE4 as a much slower cholesterol taxi system which can easily lead to a dangerous build-up of dietary fats and resulting inflammation and atherosclerosis when we make poor lifestyle choices. Individuals with an ApoE4 allele often show hyperabsorption of cholesterol, very high levels of vascular damage from smoking and alcohol, reduced response to statins, increased LDL-P and ApoB levels and decreased absorption of omega-3 fatty acids (and hence, lower Omega-3 Index).  ApoE4 is associated with the highest cardiovascular risk compared to ApoE3, and, although not diagnostic, there is an association between ApoE4 and Alzheimer’s disease in those with unhealthy lifestyle choices. This is because ApoE is the predominant cholesterol carrier in the brain, and with the slower ApoE4 variant, the brain is at much greater risk of inflammation and oxidative stress if we have a diet high in saturated fat and alcohol. If you have an ApoE4 in your genotype, personalized recommendations are:

• Limit dietary fat. In contrast to those with the ApoE2 and E3 variants, you cannot process dietary fats well. Aim for low total fat intake, VERY low saturated fats, and NO trans fats in your diet. Doing this will decrease your sdLDL-C levels and decrease your risk of heart and brain disease.
• Strongly consider alcohol cessation. In comparison to those with an ApoE2 allele who may benefit from moderate alcohol consumption, those with an ApoE4 allele do NOT process alcohol well, and alcohol leads to increased LDL-C, sdLDL-C, and IL-6 (an inflammatory cytokine) levels, and DECREASES HDL-C and HDL2 leading to an increased risk of cognitive dysfunction, Alzheimer’s Disease, and cardiovascular disease. This risk is increased in men compared to women.
• Smoking cessation (EXTREMELY important for ApoE4 because in this genotype smoking creates elevated levels of oxidized LDL in the context of smoke exposure).
• Omega 3 supplementation to normalize omega 3 index (over 8%) is especially helpful in this population because in addition to helping normalize lipids, Omega 3 fatty acids additionally help to correct cardiac conduction deficits and reduce risk of sudden cardiac death. Yes, even though this is a type of fat, this is approved and recommended for those with an ApoE4 allele.
• Stress management: ApoE4 is associated with a poor response to life stressors and prolonged stress can contribute to memory decline. To combat this, incorporate relaxation practice as a part of your daily routine (options include mindfulness meditation, diaphragmatic breathing, tai chi, journaling, and much more).
• Consider antioxidant and anti-inflammatory supplements such as vitamin C, alpha lipoic acid, curcumin (found in turmeric), and Amla (Indian gooseberry) since those with ApoE4 tend to have lower tissue antioxidant levels and are more prone to an inflammatory response to the standard American diet.
• Ensure adequate B6, B12, folic acid, magnesium, and methionine to prevent elevated homocysteine which can also contribute to inflammatory damage and vascular disease.
• Optimize lifestyle interventions as your first priority. Unfortunately, those with ApoE4 alleles don’t respond well to prescription medications (statins) to lower cholesterol levels. The good news is they respond very well to lifestyle interventions. So, in addition to the dietary intervention mentioned above, focus on physical exercise, weight loss (if indicated), low glycemic index foods including plenty of fresh veggies, and aggressive control of blood sugar, blood pressure, and other conditions that affect heart health.

If you have a single copy of E4 in your genotype (2/4 or 3/4), regardless of your other allele, I would follow the recommendations for ApoE4 as listed above. Follow these recommendations strictly if you have 2 copies of the E4 allele (4/4). If you have a 2/3 genotype, I would follow the recommendations for ApoE2 above.

Let us know if you have any questions, or if we can help you optimize your lifestyle for your ApoE genotype!