APOE

The APOE gene codes for apolipoprotein E (apoE). ApoE helps remove fats such as triglycerides and cholesterol from the blood [R]. Variants of APOE may play a role in high blood pressure by lowering the efficacy of apoE, promoting fatty deposits within blood vessels (atherosclerosis), and restricting blood flow. 

About three quarters of the ApoE in your blood is made by your liver, whereas the rest comes from the brain. ApoE cannot cross the blood-brain barrier (BBB), so all of the ApoE in your brain was produced there [R, R].

ApoE is also involved in the breakdown and aggregation of the protein beta-amyloid. Beta-amyloid has been implicated in the development of Alzheimer’s disease [R]. 

rs429358 and rs7412 are two SNPs that form three major alleles. These alleles form apoE proteins (isoforms) that differ in ability to clear fats and regulate beta-amyloid [R]:

• The apoE3 isoform (encoded by the e3 allele) is produced from a ‘T’ at rs429358 and a ‘C’ at rs7412. This isoform is effective at clearing fats and regulating beta-amyloid.
• The apoE2 isoform (encoded by the e2 allele) is produced from a ‘T’ at both rs429358 and rs7412. This isoform is more effective than apoE3 at clearing fats and regulating beta-amyloid.
• The apoE4 isoform (encoded by the e4 allele) is produced from a ‘C’ at both rs429358 and rs7412. This isoform is less effective than apoE2 and apoE3 at clearing fats and regulating beta-amyloid.

apoE2 isoforms may contribute to [R, R, R, R]: 

• Normal cholesterol levels
• Weight management 
• Protection against late-onset Alzheimer’s disease
• Age-related macular (part of eye) degeneration 

Conversely, apoE4 isoforms have been linked to [R, R, R, R, R, R]:

• High cholesterol 
• Heart disease
• Migraines
• Depression
• Late-onset Alzheimer’s disease
• Lower odds of snoring and sleep apnea

Potential isoform genotypes are as follows [R]:

• e4 / e4: rs429358-CC and rs7412-CC
• e3 / e4: rs429358-TC and rs7412-CC
• e2 / e4: rs429358-TC and rs7412-TC 
• e3 / e3: rs429358-TT and rs7412-CC
• e2 / e3: rs429358-TT and rs7412-TC
• e2 / e2: rs429358-TT and rs7412-TT

Lifestyle, diet, and supplement modifications may counteract the effects of these variants by promoting apoE activity, lowering cholesterol, and preventing atherosclerosis progression.

The APOE gene provides instructions for making a protein called apolipoprotein E. This protein combines with fats (lipids) in the body to form molecules called lipoproteins. Lipoproteins are responsible for packaging cholesterol and other fats and carrying them through the bloodstream. Maintaining normal levels of cholesterol is essential for the prevention of disorders that affect the heart and blood vessels (cardiovascular diseases), including heart attack and stroke.

There are at least three slightly different versions (alleles) of the APOE gene. The major alleles are called e2, e3, and e4. The most common allele is e3, which is found in more than half of the general population.

The APOE gene codes for apolipoprotein E (apoE), a protein that helps remove fats such as triglycerides and cholesterol from the blood [R].

rs429358 and rs7412 are two SNPs involved in generating three major alleles that form functionally similar apoE proteins (isoforms). These three isoforms differ in their ability to clear circulating fats [R]:

• The apoE3 isoform (encoded by the e3 allele) is produced from a ‘T’ at rs429358 and a ‘C’ at rs7412, and is effective at clearing fats.
• The apoE2 isoform (encoded by the e2 allele) is produced from a ‘T’ at both rs429358 and rs7412, and is more effective than apoE3 at clearing fats.
• The apoE4 isoform (encoded by the e4 allele) is produced from a ‘C’ at both rs429358 and rs7412, and is less effective than apoE2 and apoE3 at clearing fats.

People with one or more apoE2 isoforms tend to have lower blood triglycerides and cholesterol, while those with one or more apoE4 isoforms tend to have higher blood triglycerides and cholesterol [R].

Without their effective removal, fats can accumulate in the blood and form hard deposits within arteries (atherosclerosis). These deposits cause arteries to become narrowed, thereby constricting blood flow. As a result, the heart needs to work harder to maintain blood flow, and blood pressure rises [R].

Unsurprisingly, variants of APOE have been associated with high blood pressure (hypertension). These variants may reduce the efficacy of apoE, leading to higher blood fat levels and restricted blood flow [R, R].

Doctors have known for decades that two variants in the APOE gene, rs429358 and rs7412, strongly influence a person’s likelihood of developing Alzheimer’s disease and cardiovascular disease [R].

More recently, APOE has been linked with lifespan [R, R, R].

Six Genotypes Affecting Mortality Risk

The two SNPs above have a uniquely strong effect on disease risk, so they’re almost always studied together. Rather than referring to any one allele at any single variant, researchers and doctors discuss the two SNPs in combination. These combinations are called isoforms, and there are three especially important ones: 𝛆2, 𝛆3, and 𝛆4 [R].

• 𝛆2 is produced from a ‘T’ allele at both rs429358 and rs7412
• 𝛆3 is produced from a ‘T’ at rs429358 and a ‘C’ at rs7412
• 𝛆4 is produced from a ‘C’ allele at both rs429358 and rs7412

Technically speaking, other isoforms (𝛆1 and 𝛆5) exist, but they appear in less than 0.1% of the global population [R].

Very nearly 100% of people will therefore have one of six APOE genotypes: 𝛆2/𝛆2, 𝛆2/𝛆3, 𝛆3/𝛆3, 𝛆3/𝛆4, 𝛆4/𝛆4, or 𝛆2/𝛆4. 𝛆3 is the most common isoform, and 𝛆3/𝛆3 is the most common genotype [R].

APOE Isoforms and Longevity

The APOE isoforms that increase Alzheimer’s risk may also decrease lifespan, and vice versa. More specifically [R]:

• 𝛆2 decreases Alzheimer’s risk and is more common in long-lived people
• 𝛆4 increases Alzheimer’s risk and is less common in long-lived people

To say it another way, the more copies of 𝛆2 you have, the more likely you are to live an exceptionally long life. The more copies of 𝛆4 you have, the less likely you are to live an exceptionally long life.

According to a study of over 28,000 people, people with even one copy of the 𝛆4 isoform are only about half as likely to live to 100 as those without. Furthermore, those with the 𝛆2/𝛆3 and 𝛆2/𝛆2 genotypes are about 32% more likely to live to 100 as those with 𝛆3/𝛆3 [R].

How Does APOE Affect Your Lifespan?

Increased Blood Cholesterol

The ApoE protein is required to transport LDL cholesterol and triglycerides (two types of fats) into cells like neurons and muscle cells. The better ApoE functions, the more efficiently these fats can be transported out of the bloodstream and into target cells [R, R].

As a result, people with more effective ApoE (𝛆2) tend to have lower blood cholesterol and triglycerides, and people with less effective ApoE (𝛆4) tend to have higher blood cholesterol and triglycerides [R].

High LDL cholesterol is linked with potentially life-threatening cardiovascular diseases, including heart attack and stroke [R].

Increased Inflammation

ApoE may help balance the immune system and reduce inflammation. Macrophages (a type of white blood cell) may use ApoE to lower an overactive immune response. Meanwhile, mice with the 𝛆4/𝛆4 genotype experience a more severe inflammatory immune response than 𝛆3/𝛆3 mice when bacterial toxins are injected into their brains [R, R].

Chronic inflammation plays a key role in the development of many chronic diseases, including [R, R]:

• Heart disease
• Diabetes
• Autoimmune diseases
• Arthritis
• Allergies
• Inflammatory bowel disease (IBD)
• Cancer

Alzheimer’s Disease & Its Complications

Of course, the disease most famously linked with ApoE 𝛆4 is Alzheimer’s disease; people with even a single copy of 𝛆4 have a lifetime risk of AD of about 30%, compared to 9% for those with the 𝛆3/𝛆3 genotype [R].

Alzheimer’s disease is degenerative and fatal. It can shorten a person’s lifespan directly and through any number of associated complications. These complications include [R, R, R]:

• Swallowing disorders
• Pneumonia
• Flu
• Diabetes
• Dangerous falls

Many researchers suspect that Alzheimer’s disease is underreported as a cause of death; people with AD are much more likely to suffer from complications such as these, and the complications are reported as the direct cause of death [R, R].

If you have an APOE variety that doesn't work as well (APOE4), you can do a number of things to increase its production or function.  You should be promoting the following:

• Education: More years of education meant higher levels of APOE [R].
• Mental Exercises: Daily mental exercises (puzzles, reading, etc.) help stabilize APOE levels and prevent the decline of brain function [R].
• Diets High in Polyunsaturated Fats and Low in Carbohydrates:  Such as the Mediterannian diet or Ketogenic diet  [R].
• Lowering Cholesterol [R]- lowering serum cholesterol levels may reduce a person’s risk for Alzheimer’s disease, even if they have two ApoE4 alleles, thus reducing the risk from nine or ten times the odds of getting Alzheimer's down to just two times the odds.
• Cold Showers
• Fish oil/DHA
• Vitamin A/Retinol
• Curcumin
• Butyrate

APOE is decreased by inflammation but increased by TGF-beta.