Could You Live Longer if You Improve This Gene? (APOE)

The APOE gene provides instructions for the production of the ApoE protein, which helps transport fats (lipids) and cholesterol in particles called lipoproteins [R].

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].

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].

𝛆3 is the most common isoform of APOE. People with 𝛆2 are more likely to live longer, while people with 𝛆4 are more likely to develop life-shortening conditions like Alzheimer’s.

The link between APOE and longevity is clear, but how does it work?

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].

The 𝛆4 isoform of APOE predisposes its carriers to high cholesterol, heart disease, chronic inflammation, and Alzheimer’s disease, all of which can shorten a person’s lifespan.

Remember: if you have the 𝛆4 isoform, don’t panic! It’s better to know and to take steps to prevent Alzheimer’s disease, heart disease, and chronic inflammation.

SNP Summary and Table

Primary SNPs:

APOE rs429358

• ‘T’ = Will not produce 𝛆4, increased longevity
• ‘C’ = Produces 𝛆4, decreased longevity
• About 73% of people worldwide have the ‘TT’ genotype and no risk of 𝛆4

APOE rs7412

• ‘T’ = Produces 𝛆2, increased longevity
• ‘C’ = Will not produce 𝛆2, decreased longevity
• Only 14% of people worldwide have at least one ‘T’ allele (at least one 𝛆2)

But What Is My Isoform Genotype?

Because of the way commercial kits analyze your DNA, your data file will likely give your genotype at the two SNPs above, but may not directly report your 𝛆2/𝛆3/𝛆4 genotype. If you just want to know your relative likelihood of living a long life, check out the blue summary box above.

If you want to determine your isoform genotype in more detail, check your SNP table above and match your alleles with the following options:

• 𝛆4/𝛆4: rs429358-CC and rs7412-CC
• 𝛆3/𝛆4: rs429358-CT and rs7412-CC
• 𝛆3/𝛆3: rs429358-TT and rs7412-CC
• 𝛆2/𝛆3: rs429358-TT and rs7412-CT
• 𝛆2/𝛆2: rs429358-TT and rs7412-TT
• 𝛆2/𝛆4: rs429358-CT and rs7412-CT (may rarely be 𝛆1/𝛆3)

Technically, there are other possibilities, but they are extremely rare. For example, if you have a ‘C’ allele at rs429358 and ‘TT’ at rs7412, you have the so-called “missing allele,” 𝛆1. This isoform is so rare that researchers haven’t been able to effectively study it and don’t know what its effect is on human health [R, R].