Alzheimer’s Genes: APOE

One very important gene that has been extremely well researched for Alzheimer’s disease is the APOE gene. This gene is involved in carrying cholesterol and other fats in your bloodstream, and a common variant of the gene is strongly linked to a higher risk of Alzheimer’s.[ref]

Late-onset Alzheimer’s disease (after age 60) is influenced both by genes and environmental factors. So keep in mind when looking at your genetic risk that your genes are only one part of the equation for Alzheimer’s.

Knowing your risk can help you understand the importance of doing all that you can to prevent Alzheimer’s disease.

APOE Variants:

Your APOE type is defined as combinations of three different alleles (ε2, ε3, or ε4), and you will have one APOE allele from each parent.

The NIH website explains:

  • APOE ε2 is not very common and is associated with a decreased risk of Alzheimer’s.
  • APOE ε3 is the most common allele and neither increases nor decreases the risk of Alzheimer’s.
  • APOE ε4 is found in about 15% of the population and increases the risk of Alzheimer’s disease. About 40% of people with Alzheimer’s carry this allele.

Determining APOE Variants from 23andMe Data:

To determine your APOE type from your 23andMe data or another source, you will need to look at the following two rs id’s: rs429358 and rs7412.

AncestryDNA data should not be used for determining APOE type. There is a known error in the APOE gene data for certain years of data.[ref]

APOE Allele rs429358 rs7412 Risk of Alzheimer’s
ε2/ε2 T/T T/T lower risk
ε2/ε3 T/T C/T lower risk
ε2/ε4 C/T C/T slightly higher risk than normal
ε3/ε3 T/T C/C normal risk
ε3/ε4 C/T C/C higher than normal risk
ε4/ε4 C/C C/C highest risk[ref]

Help! I don’t understand this chart (video explanation).

Again, your genetic risk isn’t the only factor involved in getting Alzheimer’s Disease. Some people who have the highest risk factors will never get the disease.

Environmental factors play a role, and other genes could add to or decrease your risk. Check out my article on genetic mutations that decrease the risk of Alzheimer’s.

Other genes add a little bit to your risk for Alzheimer’s, and rare mutations found in a small percentage of the population significantly increase the risk.

Thus, your APOE type isn’t the complete picture, but it is (by far!) the most significant genetic risk factor for Alzheimer’s disease.


Lifehacks:

If you are at an increased risk for Alzheimer’s, the key is to use this knowledge to do all that you can to decrease your risk.

Below are a few of the studies I’ve read through on the topic. It is not an exhaustive list by any means, and I highly encourage you to keep up to date with current information on the topic.

Alzheimer’s Prevention: Circadian Rhythms, Sleep, and Melatonin

Number one on my list for preventing Alzheimer’s is to block blue light at night with some nerdy-looking orange glasses. It helps to boost melatonin and has increased my sleep quality.

Many have found a link between sleep quality and the risk of dementia or Alzheimer’s.[ref] Our natural circadian rhythm causes melatonin to rise in the evening and stay elevated until morning. Light in the shorter, blue wavelengths signals through receptors in our eyes to turn off melatonin production in the morning. Our modern reliance on lights at night, especially from TVs and phones, disrupts natural circadian rhythms.

Blue-blocking glasses, worn in the evening for several hours before bed, have increased natural melatonin production by about 50% in just two weeks.[ref]

Research studies show a strong connection between circadian rhythm disruption, melatonin, insulin regulation, and healthy brain aging.[ref][ref][ref]

Trials are also evaluating the use of melatonin supplements for Alzheimer’s.[ref]

Read more about Light at Night and Alzheimer’s Risk

Alzheimer’s Prevention: Lifestyle changes

Exercise:
Staying active, eating well, and keeping your blood pressure low should lower your risk of Alzheimer’s.[ref]

NSAIDs:
Inflammation in the brain is one contributor to Alzheimer’s pathology. Several studies show that both aspirin and non-aspirin NSAID use reduced the risk of Alzheimer’s Disease. Keep in mind that these are population-wide studies that don’t consider genetic differences; you also need to weigh the risk of liver damage from long-term NSAID usage.[ref][ref][ref] Check your CYP2C9 and CYP2C8 genes also. These enzymes are involved in the metabolism of some NSAIDs, such as ibuprofen.

Cardiovascular Health:
There have been several studies that link cardiovascular health markers to the risk of Alzheimer’s. One study showed an elevated homocysteine level was associated with a higher risk of Alzheimer’s.[ref]

MTHFR and homocysteine:
Homocysteine levels are often genetically related to your MTHFR genes, methylation, and your B2, B6, and B12 levels. Overall, though, carrying the MTHFR variant doesn’t seem to be a risk factor for Alzheimer’s unless homocysteine is high. Test your homocysteine level to see if it is high.

Decrease Alcohol Consumption in late life with APOE ε4
A 2014 study found that for older adults who carry the APOE ε4 polymorphism, light to moderate drinking increased their risk for cognitive decline. From the study: “Light and moderate alcohol consumption during late life were associated with greater decline in learning and memory among APOE ε4 carriers, whereas light and moderate alcohol consumption were associated with an increase in learning and memory among non-APOE ε4 carriers. There was no significant interaction between midlife alcohol consumption status and APOE ε4 on the trajectory of learning and memory.[ref]

Focus on Liver Health:
Check out how the liver and bile acids are important in Alzheimer’s prevention on Longevity Lifehacks.

Supplements that may help in Alzheimer’s prevention

Antioxidants
There have been many studies on antioxidants and Alzheimer’s disease; unfortunately, most are contradictory or inconclusive. Eating a healthy diet is, of course, essential for brain health.

Luteolin:
Luteolin, a flavonoid found in fruits and vegetables, has been studied recently with interesting potential for Alzheimer’s via reducing neuroinflammation.[refRead more about luteolin on Longevity Lifehacks.

Lithium Orotate:
One mineral tied to a reduced risk of Alzheimer’s is lithium. Lithium is naturally found in food sources; most people consume between 0.1 and 3 mg/day from food. Lithium can be purchased as a mineral supplement in 5 mg doses. (Note, this is a much, much lower dose than is used in the lithium carbonate prescription medication for bipolar disorder.)

Epidemiological studies show that higher lithium levels in drinking water may help protect against dementia. A clinical trial showed that low lithium doses helped AD patients have no decrease in cognitive impairment over 15 months.[ref]  There are interactions between lithium and several prescription drugs, so always check before starting any supplement. Here is another source that looks at several studies on lithium.

Related article: Lithium Orotate: Mood, Alzheimer’s, and Aging


Related Articles and Genes:

Genetic Mutations that Protect Against Alzheimer’s Disease
Alzheimer’s disease is a scary possibility that faces many of us today — whether for ourselves or aging parents and grandparents. Currently, 10% of people aged 65 or older have Alzheimer’s disease (AD).  It is a disease for which prevention needs to start decades before the symptoms appear.

Alzheimer’s and Light at Night: Taking action to prevent this disease
With the advent of consumer genetic testing from 23andMe, AncestryDNA, etc., it is now easy to know if you are at a higher risk of getting Alzheimer’s Disease (AD). Those with APOE-ε3 are at normal risk for Alzheimer’s, and those who carry an APOE-ε4 allele (or two) are at an increased risk.

TREM2 and Alzheimer’s Disease Risk:
Another important gene to check for Alzheimer’s risk is TREM2. Uncommon variants in this gene affect your brain’s immune response.

Serotonin 2A receptor variants: psychedelics, brain aging, and Alzheimer’s disease
Learn how new research on brain aging and dementia connects the serotonin 2A receptor with psychedelics, brain aging, and Alzheimer’s.

References:

“Alzheimer’s Disease Genetics Fact Sheet.” National Institute on Aging, https://www.nia.nih.gov/health/alzheimers-disease-genetics-fact-sheet. Accessed 29 Apr. 2022.

APOE – SNPedia. https://www.snpedia.com/index.php/APOE. Accessed 29 Apr. 2022.

Bessone, Fernando. “Non-Steroidal Anti-Inflammatory Drugs: What Is the Actual Risk of Liver Damage?” World Journal of Gastroenterology : WJG, vol. 16, no. 45, Dec. 2010, pp. 5651–61. PubMed Central, https://doi.org/10.3748/wjg.v16.i45.5651.

Downer, Brian, et al. “The Relationship between Midlife and Late Life Alcohol Consumption, APOE E4 and the Decline in Learning and Memory among Older Adults.” Alcohol and Alcoholism (Oxford, Oxfordshire), vol. 49, no. 1, Feb. 2014, pp. 17–22. PubMed, https://doi.org/10.1093/alcalc/agt144.

Farrer, L. A., et al. “Effects of Age, Sex, and Ethnicity on the Association between Apolipoprotein E Genotype and Alzheimer Disease. A Meta-Analysis. APOE and Alzheimer Disease Meta Analysis Consortium.” JAMA, vol. 278, no. 16, Oct. 1997, pp. 1349–56.

in ’t Veld, Bas A., et al. “Nonsteroidal Antiinflammatory Drugs and the Risk of Alzheimer’s Disease.” New England Journal of Medicine, vol. 345, no. 21, Nov. 2001, pp. 1515–21. Taylor and Francis+NEJM, https://doi.org/10.1056/NEJMoa010178.

Jenwitheesuk, Anorut, et al. “Melatonin Regulates Aging and Neurodegeneration through Energy Metabolism, Epigenetics, Autophagy and Circadian Rhythm Pathways.” International Journal of Molecular Sciences, vol. 15, no. 9, Sept. 2014, pp. 16848–84. PubMed Central, https://doi.org/10.3390/ijms150916848.

Kim, Mari, et al. “Short-Term Exposure to Dim Light at Night Disrupts Rhythmic Behaviors and Causes Neurodegeneration in Fly Models of Tauopathy and Alzheimer’s Disease.” Biochemical and Biophysical Research Communications, vol. 495, no. 2, Jan. 2018, pp. 1722–29. PubMed, https://doi.org/10.1016/j.bbrc.2017.12.021.

Metformin | Cognitive Vitality | Alzheimer’s Drug Discovery Foundation. http://www.alzdiscovery.org/cognitive-vitality/condition/lithium-drug-treatments. Accessed 29 Apr. 2022.

Nunes, Marielza Andrade, et al. “Microdose Lithium Treatment Stabilized Cognitive Impairment in Patients with Alzheimer’s Disease.” Current Alzheimer Research, vol. 10, no. 1, Jan. 2013, pp. 104–07. PubMed, https://doi.org/10.2174/1567205011310010014.

Paterniti, Irene, et al. “Neuroprotection by Association of Palmitoylethanolamide with Luteolin in Experimental Alzheimer’s Disease Models: The Control of Neuroinflammation.” CNS & Neurological Disorders Drug Targets, vol. 13, no. 9, 2014, pp. 1530–41. PubMed, https://doi.org/10.2174/1871527313666140806124322.

Rovio, Suvi, et al. “Leisure-Time Physical Activity at Midlife and the Risk of Dementia and Alzheimer’s Disease.” The Lancet Neurology, vol. 4, no. 11, Nov. 2005, pp. 705–11. www.thelancet.com, https://doi.org/10.1016/S1474-4422(05)70198-8.

Seshadri, Sudha, et al. “Plasma Homocysteine as a Risk Factor for Dementia and Alzheimer’s Disease.” New England Journal of Medicine, vol. 346, no. 7, Feb. 2002, pp. 476–83. Taylor and Francis+NEJM, https://doi.org/10.1056/NEJMoa011613.

Shechter, Ari, et al. “Blocking Nocturnal Blue Light for Insomnia: A Randomized Controlled Trial.” Journal of Psychiatric Research, vol. 96, Jan. 2018, pp. 196–202. PubMed, https://doi.org/10.1016/j.jpsychires.2017.10.015.

Shi, Le, et al. “Sleep Disturbances Increase the Risk of Dementia: A Systematic Review and Meta-Analysis.” Sleep Medicine Reviews, vol. 40, Aug. 2018, pp. 4–16. PubMed, https://doi.org/10.1016/j.smrv.2017.06.010.

Shukla, Mayuri, et al. “Mechanisms of Melatonin in Alleviating Alzheimer’s Disease.” Current Neuropharmacology, vol. 15, no. 7, 2017, pp. 1010–31. PubMed, https://doi.org/10.2174/1570159X15666170313123454.

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About the Author:
Debbie Moon is the founder of Genetic Lifehacks. Fascinated by the connections between genes, diet, and health, her goal is to help you understand how to apply genetics to your diet and lifestyle decisions. Debbie has a BS in engineering and also an MSc in biological sciences from Clemson University. Debbie combines an engineering mindset with a biological systems approach to help you understand how genetic differences impact your optimal health.