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 for aging parents and grandparents.

Currently, 10% of people age 65 or older have Alzheimer’s disease (AD).  It is a disease for which prevention needs to start decades before the symptoms appear.[ref]

Genes that protect against Alzheimer’s:

Genes combine with environmental exposure and lifestyle to determine your risk for Alzheimer’s disease. There are genetic variants that increase your risk for Alzheimer’s disease. Other variants decrease your risk for the disease.

This article focuses on that protective side of the equation, something that many people worried about AD fail to consider.

Most Alzheimer’s research focuses on the accumulation of amyloid-β plaque and the tangled tau fibrils. These proteins lead to the death of neurons in the brain.

Thirty plus years of research and clinical drug trials on amyloid-β have shown very few positive results.

Amyloid-β is a protein formed when enzymes cut the APP (amyloid precursor protein) protein into smaller fragments. Some of the protein fragments move out of the brain. But amyloid-β that isn’t cleared can build up around neurons, forming plaque.

APP gene:

Early-onset or familial Alzheimer’s occurs before the age of 65. Researchers discovered almost 50 mutations in the APP gene that cause early-onset Alzheimer’s.

Not all APP mutations are bad. Researchers discovered an APP mutation that is protective against getting Alzheimer’s. Less than 0.1% of the population carries this rare variant. The mutation is more common in people from Iceland, Norway, and Sweden than the rest of the world.

Check your genetic data for rs63750847 (23andMe v4 only, AncestryDNA):

  • T/T: resistance to Alzheimer’s disease[ref][ref]
  • C/T: reduced risk of Alzheimer’s disease
  • C/C: normal

APOE gene:

Researchers connect the APOE gene with Alzheimer’s risk. APOE (apolipoprotein E) is a lipoprotein that transports cholesterol to the neurons. In the brain, APOE binds and clears amyloid-β protein.

There are three different forms of APOE -ε2, ε3, and ε4.  APOE ε4 causes a significant increase in the risk of Alzheimer’s. (Check it here, if you want to know.) But the APOE ε2 version decreases the risk of AD.

About 10% of the population carries the APOE ε2 allele, which slows the accumulation of amyloid-beta in the brain.[ref]

Check your genetic data for rs7412 (23andMe v4, v5; AncestryDNA):

  • T/T: two APOE ε2 alleles, protective against Alzheimer’s[ref][ref]
  • C/T: one APOE ε2 allele, protective against Alzheimer’s
  • C/C: no APOE ε2 allele

RAB10 Gene:

In 2017, a research study showed that a variant in the RAB10 gene protects carriers against getting Alzheimer’s disease. The rs142787485 G-allele, found in about 3% of the population, cuts the risk of Alzheimer’s in half. (This is not covered in 23andMe or AncestryDNA data).[ref]

Other genes:

There are also several genetic variants that slightly decrease the risk of Alzheimer’s. Most of these decrease the risk by 10-15%.

Check your 23andMe data for rs8070723 (23andMe v4, v5; AncestryDNA):

  • G/G: 10% reduction in risk of Alzheimer’s disease (+ greatly reduced risk of Parkinson’s)[ref]
  • A/G: 10% reduction in risk of Alzheimer’s disease
  • A/A: normal

Check your genetic data for rs1476679 (23andMe v5 only; AncestryDNA):

  • C/C: slightly decreased risk of Alzheimer’s[ref][ref]
  • C/T: slightly decreased risk of Alzheimer’s
  • T/T: normal

Check your genetic data for rs11136000 (23andMe v4, v5; AncestryDNA):

  • C/C: slightly decreased risk of Alzheimer’s[ref]
  • C/T: slightly decreased risk of Alzheimer’s
  • T/T: normal

Check your genetic data for rs3851179 (23andMe v4,v5;  AncestryDNA):

  • C/C: slightly decreased risk of Alzheimer’s[ref]
  • C/T: slightly decreased risk of Alzheimer’s
  • T/T: normal

 


Lifehacks:

I’ve written before on the links between circadian rhythm disruption and Alzheimer’s disease as well as other lifehacks that may help with prevention.

Cholesterol:
Lower cholesterol levels may decrease the risk of Alzheimer’s. This protective effect comes from having lower cholesterol throughout life. People who carry certain PCSK9 variants have lower lifetime cholesterol.[ref]

This is something to consider when adopting a ketogenic diet that may cause an increase in cholesterol. Some people argue that there is no need to worry when their cholesterol level rises with a high-fat diet. The link between cholesterol and cardiovascular disease may be questionable.  But the link between Alzheimer’s and cholesterol is one to take into consideration as well.

Other causes?
Some researchers are pursuing alternatives to the amyloid-beta theory as the cause of neurodegenerative diseases. A researcher named Dr. Paul Cox has been pursuing the idea that the incorporation of BMA/A (a neurotoxin found in cyanobacteria) into the brain in place of the amino acid serine is causing neurodegenerative diseases such as Alzheimer’s, ALS, and Parkinson’s.

There are clinical trials going on now to determine if supplementing with l-serine will help ALS patients. Here is a good article in Fortune on Paul Cox’s work: Could This Radical New Approach to Alzheimer’s Lead to a Breakthrough?

Whether the serine hypothesis is correct or not remains to be seen. People interested in preventing Alzheimer’s may want to keep an eye out for new research on the topic.

More to read:

Alzheimer’s and Light at Night: Taking action to prevent this disease

Alzheimer’s and APOE genotype

 

 

 



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6 Comments on “Genetic Mutations that Protect Against Alzheimer’s Disease

  1. As far as I know, Alzheimer’s is indeed a possibility for me given my grandparents’ condition in the past and my parents’ slow progression to displaying symptoms of the disease. It’s a good thing you mentioned that the APOE gene can be connected with being at risk in getting it so I might get my genes tested to see if I am at risk. Since all I need to watch out is the APOE ε4 variant, I’ll find a clinic that can detect that so that I can prepare when I get older.

    • I was a bit confused by your comment here, but now I see that you are simply commenting as a way to link back to your Alzheimer’s testing and research group website.

  2. I am APOE 3/4 (per 23 and Me raw data) and need to find out if I have gene mutations that might decrease my risk and what supplements and actions I can take to offset my risk (besides the obvious of exercising, keeping cholesterol down, keeping diabetes away). I have read a lot, but it’s so confusing and scary.

    • Hi Linda,
      The things that you mentioned – exercise, good diet, blood glucose control – have all been shown to be important in preventing Alzheimer’s.
      I’ve read through a lot of research on Alzheimer’s and prevention of it. One thing that struck me as an underlying cause is that a lot of the changes in the brain are all related to circadian rhythm. Here is an article that I’ve written on how circadian rhythm disruption plays a causal role in Alzheimer’s: Alzheimer’s and Light at Night: Taking action to prevent this disease
      I think that one part of the modern Alzheimer’s epidemic is the change that electric lighting has brought — physically changing melatonin production and circadian rhythm. Where I’ve chosen to focus, then, isn’t on supplements but on blocking out blue light at night and increasing melatonin.
      Thanks for reading and commenting! Let me know if you want more information on circadian rhythm and Alzheimer’s.
      Debbie

  3. I think that there should be the distinction that high levels of LDL cholesterol can be the contributor, b/c it causes sticky plaques to form and those are the plaques that can travel up the spine and to the brain. A build up of sticky plague in brain with insufficient clearing over a long period of time, is one of the biggest factors. It causes inflammation & a myriad of issues that impact the brain and inhibit acetyl choline formation. It’s not the only factor (sugar and insulin spikes, high homocysteine, and other things hasten the situation, as well) – You want to keep your total cholesterol under 200 & if HDL is higher, that’s a bonus. HDL helps to thwart sticky plaque buildup in any part of the body while high LDL does the opposite) – Even if you are under 200 as a total, you still want to ensure that your LDL is not over 100. I’ve read that turmeric can help to thwart sticky plaque buildup, as well as foods that lower LDL, but i’m not positive.

    • Hi Tamara,
      Thanks for reading and posting a comment here. I spent a little time poking through the research on Alzheimer’s and LDL this afternoon. There are a few studies that find a very modest increase in risk for Alzheimer’s from both very low LDL and very high LDL. But the increase in relative risk is pretty minor, especially when compared to the increase in risk from APOE E4 alleles.
      Here is one of the recent studies on the topic: https://www.ncbi.nlm.nih.gov/pubmed/30289959
      Debbie

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