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 or grandparents.

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

One way to understand your Alzheimer’s risk – and to understand the mechanisms by which the disease occurs – is to look at genetic variants that increase the risk for Alzheimer’s.  On the other hand, you can also learn a lot by looking at genetic variants that protect against Alzheimer’s.

Genetic variants that protect against Alzheimer’s disease:

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.

Even if you don’t carry the protective variants below, a lot can be gleaned from understanding how the variants work and why they decrease the risk of Alzheimer’s. This seems to be a relatively new field of research, but it is interesting to note that several of these protective genetic variants are involved in either cholesterol or lipid metabolism in the brain.

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. Unfortunately, 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.


Genetic variants that are protective against Alzheimer’s:

Members: Log in to see your data below.
Not a member? Join now.

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.

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

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

Members: Your genotype for rs63750847 is .

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

Members: Your genotype for rs7412 is .

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]

The RAB10 gene codes for a protein that is important in the structure of the endoplasmic reticulum, the organelle in cells that is important in the production of lipids. Specifically, RAB10 is also linked to the expression of CEPT1, which is an enzyme involved in the synthesis of choline-containing phospholipids. [ref]

HMGCR Gene:  

The HMGCR gene codes for the 3-hydroxy-3-methylglutaryl-CoA reductase enzyme. This is a key enzyme in cholesterol synthesis.[ref] While cholesterol is vital to brain function, it needs to be maintained at the right levels.

Check your genetic data for rs3846662 (23andMe v4, v5):

  • A/A: decreased risk of Alzheimer’s[ref][ref]
  • A/G: typical risk of Alzheimer’s
  • G/G: typical

Members: Your genotype for rs3846662 is .

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: typical

Members: Your genotype for rs8070723 is .

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: typical

Members: Your genotype for rs1476679 is .

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: typical

Members: Your genotype for rs11136000 is .

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: typical

Members: Your genotype for rs3851179 is .


Lifehacks for preventing Alzheimer’s:

There are currently no medications for curing Alzheimer’s disease, and research shows that preventative actions need to start decades before the onset of the disease.

Circadian rhythm, Sleep, and Light at Night:
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 and possibly half the risk of Alzheimer’s.[ref]

This is something to consider when adopting a ketogenic diet high in saturated fat, which 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 have some questions surrounding it, but the link between Alzheimer’s and cholesterol is something to consider 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 BMAA (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.

There seems to be a theme, though, in that substances that cause stress in the cells of the brain are linked with Alzheimer’s disease. This is true of metals such as aluminum, iron, copper, and zinc. [ref] Microbes and neuroinflammation are also implicated in Alzheimer’s pathology.[ref] Additionally, long -term psychological stress has also been linked to changes in the brain related to Alzheimer’s disease. [ref]


Related Genes and Topics:

NAD+
Explore the research about how nicotinamide riboside (NR) and NMN are being used to reverse aging. Learn about how your genes naturally affect your NAD+ levels, and how this interacts with the aging process.

Preventing Alzheimer’s
Billions of dollars have been spent in the last couple of decades has been spent on trying to find drugs to stop the tangled accumulation of beta-amyloid plaque without much success. A new direction of research is looking into the ties between circadian rhythm dysfunction and Alzheimer’s disease.

 

 


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.