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.

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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 the protective side of the equation, something many people worry about AD fails 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.

Alzheimer’s Protection Genotype Report:

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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 —.

APOE mutations that are rare and protective against Alzheimer’s:
A study in JAMA recently showed that two rare mutations are protective against Alzheimer’s, decreasing the risk by more than half.[ref] Please keep in mind that AncestryDNA and 23andMe raw data files aren’t guaranteed to be clinically accurate, so a false positive or false negative is possible with rare mutations.

Check your genetic data for rs199768005 V236E (23andMe v4 i5000207):

A/T: one copy of a rare mutation that significantly decreases the risk of Alzheimer’s[ref][ref]
T/T: typical (no protective mutation)

Members: Your genotype for rs199768005 is — or for i5000207 is —.

Check your genetic data for rs267606661 R251G (23andMe v4 i5000206):

C/G: one copy of a rare mutation that significantly decreases the risk of Alzheimer’s[ref]
C/C: typical (no protective mutation)

Members: Your genotype for rs267606661 is — or for i5000206 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 —.

Additional genes that slightly decrease risk:

There are also several genetic variants that researchers have identified as slightly decreasing the relative risk of Alzheimer’s. I’ve included them here so that you can see the variety of genetic pathways involved in preventing Alzheimer’s disease.

MAPT gene: microtubule-associated protein tau. Rare mutations in this gene are associated with neurodegenerative disorders, while common variants may give slight protection against neurodegenerative disorders.

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 —.

ZCWPW1 gene: histone methylation reader

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 —.

CLU gene: encodes a protein found in the brain thought to be involved in cell death and neurodegenerative disorders.

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 —.

PICALM gene: involved in the regulation of the amyloid precursor protein

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 —.

CHI3L1 gene: encodes a glycoprotein important in neuroinflammation.[ref]

Check your genetic data for rs4950928 (23andMe v4,v5; AncestryDNA):

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

Members: Your genotype for rs4950928 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.

Download my free eBook on Alzheimer’s prevention

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Genetic Mutations that Protect Against Alzheimer’s Disease