A Klotho Gene Variant Reduces Alzheimer’s Risk for APOE E4 Carriers

A new study published in JAMA found that a Klotho gene variant significantly impacts the risk of Alzheimer’s disease in people who carry the APOE E4 variant. This is good news for a lot of people who carry the variant — and it also points to ways that we all can modify our lives to increase or protect Klotho levels as we age.

Alzheimer’s, APOE, and KLOTHO:

Quick APOE and Alzheimer’s overview:

APOE is a glycoprotein that binds to lipids (fats) and helps with the transport of cholesterol. It is especially important in the brain, where it is produced by astrocytes and moves cholesterol to the neurons.

There are three common forms of APOE, known as E2, E3, and E4.

People who carry the APOE E4 allele are at a higher risk of late-onset Alzheimer’s disease. In fact, this is the most well-studied variant for Alzheimer’s, with hundreds of studies on it over the last few decades. Importantly, though, the APOE E4 allele is not sufficient by itself to cause Alzheimer’s. While carrying two copies of the E4 allele is linked with a very high rate of Alzheimer’s, there are people carrying two copies who live to be in their 90’s without dementia. Similarly, there are many people without the APOE E4 allele who succumb to this terrible disease.

Researchers have looked at this question of why the APOE E4 allele is such a huge risk factor for some people, but yet not a complete cause of Alzheimer’s. They have investigated it from many angles– lifestyle factors, diet, toxins, infectious diseases, and more. And all of these seem to play some sort of a role in the risk of Alzheimer’s.

Klotho overview:

Klotho is a protein linked to longevity and cognitive function. It is named after the Greek goddess Clotho, one of the Three Fates who was the spinner of the thread of life.

The klotho protein was originally identified in mice who carried a mutation that caused accelerated aging. These mice were found to have a loss of function mutation in the klotho gene, which caused atherosclerosis, osteoporosis, muscle loss, kidney disease, and sagging skin – starting at 3 to 4 weeks of age. Likewise, creating a mouse strain that overexpresses the klotho gene causes a longer lifespan. [ref][ref] This holds true for humans and other mammals as well, with lower klotho levels linked to the signs and diseases of aging and klotho levels generally decreasing with age.

The klotho protein is found on the membrane of cells in specific parts of the kidneys and in the brain. In the kidneys, klotho regulates phosphorous and calcium levels and also acts as a co-receptor for fibroblast growth factor receptors.  Specifically, Klotho interacts with the fibroblast growth factor 23 (FGF23) to increase phosphate excretion and suppress vitamin D synthesis.[ref]  Basically, when the diet is high in phosphate, klotho causes lower active vitamin D (1,25 OH-D). [ref]

Within the brain, the region called the choroid plexus produces the most klotho protein. The choroid plexus is the area in the brain ventricles that produces cerebrospinal fluid, which is important for removing metabolic waste and other toxins from the brain. Researchers have found that within the choroid plexus, klotho helps to suppress inflammation in the brain through modulating vitamin D activation. [ref]

The latest research on how Klotho Variants affect Alzheimer’s:

I’m going to try to explain the recent study in the Journal of the American Medical Association (JAMA)  more thoroughly than usual because it is behind a paywall. (sigh). [ref]

The 24,000+ study participants were 60 years of age or older and Caucasian. Researchers looked at both APOE status and KLOTHO variants to see if there was an interaction with the risk of Alzheimer’s. The researchers used both population data, measures of amyloid-beta 42 in the cerebrospinal fluid, and brain imaging in the study. The study participants were groups by APOE type (E4 allele carriers, and non-E4 carriers) and evaluated across three age ranges (age 60+, age 60-80, and age 80+)

The results of the study showed that people with the APOE E4 allele were at an increased risk of Alzheimer’s, which is in line with all the other hundreds of studies on the gene.  But, people with both the KLOTHO VS variant and the APOE E4 were at less of an increased risk. In fact, carrying the KLOTHO VS variant reduced the risk of Alzheimer’s for APOE E4 carriers by 30% compared with E4 carriers without the KLOTHO variant. Additionally, the researchers found that PET scans showed decreased amyloid-beta in those who were both APOE E4 positive and carried the KLOTHO VS variant.

You may be wondering why the study only used people who were heterozygous (carried one copy) for the KLOTHO VS variant. I think it is due to the small percentage of the population that carries two copies of the variant. While up to 25% of most population groups carry one copy of the KLOTHO VS variant, less than 5% carry two copies. Considering how that would combine with the 20% of the population carrying APOE E4 alleles, and there would be a very small number who carry both two copies of the KLOTHO VS variant and the APOE E4 allele.

This recent study published in JAMA backs up the results of a 2019 study where the KLOTHO VS variant was also found to help mitigate the increased risk of the APOE E4 allele.  The previous study was quite a bit smaller but showed very similar results for both risk and amyloid-beta reduction. [ref]


Genetic variants:

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KL gene variant:

Check your genetic data for rs9536314 (23andMe v4; AncestryDNA):

  • G/G: increased klotho, increased lifespan, decreased cognitive decline in aging, known as KL-VS variant [ref][ref][ref]
  • G/T: increased klotho, known as KL-VS, Protective in people with the APOE E4 allele against the increase in the risk for Alzheimer’s[ref]
  • T/T: typical

Members: Your genotype for rs9536314 is .

APOE variants:

To determine the APOE genotype, you will need to look at your genotype combos for two different variants.
***Note: Certain versions of AncestryDNA data are not accurate for APOE genotyping.

APOE Allele rs429358

Members: Your genotype is .

rs7412

Members: Your genotype is .

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]

Lifehacks:

A variety of diet and lifestyle factors influence your risk of Alzheimer’s disease, and changes to your diet and lifestyle can help to prevent Alzheimer’s. Check out the full article on APOE variants for lots of prevention suggestions. 

What about boosting Klotho levels? While there are no specific studies showing that boosting klotho levels in people with APOE E4 will modify Alzheimer’s risk, it follows that increasing klotho may help and shouldn’t hurt.

Diet and Exercise:

Cordyceps mushrooms: Several studies show that cordyceps mushrooms may increase klotho levels.

  • An extract of cordyceps was tested on kidney cells. The cordyceps increased the expression of klotho.[ref]
  • An animal study also showed that cordyceps improved klotho protein levels in a mouse model that mimicked kidney problems. [ref]

Cordyceps mushroom extract is available as a powder, making it easy to add to any beverage.

Exercise increases klotho: A study on sedentary middle-aged adults found that exercise (moderate, high intensity, or high intensity plus electromyostimulation) all increased klotho plasma levels. There was no difference between the types of exercise. So get active to increase klotho. [ref][ref]

Animal studies show that melatonin helps to attenuate the damage to memory in mice that are bred to have low klotho levels. Melatonin was able to counteract the oxidative damage in the brain.[ref]  (Article – Light and Night and Alzheimer’s Prevention)

The level of phosphate in the diet may be important here. Mouse studies clearly show the interaction between klotho, high phosphate diet, and vitamin D.[ref]  What type of diet is a ‘high phosphate diet’? Basically that defines the Standard American Diet including soda and processed foods.  Processed meats and meats that have added fluids and flavors can increase phosphate levels, as can sports drinks and some flavored water. Fake cheese and processed baked goods often have phosphates added. [article] While I am not finding any human studies that link high phosphate diets, vitamin D, klotho, and Alzheimer’s, it is something to consider and keep an eye out for new research on.


Related Articles and Topics

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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.



Author Information:   Debbie Moon
Debbie Moon is the founder of Genetic Lifehacks. She holds a Master of Science in Biological Sciences from Clemson University and an undergraduate degree in engineering. Debbie is a science communicator who is passionate about explaining evidence-based health information. Her goal with Genetic Lifehacks is to bridge the gap between the research hidden in scientific journals and everyone's ability to use that information. To contact Debbie, visit the contact page.