Certain Gene Might Help Shield At-Risk People From Alzheimer's

MONDAY, April 13, 2020 (HealthDay News) -- People who carry a gene called APOE4 face an increased risk of Alzheimer's. But that effect may be lessened if they got luckier with a different gene, researchers have found.

Scientists have long known that the APOE gene is the strongest genetic influence over whether people develop Alzheimer's late in life. Those who carry a form of the gene called E4 have a higher-than-average risk.

However, not all APOE4 carriers develop Alzheimer's -- and it's important to understand what protects those people, said study co-author Dr. Michael Greicius, an associate professor of neurology at Stanford University School of Medicine in California.

Based on his team's findings, a lot may ride on another gene, called klotho. Among APOE4 carriers, those who also have a "protective" form of klotho are 30% less likely to develop Alzheimer's by age 80.

Neurologist Dr. Dena Dubal said it suggests that the klotho variant can help the brain "altogether avert harmful effects of APOE4."

Dubal is an associate editor of JAMA Neurology, which published the study online April 13. She authored an editorial accompanying the findings.

The klotho gene is named for a Greek Fate and daughter of Zeus, who was said to spin the thread of life. It's so-called because recent studies have revealed the gene to be important in healthy aging, in lab mice and in people.

"It's basically a longevity gene," said Greicius.

What's not clear, he said, is exactly how klotho counteracts some of the harm of APOE4. If researchers can figure that out, Greicius added, it could potentially lead to new treatments or ways to prevent Alzheimer's.

We all inherit two copies of every gene -- one from each parent. In the United States, about 25% of the population carries one copy of APOE4, and their Alzheimer's risk is three to four times higher than average, according to the U.S. National Institute on Aging. A small percentage carries two copies, and their risk is higher still.

With klotho, Greicius explained, it's best to inherit just one copy of the protective form. That seems to boost levels of klotho protein in the blood. What's more, people who carry one copy tend to live longer and healthier, versus those who carry either two copies or none.

It turns out that the ideal klotho scenario is just as common as the APOE4 gene variant: About one-quarter of Americans carry one copy of the protective form of the gene, according to Greicius.

For the current study, his team combed through publicly available research databases, collecting data on more than 20,000 people age 60 and up -- some with Alzheimer's, some with milder impairment, and some with intact thinking and memory skills.

Among APOE4 carriers, those who also had one copy of the protective klotho variant were 30% less likely to develop Alzheimer's by age 80. There was no evidence, however, that the klotho variant protected people who did not carry the APOE4 variant.

"That suggests to us there could be an interaction between the klotho variant and APOE4," Greicius said.

It will be important to understand what is going on, Dubal said. At this point, she noted, there are some clues from animal research: In lab mice, higher klotho levels boost brain function.

"Maybe klotho, along with a healthy lifestyle, could be an effective treatment for APOE4 carriers in staving off Alzheimer's," Dubal speculated. "We need more work down this pathway."

It does seem logical that raising klotho levels in the body could be beneficial, Greicius agreed. However, he stressed, no one knows if that's actually the case.

The findings raise another question: Should APOE4 carriers be tested for their klotho genotype? Greicius said he thinks more research is needed first.

That point was echoed by Rebecca Edelmayer, director of scientific engagement for the Alzheimer's Association.

"I don't think this is something you can talk to your doctor about today -- though it may be in future," Edelmayer said. She noted that researchers are continuing to dig into the genetics of Alzheimer's, and it may well turn out that other genes (and gene interactions) are key to the puzzle, too.

And then there are lifestyle measures: a healthy diet, exercise, controlling health conditions like high blood pressure and diabetes, and challenging the mind with mentally engaging activities. Research suggests that in general, those things can help protect the aging brain, Edelmayer said.

More information

The U.S. National Institute on Aging has more on the genetics of Alzheimer's.

SOURCES: Michael Greicius, M.D., M.P.H., associate professor, neurology, and director, Stanford Center for Memory Disorders, Stanford University School of Medicine, California; Dena Dubal, M.D., Ph.D., associate editor, JAMA Neurology, and associate professor, neurology, University of California, San Francisco; Rebecca Edelmayer, Ph.D., director, scientific engagement, Alzheimer's Association, Chicago; April 13, 2020, JAMA Neurology, online

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