June 5, 2020

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Longevity Gene May Protect against a Notorious Alzheimer’s Risk Gene

Consumer genetic tests can sometimes result in a terrible surprise appearing in the same report...

Consumer genetic tests can sometimes result in a terrible surprise appearing in the same report that divulges whether one has a cilantro aversion or wet or dry earwax. Test takers may receive the devastating news that they have a version of a gene—apolipoprotein E epsilon 4 (APOE e4)—that greatly increases their chances of getting Alzheimer’s disease. The shock can be so great that some will seek solace in a support group to help them adjust to the possibility that they could run into cognitive problems beginning in their 50s or 60s.

One thing that makes the information so difficult to absorb is that there is no certainty about it. A person with one copy of the APOE e4 gene is more than three times as likely to wind up with Alzheimer’s (one copy can be inherited from each parent). A hit of two copies increases the risk by 10 times or more. APOE e4 may also reduce the age of the disease’s onset by up to a decade.

Still, not everyone who is an APOE e4 carrier will ultimately receive a diagnosis for Alzheimer’s, the most common form of dementia. Given the ambiguities, scientists have long wondered whether other genes might counterbalance APOE e4’s effects. A new paper may have found a candidate for just such a gene.

An analysis across multiple studies—with results from more than 20,000 individuals—found that APOE e4 carriers between the ages of 60 and 80 who also had a particular variant of a gene called klotho (named for Clotho, one of the Greek Fates, who spins the thread of life) were 30 percent less likely to receive an Alzheimer’s diagnosis than carriers without it. People in their late 70s with a single copy of the klotho variant were also less apt to experience the initial cognitive losses (mild cognitive impairments) that often precede an Alzheimer’s diagnosis. Study participants with the relevant variant also had reduced signs of the hallmark clumps of beta-amyloid protein that turn up in the brain before symptoms arise.

The new study was published on Monday in JAMA Neurology. Two smaller investigations conducted in recent years had looked at whether klotho, a purported longevity gene, might provide some benefit for APOE e4 carriers. One of those studies affirmed that the gene variant did so, and the other suggested the opposite. Michael Greicius—senior author of the JAMA Neurology paper, an associate professor of neurology at Stanford University and medical director of the Stanford Center for Memory Disorders—had been considering doing research on klotho when he learned of the study with negative results. “I was kind of prepared to throw in the towel,” he says. “But Michael Belloy [of Stanford], the first author on the [new] paper, had already gotten his teeth into this, thankfully. And we got all of these data sets about these APOE e4 interactions. And [they are] really quite strong and consistent.”

The klotho variant studied by Greicius and his Stanford colleagues is not rare. Of the 10,000 subjects with at least one copy of APOE e4 examined by the researchers within the larger data compilation, there were 2,700 who carried the advantageous variant. APOE e4 is not uncommon either: the gene turns up in at least 15 to 20 percent of the population. It is present, however, in about half of the more than five million Alzheimer’s cases in the U.S.

The new finding may add precision to the design of clinical trials and could potentially provide ideas for therapeutics. APOE e4 carriers are sometimes recruited for studies of drugs to prevent Alzheimer’s because of the likelihood that they will get the disease. Excluding carriers who have the klotho variant might ensure that the pool of study participants is truly at high risk, as intended. Greicius and his colleagues’ conclusions might also lead to new drug targets. “The whole pathway of proteins that involve klotho and its interaction with APOE e4 is now worth pursuing,” he says.

Other scientists who were not involved with the research agree that the new results warrant taking a closer look at klotho. “I think these are important findings, and this genetic variant should be considered for incorporation into ongoing and future clinical research related to [Alzheimer’s],” says David M. Holtzman, a professor and chair of the department of neurology at Washington University School of Medicine in St. Louis. He says that human-, animal- and cell-based research should now investigate why the klotho variant may partially protect APOE e4 carriers—and whether it might help early or late in the course of the disease. New studies must also focus on people who are not of northwestern European descent, as were those in the Stanford paper.

“I think this is an exciting finding,” says Guojun Bu, who researches the APOE gene and is a professor and chair of the department of neuroscience at the Mayo Clinic. He points out that whereas klotho is considered a longevity gene, APOE e4 has been found to shorten life spans in humans—even when its link to Alzheimer’s was discounted. But scientists have suspected that there are other genes that protect against its ill effects. In the case of klotho, a longevity gene may be countering an antilongevity one.

The Stanford study, Bu says, needs support from other research that examines klotho levels in both blood and cerebrospinal fluid and compares them with various measures of Alzheimer’s biomarkers and pathology. Mice carrying a human version of the APOE e4 gene might also be used to look for relevant biological pathways that could explain these findings. And even some behavioral factors could be scrutinized. “As several lifestyle factors, including exercise and diet, are known to protect against APOE e4–related risk,” Bu says, “it would also be interesting to examine whether they alter the levels of klotho as a potential underlying mechanism.”

Dena Dubal, a klotho researcher who is an associate professor at the University of California, San Francisco, and an associate editor for JAMA Neurology, co-authored an accompanying commentary that called for further research on questions such as whether the gene could diminish APOE e4’s disruption of cellular and brain-network activity. “The study carries exciting implications for future therapies,” she says. “One wonders whether giving a boost of the klotho hormone itself, which drops in aging and Alzheimer’s disease, could be a new treatment for individuals in preventing or treating Alzheimer’s disease.”