Is Klotho the Key to Treating Alzheimer’s and Other Diseases of Aging?

illustration of Brain in bright colors

Since Biogen and Tokyo-based Eisai recently reported a massive failure in Alzheimer’s research for their drug aducanumab, scientists and industry watchers are scanning the tea leaves looking for other potential approaches to treating the disease. One that is of interest is a hormone called Klotho.

Dena Dubal, an assistant professor of neurology at the University of California, San Francisco (UCSF), has been studying Klotho since 2011. Findings include that mice engineered to produce additional Klotho live 30 percent longer than “normal” mice. But the hormone is also found in the brain, so Dubal originally began work to see how Klotho effected the mice’s ability to learn and remember.

One of the surprise findings was the hormone seemed to protect mice from the cognitive decline associated with Alzheimer’s disease. That original study was published in The Journal of Neuroscience in 2015. Dubal told The New York Times, “Their thinking, in every way that we could measure them, was preserved.”

And it wasn’t just a protective function, it seemed to improve cognitive function. Dubal told The New York Times, “I just couldn’t believe it—was it true, or was it just a false positive? But here it is. It enhances cognition even in a young mouse. It makes them smarter.”

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Other researchers believe Klotho may protect against other central nervous system diseases, including multiple sclerosis (MS) and Parkinson’s disease.

Although interesting, like much else in the field, there are no guarantees. Gwendalyn D. King, a neuroscientist at the University of Alabama at Birmingham, told The New York Times, “You’ve got all of this amazing stuff showing a really major impact, but we can’t really explain why. That’s where we’re stuck.”

Klotho, of course, isn’t the only area going on that looks promising—but may not be. Rudy Tanzi, Chair of the Cure Alzheimer’s Fund Research Leadership Group and the Kennedy Professor of Neurology at Harvard University and at Massachusetts General Hospital, is involved in research into a compound called Niagen (nicotinamide riboside or NR). NR is a member of the vitamin B3 family. Cells in the body use NR to create nicotinamide adenine dinucleotide (NAD+), which is essential to cellular energy generation and metabolism.

One of the results of aging is a decline of NAD. It plays significant roles in cellular metabolism, energy production, maintaining healthy mitochondria, and promotion of cellular repair.

The theory here is that it’s not the accumulation of beta-amyloid in the brain that does the most damage in Alzheimer’s, it’s the resultant inflammation and immune reaction to it that causes the damage that results in cognitive decline. And by bolstering cellular energy via the mitochondria in the brain’s immune cells, microglial cells, they more effectively fight off the damage and inflammation.

In an interview with BioSpace earlier this year, Tanzi said, “If you increase ATP levels, it continues doing a better job of clearing beta-amyloid. And it’s less likely to become neuroinflammatory. So when we talk about resilience of cells, it’s often about how much energy the cell has.”

And just this week, researchers with the Boston University School of Medicine discovered two rare genes associated with Alzheimer’s disease. One variant is in the NOTCH3 gene and the other is in the TREMN2 gene. The NOTCH3 variant hasn’t been linked to Alzheimer’s before, although mutations in the gene cause a rare type of dementia called CADASIL. Mutations in the TREM2 gene have been linked with Alzheimer’s, and it was also known that people with two copies of the Q33X mutations in the TREM2 gene have a very rare disease called Nasu-Hakola disease, characterized by dementia in midlife and polycystic bone lesions with fractures.

“Our findings indicate that different mutations in the same gene or different number of copies of a particular mutation may lead to very distinct forms of dementia,” stated Lindsay Farrer, chief of the Biomedical Genetics division at Boston University School of Medicine and corresponding author of the study. “Discovery of associations of Alzheimer’s risk with rare genetic variants can lead to new insights about biological pathways involved in AD and strategies for developing novel treatments and biomarkers.”

Which goes back to the hormone Klotho. There are people who have a genetic variation that leads to higher levels of Klotho. Dubal and her team found they scored better on cognitive tests and stayed that way as they aged. “It’s not like they didn’t undergo cognitive decline,” Dubal told The New York Times. “It’s just that they started off higher.”

Further, Dubal and her colleagues looked at a known Alzheimer’s genetic variant, APOE e4. People with this mutation are more susceptible to developing Alzheimer’s disease, although they don’t always do so. Dubal found that these people had indications they were building beta-amyloid clumps in their brains. But when they evaluated people with both APOE e4 and increased Klotho, there were no additional clumps of protein.

“Maybe,” Dubal says, “their brains are biologically younger.”

They published their research in the journal Neurology.

Will any of these lead to preventions or cure for Alzheimer’s? Or in the case of Klotho, lead to people taking the hormone to improve their brain power?

It’s still early. But each discovery—and clinical trial failure—leads a step closer to solutions.

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