Common gene variant may protect against Alzheimer's

A common gene variant associated with long life also improves learning and memory, according to a team of researchers at the Gladstone Institutes and University of California, San Francisco.

The KL gene that produces the protein klotho - named after a Greek "Fate" who is said to spin the thread of life - was first discovered in 1997. About 20% of the population carry a variant of this gene called KL-VS. This variant is known to reduce age-related cardiovascular disease. But this is the first time that KL-VS has been linked to improved cognition.

In three separate studies, spanning a period of 3 years, the researchers - who published their work in the journal Cell Reports - tested associations between KL-VS and age-related human cognition. More than 300 participants aged between 52 and 85 - who did not have dementia - took part in these studies.

Contrary to their initial expectations, the researchers found that having the KL-VS variant did not seem to protect people from age-related cognitive decline. But they did find that people who had this variant seemed to have a boost in cognition.

If increased levels of klotho can improve cognitive function, then perhaps raising these levels could help protect people from Alzheimer's.

This means that when the middle-aged participants in the study did begin their cognitive decline, the participants with the KL-VS variant were beginning their decline from a "higher point" of cognitive ability than their peers who lacked the variant.

"Based on what was known about klotho, we expected it to affect the brain by changing the aging process," says senior author Dr. Lennart Mucke. "But this is not what we found, which suggested to us that we were on to something new and different."

To further investigate, the researchers used mice engineered to produce more of the mouse version of the klotho protein. Putting the mice through a series of mazes, the researchers found that the klotho-enhanced mice were more likely than a control group to try different routes. This finding indicates that they possessed a superior working memory to the other mice.

In tests of spatial learning and memory, the mice with increased klotho also performed twice as well as the control group.

KL-VS 'increases synaptic plasticity' in the brains of mice

Analyzing the brain tissue of the mice, the researchers then found that the elevated-klotho mice had twice as many of a subunit called GluN2B within the synaptic connections of the hippocampus and frontal cortex - brain regions associated with cognitive function.

In mice, KL-VS seems to strengthen the connections between neurons responsible for learning - what is known as synaptic plasticity. To do this, it increases the action of a cell receptor called N-methyl-D-aspartate.

The cognitive advantage that the mice possessed was "switched off" when the researchers administered a drug to the mice that blocks the action of these receptors.

The researchers believe this discovery could open new routes to treating Alzheimer's disease. Scientists had previously suspected that some people may be protected from Alzheimer's because of greater cognitive capacity. If increased levels of klotho can improve cognitive function, then perhaps raising these levels could help protect people at risk from the disease.

"As the world's population ages, cognitive frailty is our biggest biomedical challenge," says Dr. Dena Dubal, lead author of the study. "If we can understand how to enhance brain function, it would have a huge impact on people's lives."

Dr. Dubal further explains her work in the video below.

In 2013, Medical News Today reported on a study investigating klotho as a potential basis for future multiple sclerosis drugs.

Written by David McNamee

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