Gene variations, known as alleles, often work like the volume knob on stereo speakers —they can raise or lower your risk of developing specific diseases. A new study from UCSF focuses on one specific KLOTHO allele, called KL-VS. People who carry this allele, which has been linked to a longer lifespan, also possess a larger brain structure in the prefrontal cortex, the region involved in planning and decision-making, the researchers say.

"Genetic variation in KLOTHO could help us predict brain health and find ways to protect people from the devastating diseases that happen to us as we grow old, like Alzheimer's and other dementias," Dr. Dena Dubal, assistant professor of neurology at UCSF, said in a release.

The gene KLOTHO codes for a protein, called klotho, which is produced in both the brain and the kidney, and from these locations this protein helps to regulate many different processes in your body. Because a mutated gene can take two or more alternate forms, known as alleles, each of us carries either one, two, or no copies of the KLOTHO allele known as KL-VS. About one in five people carry a single copy of KL-VS, which is linked to better heart and kidney function and also to longevity. Meanwhile, about three percent of all people carry two copies of KL-VS — conversely, this is associated with a shorter lifespan.

Memory and Brain Plasticity

In previous experiments, Dubal and her co-researchers found middle-aged and older people who carry a single copy of KL-VS performed better on a range of cognitive tests. Then, when they investigated KL-VS, they discovered this allele strengthened connections between neurons and enhanced learning and memory. For the current study, then, Dubal and her colleagues looked inside the brains of 422 normal men and women, all older than 53, to see if there were any correlations between carrying one, two, or no copies of this allele and how brain structures appeared on a scan.

What did they discover? People with just one copy of KL-VS, about a quarter of the study group, had a bigger right dorsolateral prefrontal cortex (rDLPFC) than either people with two copies or non-carriers. In fact, this allele predicted the size of the rDLPFC, which is known to be vulnerable to deterioration as we age and had indeed shrunk somewhat in all three groups, but least of all in people with one copy of KL-VS.

Researchers also found that the size of the rDLPFC predicted how well the three groups performed on cognitive tests, especially exams testing working memory — the ability to keep a small amount of newly acquired information in mind — and processing speed.

"The brain region enhanced by genetic variation in KLOTHO is vulnerable in aging and several psychiatric and neurologic diseases including schizophrenia, depression, substance abuse, and frontotemporal dementia," said Dr. Jennifer Yokoyama, first author and assistant professor of neurology. "In this case, bigger size means better function.”

Based on the results, Yokoyama and her colleagues believe the KL-VS allele may increase levels or change the actions of the klotho protein and this in turn enhances synaptic plasticity or the connections between neurons. Additionally, deterioration of the rDLPFC may be a fundamental reason why older people have difficulty multitasking and suppressing distracting information.

Source: Dubal D, Yokoyama J, Sturm V, et al. Annals of Clinical and Translational Neurology. 2015.