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In a study led by Washington University that includes BYU, researchers have identified a gene that doubles one's risk of developing Alzheimer's disease. The findings have been published in the journal Nature.
We all took a very thoughtful, creative approach. It's not the biggest study, but the smartest study we thought could be done. —John Kauwe, biology professor at Brigham Young University

A research collaboration led by Washington University has found a gene variation that doubles one's risk of developing Alzheimer's disease. The finding adds to a rapidly accelerating body of information about the neurodegenerative disease, which affects more than 5 million Americans.

The findings are published online in the journal Nature.

"The newly identified variations, found in a gene never before linked to Alzheimer's, occur rarely in the population, making them hard for researchers to identify," according to the study's background information. "But they're important because individuals who carry these variations are at substantially increased risk of the disease."

"Most of the genes that were discovered for Alzheimer's in the past two years have very minor effect," said John Kauwe, a biology professor at Brigham Young University who co-authored the study. He said that 19 of the "20-some-odd" genes linked to Alzheimer's in the last five years each affect risk by just 1 to 3 percent.

The methodology for this study was also important, according to Kauwe and Carlos Cruchaga, assistant professor of psychiatry at Washington University, who led the study. Cruchaga said it will open new doors to understanding the disease and how gene variants affect risk, either in combination or alone.

They took a different approach to finding the variants. Instead of taking a scattershot approach and looking at the largest number of subjects possible, they selected pedigrees that had interesting patterns of inheritance and were already identified as having multiple members with Alzheimer's, then drilled down to find the actual genetic variants.

Washington University identified and evaluated families, finding a number of things researchers wanted to focus on, then asked BYU researchers to help examine those questions.

"We all took a very thoughtful, creative approach," said Kauwe. "It's not the biggest study, but the smartest study we thought could be done."

Using DNA from the individuals in families known to have multiple members with the disease, they removed families that had common genetic mutations that had already been identified with Alzheimer's, Cruchaga said. Then they homed in on families with lots of Alzheimer's and no known genetic variant to account for it. To examine the DNA, they sequenced every protein-coding gene using what's called whole exome sequencing. They sequenced genes from both those with Alzheimer's and those without the disease.

That made it possible to find rare genetic variants that would otherwise be overlooked, said Kauwe. That led them to two families that had the same variation in the phospholipase-D 3 gene, which they shorten to PLD3. Convincingly, they didn't find it in elderly members of the families who did not have Alzheimer's. Cruchaga said it appears that people who have it have a much greater risk of developing Alzheimer's disease.

BYU researchers used the broad data sets they had from the Cache County Study on Memory, Health and Aging to run genotypes in thousands of samples to verify the findings related to the specific gene variants.

To calculate increased risk, the researchers used DNA data from 11,000 people, including those with and those without the brain disease, and found the variant doubled risk.

"The approach we've taken in this project is just as important as the discovery that this gene is involved in Alzheimer's," said co-investigator Alison M. Goate, one of Cruchaga's colleagues, in a written statement. "By studying gene variants within families, we were able to narrow down the number of variants that might cause disease. If we had been using unrelated individuals, we would not have had the statistical power to find these rare variants."

They don't yet know how PLD3 impacts the mechanism of Alzheimer's, though lab experiments showed it changes levels of amyloid-beta, which gathers in the brains of Alzheimer's patients to form plaques.

BYU noted that its team included the only undergraduate in the study. History major Cameron Schmutz joined Kauwe, biology professor Perry Ridge and post-graduate Maegan Leary as BYU authors. Schmutz genotyped, tested and analyzed more than 5,000 DNA samples.

Kauwe told the Deseret News that researchers are getting closer to figuring out Alzheimer's. He points out that for many years, there were few new discoveries. But recently, "the pace of our discoveries in Alzheimer's just accelerated in an amazing way," he said.

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