PROVO — A new way to examine Alzheimer's disease has provided a tantalizing potential treatment approach to prevent the devastating condition, according to BYU-led research published online in the journal Genome Medicine.
More than 5 million Americans are living with Alzheimer's disease, which is the sixth-leading cause of death. Expectations are the number will triple by 2050. But despite decades-long efforts, a cure or even effective treatment has eluded researchers.
That's one reason the Brigham Young University-led team decided to look at the disease from a different angle. Instead of trying to figure out why people have the disease, they looked for people who have proven risk factors that say they should have the disease, but who don't, in hopes of finding protective factors.
They identified a large number of people who have two proven risk factors — old age and having the E4 allele, or form, of the apolipoprotein E gene. Researchers have known for some time that those with the E4 variant have a five-fold risk of developing Alzheimer's. And by age 80, 30-40 percent of those people have the disease.
"You are truly exceptional if you're over 80 and have the E4 allele, but no Alzheimer's," said John "Keoni" Kauwe, assistant professor of biology at BYU and the senior study author.
Researchers found what made the difference for these "resilient" people appears to be the RAB10 gene, which has been linked to Alzheimer's in many earlier studies. A difference in how much of that gene is present provides a potential target for prevention, Kauwe said. Those who had less RAB10 did not have signs of Alzheimer's.
If the finding holds, preventive therapy is still a long way off, because converting science to treatment is a slow process, Kauwe said. But he's hopeful.
"The bright side is we are starting to feel like we have most of the pieces and are making progress," Kauwe said of Alzheimer's research in general. "A decade ago, it was like we were staring at a puzzle thinking, 'Surely we're missing something.' We couldn't really start. Now we have a table full of the pieces and are getting more confident we will be able to piece it together."
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The researchers, all part of the Alzheimer's Disease Neuroimaging Initiative, used whole-genome sequencing to see what those with no symptoms of Alzheimer's had — or lacked — compared to those with the disease. After finding the RAB10 variant, they replicated the result in cell line experiments and examination of brain samples of both those with the disease and without it.
Key to the study was identifying subjects using the Utah Population Database and the Cache County Study on Memory Health and Aging, two long-term Utah research efforts.
The Utah Population Database links 20 million genealogical records from The Church of Jesus Christ of Latter-day Saints with medical records. The Cache County study was launched more than 15 years ago to look at the association of apolipoprotein E genotype and environmental exposures on cognition and development of dementia. Cache participants provided DNA samples for the population database and have been followed since 1994.
The BYU researchers collaborated with colleagues at the University of Utah and Utah State University, and once they had their initial finding, they brought in researchers from the Mayo Clinic and the Washington University School of Medicine to help vet what they'd discovered.
The researchers hope that an effective prevention or treatment can be developed by finding a way to regulate how much of the RAB20 gene a person has, said study author Perry Ridge, also an assistant professor of biology at BYU.
With any potential treatment, there's risk of side effects, he noted, but the fact that the resilient study subjects had significantly less of the RAB10 gene and were doing well counters fears on that score, Ridge said.1 comment on this story
Ridge believes the finding is potentially very important. "At present, there's nothing we can do for people with Alzheimer's. We can't cure it or really slow down the progression. When someone gets it, that person is going to eventually die from it unless they die first from something else related to old age," he said.
Alzheimer's is especially devastating because it steals one's mind, said Ridge. Our mind is "what makes us human, how we connect to the world and to other people," he said. "Even with other terrible diseases that kill us, we still usually are able to connect and communicate."