BYU researchers narrow in on genetics of Alzheimer’s

New work reveals a gene variation that protects against Alzheimer’s disease

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Late November brought word from Brigham Young University (BYU) that researchers there had published findings in Genome Medicine—in an paper titled “Linkage, whole genome sequence, and biological data implicate variants in RAB10 in Alzheimer’s disease resilience”—that detail what BYU writer Todd Hollings notes could be “a novel and promising approach in the effort to treat Alzheimer’s disease.”
In the work, BYU professors Perry Ridge and John Kauwe looked at individuals who had high risk of developing Alzheimer's disease—that is, they were elderly and carried known genetic risk factors for the disease—but who had never progressed to Alzheimer's.
As the researchers wrote, “While age and the APOE ε4 allele are major risk factors for Alzheimer’s disease (AD), a small percentage of individuals with these risk factors exhibit AD resilience by living well beyond 75 years of age without any clinical symptoms of cognitive decline.”
And when they explored more deeply, they discovered a rare genetic variant that provides a protective effect for such high-risk individuals.
Naturally, with something that protects people who “should” acquire AD, the researchers see a potential path toward treatment for at least some patients or potential victims of the disease: drugs or gene therapies that target this specific genetic function.
“Instead of identifying genetic variants that are causing disease, we wanted to identify genetic variants that are protecting people from developing disease,” said Ridge, assistant professor of biology at BYU. “And we were able to identify a promising genetic variant.”
As BYU’s Hollings wrote of the research, “That former approach to Alzheimer’s disease has been generally effective in producing a list of genes that might impact risk for the disease, but it leaves researchers without sufficient data on what to do next. In this new approach, Ridge and Kauwe develop the biological mechanism by which a genetic variant actually impacts Alzheimer’s disease.”
Using whole-genome sequencing and a linkage analysis methodology, they looked for the DNA that those resilient individuals shared with each other that they didn’t share with loved ones who died of AD, discovering that the resilient subjects shared a variant in the RAB10 gene. They then over-expressed the gene in cells and under-expressed it to see the impact on AD-related proteins.
As the researchers noted in their paper, “Rs142787485 in RAB10 confers significant protection against AD (p value = 0.0184, odds ratio = 0.5853). Moreover, we replicated this association in an independent series of unrelated individuals (p value = 0.028, odds ratio = 0.69) and used a gene-based test to confirm a role for RAB10 variants in modifying AD risk (p value = 0.002). Experimentally, we demonstrated that knockdown of RAB10 resulted in a significant decrease in Aβ42 (p value = 0.0003) and in the Aβ42/Aβ40 ratio (p value = 0.0001) in neuroblastoma cells. We also found that RAB10 expression is significantly elevated in human AD brains (p value = 0.04).”
“There are currently no meaningful interventions for Alzheimer’s disease—no prevention, no modifying therapies, no cure,” Kauwe said. “The discoveries we’re reporting in this manuscript provide a new target with a new mechanism that we believe has great potential to impact Alzheimer’s disease in the future.”
And this potential breakthrough in understanding and treating AD may not stop with that neurodegenerative disease, with the authors of the paper writing, “Our results suggest that RAB10 could be a promising therapeutic target for AD prevention. In addition, our gene discovery approach can be expanded and adapted to other phenotypes, thus serving as a model for future efforts to identify rare variants for AD and other complex human diseases.”
BYU was the lead institution on this research effort, but collaborated with the University of Utah, Utah State University, the Mayo Clinic and the Washington University School of Medicine.

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