Summary: Researchers report people with a genetic predisposition to Alzheimer’s and who carry a variant in the RAB10 gene, may be more resilient to the disease than those without the genetic variant.
Source: Brigham Young University.
Research published Wednesday in Genome Medicine details a novel and promising approach in the effort to treat Alzheimer’s disease.
Brigham Young University professors Perry Ridge and John Kauwe led the discovery of a rare genetic variant that provides a protective effect for high-risk individuals — elderly people who carry known genetic risk factors for Alzheimer’s– who never acquired the disease.
In other words, there’s a specific reason why people who should get Alzheimer’s remain healthy. Study authors believe this genetic function could be targeted with drugs to help reduce the risk of people getting the disease.
“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.”
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 data from the Utah Population Database — a 20-million-record database of the LDS Church’s genealogical records combined with historical medical records from Utah — Ridge and Kauwe first identified families that had a large number of resilient individuals: those who carried the main genetic risk factor for Alzheimer’s (E4 Allele) but remained healthy into advanced age.
Using whole genome sequencing and a linkage analysis methodology, they then looked for the DNA that those resilient individuals shared with each other that they didn’t share with loved ones who died of Alzheimer’s. They discovered the resilient subjects shared a variant in the RAB10 gene while those who got the disease did not share the genetic variant.
Once the researchers identified the potentially protective gene variant, they over expressed it in cells and under expressed it in cells to see the impact on Alzheimer’s disease related proteins. They learned that when this gene is reduced in your body, it has the potential to reduce your risk for Alzheimer’s.
“There are currently no meaningful interventions for Alzheimer 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.”
BYU was the lead institution on this research effort and collaborated with the University of Utah, Utah State University, the Mayo Clinic and the Washington University School of Medicine. Celeste M. Karch contributed equally as a first author and Lisa A. Cannon-Albright was a co-author on the paper. John Kauwe served as senior author.
Funding: NIH/National Institute on Aging, NIH/National Institute of Neurological Disorders and Stroke, Mayo Clinic Center for Individualized Medicine funded the study.
Source: Todd Hollingshead – Brigham Young University
Publisher: Organized by NeuroscienceNews.com.
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Original Research: Full open access research for “Linkage, whole genome sequence, and biological data implicate variants in RAB10 in Alzheimer’s disease resilience” by Perry G. Ridge, Celeste M. Karch, Simon Hsu, Ivan Arano, Craig C. Teerlink, Mark T. W. Ebbert, Josue D. Gonzalez Murcia, James M. Farnham, Anna R. Damato, Mariet Allen, Xue Wang, Oscar Harari, Victoria M. Fernandez, Rita Guerreiro, Jose Bras, John Hardy, Ronald Munger, Maria Norton, Celeste Sassi, Andrew Singleton, Steven G. Younkin, Dennis W. Dickson, Todd E. Golde, Nathan D. Price, Nilüfer Ertekin-Taner, Carlos Cruchaga, Alison M. Goate, Christopher Corcoran, JoAnn Tschanz, Lisa A. Cannon-Albright, John S. K. Kauwe, and for the Alzheimer’s Disease Neuroimaging Initative in Genome Medicine. Published online November 29 2017 doi:10.1186/s13073-017-0486-1
Linkage, whole genome sequence, and biological data implicate variants in RAB10 in Alzheimer’s disease resilience
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.
We used over 200 “AD resilient” individuals and an innovative, pedigree-based approach to identify genetic variants that segregate with AD resilience. First, we performed linkage analyses in pedigrees with resilient individuals and a statistical excess of AD deaths. Second, we used whole genome sequences to identify candidate SNPs in significant linkage regions. Third, we replicated SNPs from the linkage peaks that reduced risk for AD in an independent dataset and in a gene-based test. Finally, we experimentally characterized replicated SNPs.
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).
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.
“Linkage, whole genome sequence, and biological data implicate variants in RAB10 in Alzheimer’s disease resilience” by Perry G. Ridge, Celeste M. Karch, Simon Hsu, Ivan Arano, Craig C. Teerlink, Mark T. W. Ebbert, Josue D. Gonzalez Murcia, James M. Farnham, Anna R. Damato, Mariet Allen, Xue Wang, Oscar Harari, Victoria M. Fernandez, Rita Guerreiro, Jose Bras, John Hardy, Ronald Munger, Maria Norton, Celeste Sassi, Andrew Singleton, Steven G. Younkin, Dennis W. Dickson, Todd E. Golde, Nathan D. Price, Nilüfer Ertekin-Taner, Carlos Cruchaga, Alison M. Goate, Christopher Corcoran, JoAnn Tschanz, Lisa A. Cannon-Albright, John S. K. Kauwe, and for the Alzheimer’s Disease Neuroimaging Initative in Genome Medicine. Published online November 29 2017 doi:10.1186/s13073-017-0486-1