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Alzheimer's Disease Study Finds Potentially Protective Genetic Variants

NEW YORK (GenomeWeb) – New research suggests variants in the RAB10 gene may protect against Alzheimer's disease (AD) in individuals at heightened genetic risk of the neurodegenerative disorder.

"Our results suggest that RAB10 variants impact risk for AD and that RAB10 represents a promising therapeutic target for AD prevention," corresponding author John Kauwe, a biology and neuroscience researcher at Brigham Young University, and his co-authors wrote in a study published online in Genome Medicine last night.

Kauwe and colleagues from the Alzheimer's Disease Neuroimaging Initiative used linkage analyses and whole-genome sequencing to search for protective variants in more than 200 individuals with at least one copy of a risky apolipoprotein E epsilon 4 (APOE ɛ4) allele who remained free of Alzheimer's disease and cognitively intact into their late 70s and beyond, starting with large AD-affected families from Utah.

The team narrowed in on a rare variant called rs142787485 in the RAB10 gene that was overrepresented in the Alzheimer's disease "resilient" individuals — results that were replicated in unrelated individuals. Gene-based analyses, cell line experiments, and expression profiling on post-mortem brain samples from dozens of individuals with or without AD suggested variants dialing down RAB10 set off a chain of events that alters levels of amyloid beta 42 peptide, which has been implicated in AD.

For their analysis, the researchers began by searching the Utah Population Database for families that were inordinately affected by AD mortality, but contained at least four individuals with risky AD-related variants who had not developed the disease.

Through linkage analyses on two of these large families, which included 232 AD-resilient individuals who were 75 years old or older, the team narrowed in on two linkage peaks.

Whole-genome sequencing on 212 of the AD-resilient individuals refined the view of these sites, leading to suspicious variants in and around two genes — RAB10 and SAR1A — that are known to interact with APP, which encodes the amyloid beta precursor protein.

The researchers validated the RAB10 variant association, but not the SAR1A association, using data for another 544 cases and 3,605 controls. With RNA sequencing on post-mortem brain samples from 80 individuals with AD and 76 elderly controls, they saw hints that the temporal cortex brain region of AD-affected individuals tended to have higher-than-usual RAB10 levels.

Likewise, notching up RAB10 in mouse neuroblastoma cells led to enhanced amyloid beta 42 in relation to the amyloid beta 40 peptide, and neuroblastoma cells with knocked down RAB10 had lower-than-usual amyloid beta 42 levels without corresponding changes in the levels of splicing of APP and its gene product.

"Based on our results, we hypothesize that Rab10 impacts APP processing through direct interaction with APP," the authors wrote. "The relationship between RAB10 and [amyloid-beta] suggests RAB10 may affect gamma-secretase-mediated cleavage of APP, and the secretion and degradation of cleaved [amyloid-beta]."

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