Linkage, whole genome sequence, and biological data implicate variants in RAB10 in Alzheimer’s disease resilience

Abstract

BackgroundWhile 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.MethodsWe 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.ResultsRs142787485 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).ConclusionsOur 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s13073-017-0486-1) contains supplementary material, which is available to authorized users.

LRRK2 and Rab10 Coordinate Macropinocytosis to Mediate Immunological Responses in Phagocytes

“…The Rab10 gene is linked to human disease in several ways. Genetic variants in Rab10 associate with resilience to AD, and a phosphorylation site in the Rab10 switch II domain is upregulated by PD-associated mutations in the LRRK2 protein kinase 11 . LRRK2-mediated phosphorylation of Rab10 is strongly affected by all known pathogenic mutations as well as PD-risk factor genetic variants like G2385R, with Rab10 phosphorylation changing the affinity of different binding proteins to the Rab10 effector loops 12 .…”

Rab10 Phosphorylation is a Prominent Pathological Feature in Alzheimer’s Disease

“…Further, a rare variant of the Rab10 gene has been shown to confer resilience for AD development in people over the age of 75 who carry at least one APOE ε 4 allele. This, together with the reported increased expression of Rab10 mRNA in the temporal cortex of AD brains [6] and the in vitro studies showing overexpression of Rab10 increases Aβ production in cultured neuroblastoma cells [6], provide compelling evidence for an important role of Rab10 in AD.…”

“…Interestingly, a recent study has identified a rare variant of the Rab10 gene in cognitively normal individuals over the age of 75 who carry at least one APOE ε 4 allele, a known AD genetic risk factor [6], suggesting the Rab10 genetic variation may be protective against AD development.…”

“…In neurons, Rab10 has been reported to recycle AMPARs from endosomal compartments to synapses [10], and regulates intracellular vesicular trafficking to mediate axonogenesis [11, 12] and dendrite arborization [13, 14]. Increased expression of Rab10 mRNA in the temporal cortex of AD brains has been reported [6]. In vitro studies have found that knockdown of Rab10 decreased Aβ production, whereas the overexpression of Rab10 increased Aβ production in cultured neuroblastoma cells [6].…”

“…Increased expression of Rab10 mRNA in the temporal cortex of AD brains has been reported [6]. In vitro studies have found that knockdown of Rab10 decreased Aβ production, whereas the overexpression of Rab10 increased Aβ production in cultured neuroblastoma cells [6]. …”