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.

ObjectiveThe inherited component for Alzheimer disease (AD) risk has focused on close relatives; consideration of the full family history may improve accuracy and utility of risk estimates.MethodsA population resource including a genealogy of Utah pioneers from the 1800s linked to Utah death certificates was used to estimate relative risk for AD based on specific family history constellations, including from first- to third-degree relatives.ResultsAny affected first-degree relatives (FDR) significantly increased risk of AD (≥1 FDRs: relative risk [RR] 1.73, 95% confidence interval [CI] [1.59–1.87]; ≥2 FDRs: RR 3.98 [3.26–4.82]; ≥3 FDRs: RR 2.48 [1.07–4.89]; ≥4 FDRs: RR 14.77 [5.42–32.15]). Affected second-degree relatives (SDR) increased risk even in the presence of affected FDRs (FDR = 1 with SDR = 2: RR 21.29 [5.80–54.52]). AD only in third-degree relatives (TDR) also increased risk (FDR = 0, SDR = 0, TDR ≥3: RR 1.43 [1.21–1.68]). Mixed evidence was observed for differences in risk based on maternal compared to paternal inheritance; higher risks for men than women with equivalent family history, and higher risk for individuals with at least one affected FDR regardless of the relative's age at death, were observed.ConclusionsThis population-based estimation of RRs for AD based on family history ascertained from extended genealogy data indicates that inherited genetic factors have a broad influence, extending beyond immediate relatives. Providers should consider the full constellation of family history when counseling patients and families about their risk of AD.