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.

Key Points Question Can rare genetic variants for Alzheimer disease be identified using nonstatistical approaches? Findings In this genetic association study, variants with high functional effect were observed in participants with Alzheimer disease but not in controls in NOTCH3 , a gene previously associated with cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), and TREM2 (Q33X) that in homozygous form causes Nasu-Hakola disease. Meaning Different mutations in the same gene or variable dose of a particular mutation may be associated with dissimilar types of dementia.

Recent studies have identified the R47H variant in TREM2 as an Alzheimer’s disease (AD) risk factor with estimated odds ratio ranging from 2.9–5.1. The Cache County Memory Study is a large, population-based sample designed for the study of memory and aging. We genotyped rs75932628 (R47H) in 2974 samples (427 cases and 2540 controls) from the Cache County study using a custom Taqman Assay. We observed 7 heterozygous cases and 12 heterozygous controls with an odds ratio of 3.5 (95% confidence interval, 1.3–8.8; p = 0.0076). The minor allele frequency and population attributable fraction for R47H were 0.0029 and 0.004, respectively. This study replicates the association between R47H and AD risk in a large, population-based sample and estimates the population frequency and attributable risk of this rare variant.

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A recent genome-wide association study (GWAS) of 59 cerebrospinal fluid (CSF) proteins with a connection to Alzheimer's disease (AD) demonstrated an association between increased levels of chemokine ligand 2 (CCL2) with an atypical chemokine receptor chemokine-binding protein 2 variant V41A (ACKR2-V41A; rs2228467). High levels of CCL2 are associated with increased risk of AD development as well as other inflammatory diseases. In this study we characterized the biological function of the ACKR2-V41A receptor compared to the wild type allele by measuring its ligand binding affinity, CCL2 scavenging efficiency, and cell activation sensitivity. We transfected Chinese hamster ovary cells with plasmids carrying wild type ACKR2 (ACKR2-WT) or the mutant ACKR2-V41A receptor. Binding affinity assays showed that ACKR2-V41A has a lower binding affinity for CCL2 and CCL4 than ACKR2-WT. CCL2 scavenging results aligned with binding affinity assays, with ACKR2-V41A cells scavenging CCL2 with a lower efficiency than ACKR2-WT. Cell activation assays also showed that ACKR2-V41A cells had significantly lower receptor upregulation (β-Arrestin-dependent signaling pathway) upon stimulation compared to ACKR2-WT cells. These findings provide molecular and biological mechanistic insights into the GWAS association of ACKR2-V41A with increased levels of CCL2 in CSF and possibly other chemokine ligands. Increased CCL2 levels are associated with accelerated cognitive decline and increased risk of AD. Understanding how this atypical chemokine receptor allele increases serum markers of inflammation could lead to novel therapeutic solutions for AD. Inflammation is associated with increased risk of developing cancer, autoimmune disorders, and neurodegenerative diseases such as Alzheimer's disease (AD) 1. Acute inflammation plays an essential role in the normal response to tissue injury 2,3. This inflammatory response initiates a cascade of cellular activation signals in innate immune cells (e.g. macrophages, mast cells, and endothelial cells), resulting in increased production of proinflammatory cytokines and chemokines 4-6. These cytokines and chemokines are essential to the recruitment and activation of other cells in the innate and adaptive immune systems. An inappropriate response to inflammation or alterations in the production of these chemokines can result in disease development.