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The neuronal sortilin-related receptor SORL1 is genetically associated with Alzheimer disease.

ABSTRACT: The recycling of the amyloid precursor protein (APP) from the cell surface via the endocytic pathways plays a key role in the generation of amyloid beta peptide (Abeta) in Alzheimer disease. We report here that inherited variants in the SORL1 neuronal sorting receptor are associated with late-onset Alzheimer disease. These variants, which occur in at least two different clusters of intronic sequences within the SORL1 gene (also known as LR11 or SORLA) may regulate tissue-specific expression of SORL1. We also show that SORL1 directs trafficking of APP into recycling pathways and that when SORL1 is underexpressed, APP is sorted into Abeta-generating compartments. These data suggest that inherited or acquired changes in SORL1 expression or function are mechanistically involved in causing Alzheimer disease.

SUBMITTER: Rogaeva E

PROVIDER: S-EPMC2657343 | biostudies-literature | 2007 Feb

REPOSITORIES: biostudies-literature

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The neuronal sortilin-related receptor SORL1 is genetically associated with Alzheimer disease.

Rogaeva Ekaterina E Meng Yan Y Lee Joseph H JH Gu Yongjun Y Kawarai Toshitaka T Zou Fanggeng F Katayama Taiichi T Baldwin Clinton T CT Cheng Rong R Hasegawa Hiroshi H Chen Fusheng F Shibata Nobuto N Lunetta Kathryn L KL Pardossi-Piquard Raphaelle R Bohm Christopher C Wakutani Yosuke Y Cupples L Adrienne LA Cuenco Karen T KT Green Robert C RC Pinessi Lorenzo L Rainero Innocenzo I Sorbi Sandro S Bruni Amalia A Duara Ranjan R Friedland Robert P RP Inzelberg Rivka R Hampe Wolfgang W Bujo Hideaki H Song You-Qiang YQ Andersen Olav M OM Willnow Thomas E TE Graff-Radford Neill N Petersen Ronald C RC Dickson Dennis D Der Sandy D SD Fraser Paul E PE Schmitt-Ulms Gerold G Younkin Steven S Mayeux Richard R Farrer Lindsay A LA St George-Hyslop Peter P

Nature genetics 20070114 2

The recycling of the amyloid precursor protein (APP) from the cell surface via the endocytic pathways plays a key role in the generation of amyloid beta peptide (Abeta) in Alzheimer disease. We report here that inherited variants in the SORL1 neuronal sorting receptor are associated with late-onset Alzheimer disease. These variants, which occur in at least two different clusters of intronic sequences within the SORL1 gene (also known as LR11 or SORLA) may regulate tissue-specific expression of S ...[more]

PMID: 17220890

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Project description:BACKGROUND:Single-nucleotide polymorphisms (SNPs) in 2 distinct regions of the gene for the sortilin-related receptor (SORL1) (bounded by consecutively numbered SNPs 8-10 and 22-25) were shown to be associated with Alzheimer disease (AD) in multiple ethnically diverse samples. OBJECTIVE:To test the hypothesis that SORL1 is associated with brain magnetic resonance imaging (MRI) measurements of atrophy and/or vascular disease. DESIGN, SETTING, AND PATIENTS:We evaluated the association of 30 SNPs spanning SORL1 with MRI measures of general cerebral atrophy, hippocampal atrophy, white matter hyperintensities, and overall cerebrovascular disease in 44 African American and 182 white sibships from the MIRAGE Study. We performed single- and 3-SNP haplotype association analyses using family-based tests. Haplotypes found to be significantly associated with at least 1 MRI trait were tested for association with 6 pathological traits in a separate sample of 69 white patients with autopsy-confirmed AD. RESULTS:In white patients, white matter hyperintensities were associated with multiple markers in the region encompassing SNPs 6 to 10, whereas cerebral and hippocampal atrophy were associated with markers from the region including SNPs 21 to 26. Examination of specific 3-SNP haplotypes from these 2 regions in the autopsy-confirmed cases of AD revealed association of white matter disease with SNPs 8 to 10 and association of hippocampal atrophy with SNPs 22 to 26. The haplotype CGC at SNPs 8 to 10 was associated with fewer white matter changes in the clinical (P<.001) and autopsy (P=.02) samples. CONCLUSIONS:Variants of SORL1 previously associated with AD are also associated with MRI and neuropathological measures of neurodegenerative and cerebrovascular disease. These findings not only support the hypothesis that multiple areas in SORL1 are of functional importance but also raise the possibility that multiple SORL1 variants influence amyloid precursor protein or endothelial lipoprotein processing or both in different regions of the brain.

Project description:OBJECTIVE:To reexamine the association between the neuronal sortilin-related receptor gene (SORL1) and Alzheimer disease (AD). DESIGN:Comprehensive and unbiased meta-analysis of all published and unpublished data from case-control studies for the SORL1 single-nucleotide polymorphisms (SNPs) that had been repeatedly assessed across studies. SETTING:Academic research institutions in the United States, the Netherlands, Canada, Belgium, the United Kingdom, Singapore, Japan, Sweden, Germany, France, and Italy. PARTICIPANTS:All published white and Asian case-control data sets, which included a total of 12,464 cases and 17,929 controls. MAIN OUTCOME MEASURES:Alzheimer disease according to the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) and the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association (now known as the Alzheimer's Association). RESULTS:In the white data sets, several markers were associated with AD after correction for multiple testing, including previously reported SNPs 8, 9, and 10 (P < .001). In addition, the C-G-C haplotype at SNPs 8 through 10 was associated with AD risk (P < .001). In the combined Asian data sets, SNPs 19 and 23 through 25 were associated with AD risk (P < .001). The disease-associated alleles at SNPs 8, 9, and 10 (120,873,131-120,886,175 base pairs [bp]; C-G-C alleles), at SNP 19 (120,953,300 bp; G allele), and at SNPs 24 through 25 (120,988,611 bp; T and C alleles) were the same previously reported alleles. The SNPs 4 through 5, 8 through 10, 12, and 19 through 25 belong to distinct linkage disequilibrium blocks. The same alleles at SNPs 8 through 10 (C-G-C), 19 (G), and 24 and 25 (T and C) have also been associated with AD endophenotypes, including white matter hyperintensities and hippocampal atrophy on magnetic resonance imaging, cerebrospinal fluid measures of amyloid ?-peptide 42, and full-length SORL1 expression in the human brain. CONCLUSION:This comprehensive meta-analysis provides confirmatory evidence that multiple SORL1 variants in distinct linkage disequilibrium blocks are associated with AD.

Dataset Information

The neuronal sortilin-related receptor SORL1 is genetically associated with Alzheimer disease.

Publications

The neuronal sortilin-related receptor SORL1 is genetically associated with Alzheimer disease.

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