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 β peptide (Aβ) 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 Aβ-generating compartments. These data suggest that inherited or acquired changes in SORL1 expression or function are mechanistically involved in causing Alzheimer disease.
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Acknowledgements
The authors thank J. Ott for advice on the statistical analysis. The authors acknowledge the work of B. Tycko, M. Medarano, R. Lantigua, Y. Stern, A. Akomolafe, J. Browndyke, H. Chui, R. Go, A. Kurz, H. Petrovitch, N. Relkin, D. Sadovnick, P. Erlich, S. Sunyaev, L. Ma, J. Lok and S. Younkin. This work was supported by the Canadian Institutes of Health Research, the Howard Hughes Medical Institute, the Canadian Institutes of Health Research–Japan Science and Technology Trust, the Alzheimer Society of Ontario, the Canada Foundation for Innovation, the Ontario Research and Development Challenge Fund, the Ontario Mental Health Foundation, Genome Canada, the US National Institutes of Health and the National Institute on Aging (grants R37-AG15473 and P01-AG07232 (R.M.), R01-AG09029 (L.A.F.), RO1-HG/AG02213 (R.C.G.), P30-AG13846 (L.A.F., R.C.G.), R01-AG017173 (R.P.F., L.A.F.), P50-AG16574 (R.C.P., S.Y., N.G.R.) and U01-AG06786 (R.C.P.)), the Alzheimer Association, the Alzheimer Society of Canada, the Blanchett Hooker Rockefeller Foundation, the Charles S. Robertson Gift (R.M.), Fonds de la Recherche en Santé (Y.M.), Assessorato Regionale alla Sanità-Regione Calabria, Finalized Project of the Ministry of Health (2003–2005) (A.C.B.), Fondation pour la Recherche Médical, Robert and Clarice Smith and Abigail Van Buren, the Alzheimer Disease Research Program (R.P., S.Y.) and the W. Garfield Weston Fellowship (E.R., G.S.U.).
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Supplementary information
Supplementary Table 1
Characteristics of genotyped subjects. (PDF 17 kb)
Supplementary Table 2
Single SNP results for VPS10 genes other than SORL1. (PDF 27 kb)
Supplementary Table 3
Characteristics of SNPs in SORL1. (PDF 579 kb)
Supplementary Table 4
Single SNP results for all 29 SORL1 SNPs in the six primary datasets. (PDF 355 kb)
Supplementary Table 5
Three-SNP haplotypes for all SORL1 SNPs. (PDF 245 kb)
Supplementary Table 6
Two-SNP haplotypes for all SORL1 SNPs. (PDF 232 kb)
Supplementary Table 7
Four-SNP haplotypes for all SORL1 SNPs. (PDF 284 kb)
Supplementary Table 8
Five-SNP haplotypes for all SORL1 SNPs. (PDF 261 kb)
Supplementary Table 9
Six-SNP haplotypes for all SORL1 SNPs. (PDF 372 kb)
Supplementary Table 10
Rare sequence variants in SORL1. (PDF 65 kb)
Supplementary Table 11
Authors' roles in the study. (PDF 21 kb)
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Rogaeva, E., Meng, Y., Lee, J. et al. The neuronal sortilin-related receptor SORL1 is genetically associated with Alzheimer disease. Nat Genet 39, 168–177 (2007). https://doi.org/10.1038/ng1943
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DOI: https://doi.org/10.1038/ng1943
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