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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.).

Author information

Author notes

    • Ekaterina Rogaeva
    • , Yan Meng
    • , Joseph H Lee
    • , Yongjun Gu
    • , Toshitaka Kawarai
    •  & Fanggeng Zou

    These authors contributed equally to this work.

Affiliations

  1. Centre for Research in Neurodegenerative Diseases, Department of Medicine, Department of Laboratory Medicine and Pathobiology and Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada; and Toronto Western Hospital Research Institute, Toronto, Ontario M5S 3H2, Canada.

    • Ekaterina Rogaeva
    • , Yongjun Gu
    • , Toshitaka Kawarai
    • , Taiichi Katayama
    • , Hiroshi Hasegawa
    • , Fusheng Chen
    • , Nobuto Shibata
    • , Raphaelle Pardossi-Piquard
    • , Christopher Bohm
    • , Yosuke Wakutani
    • , Sandy D Der
    • , Paul E Fraser
    • , Gerold Schmitt-Ulms
    •  & Peter St George-Hyslop
  2. Department of Medicine (Genetics Program), Department of Neurology, Department of Genetics & Genomics, Boston University School of Medicine, Department of Epidemiology and Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts 02118, USA.

    • Yan Meng
    • , Clinton T Baldwin
    • , Kathryn L Lunetta
    • , L Adrienne Cupples
    • , Karen T Cuenco
    • , Robert C Green
    •  & Lindsay A Farrer
  3. The Taub Institute on Alzheimer's Disease and the Aging Brain and The Gertrude H. Sergievsky Center, College of Physicians and Surgeons, Columbia University, New York, NY, USA; and Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, New York 10032, USA.

    • Joseph H Lee
    • , Rong Cheng
    •  & Richard Mayeux
  4. Department of Neuroscience and Department of Neurology, Mayo Clinic Jacksonville, 4500 San Pablo Road, Jacksonville, Florida 32224, USA; and Department of Neurology, Mayo Clinic Rochester, 200 First Street SW, Rochester, Minnesota 55905, USA.

    • Fanggeng Zou
    • , Neill Graff-Radford
    • , Ronald C Petersen
    • , Dennis Dickson
    •  & Steven Younkin
  5. Department of Neuroscience, University of Turin, Via Cherasco 15, 10126 Turin, Italy.

    • Lorenzo Pinessi
    •  & Innocenzo Rainero
  6. Department of Neurological and Psychiatric Sciences, Centre for Research, Transfer, and High Education on Chronic, Inflammatory, Degenerative and Neoplastic Disorders, University of Florence, Viale Pieraccini 6, 50139 Florence, Italy.

    • Sandro Sorbi
  7. Regional Center of Neurogenetics, AS6, 88046 Lamezia Terme (CZ), Italy.

    • Amalia Bruni
  8. Wien Center for Alzheimer's Disease and Memory Disorders, Mount Sinai Medical Center, Miami Beach, Florida 33140, USA; and Department of Psychiatry and Department of Behavioral Sciences and Medicine, University of Miami School of Medicine, Miami, Florida 33140, USA.

    • Ranjan Duara
  9. Department of Neurology, Case Western Reserve University, Cleveland, Ohio 44106, USA.

    • Robert P Friedland
  10. Meir Hospital, Kfar Saba and Rappaport Faculty of Medicine, Technion, Haifa, Israel 47441.

    • Rivka Inzelberg
  11. Department of Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, Martinstrasse 52, 20246 Hamburg, Germany.

    • Wolfgang Hampe
  12. Department of Genome Research and Clinical Application (M6), Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan.

    • Hideaki Bujo
  13. Department of Biochemistry, Department of Orthopaedic Surgery and The Genome Research Centre, University of Hong Kong, Hong Kong.

    • You-Qiang Song
  14. Department of Molecular Cardiovascular Research, Max Delbrueck Center for Molecular Medicine, Robert Roessle Str. 10, D-13125 Berlin, Germany.

    • Olav M Andersen
    •  & Thomas E Willnow

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Contributions

The authors' roles are described in Supplementary Table 11 online.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Richard Mayeux or Lindsay A Farrer or Peter St George-Hyslop.

Supplementary information

PDF files

  1. 1.

    Supplementary Table 1

    Characteristics of genotyped subjects.

  2. 2.

    Supplementary Table 2

    Single SNP results for VPS10 genes other than SORL1.

  3. 3.

    Supplementary Table 3

    Characteristics of SNPs in SORL1.

  4. 4.

    Supplementary Table 4

    Single SNP results for all 29 SORL1 SNPs in the six primary datasets.

  5. 5.

    Supplementary Table 5

    Three-SNP haplotypes for all SORL1 SNPs.

  6. 6.

    Supplementary Table 6

    Two-SNP haplotypes for all SORL1 SNPs.

  7. 7.

    Supplementary Table 7

    Four-SNP haplotypes for all SORL1 SNPs.

  8. 8.

    Supplementary Table 8

    Five-SNP haplotypes for all SORL1 SNPs.

  9. 9.

    Supplementary Table 9

    Six-SNP haplotypes for all SORL1 SNPs.

  10. 10.

    Supplementary Table 10

    Rare sequence variants in SORL1.

  11. 11.

    Supplementary Table 11

    Authors' roles in the study.

About this article

Publication history

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DOI

https://doi.org/10.1038/ng1943

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