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 peptide (A) 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 A-generating compartments. These data suggest that inherited or acquired changes in SORL1 expression or function are mechanistically involved in causing Alzheimer disease.

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.
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.
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.
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.
5. Department of Neuroscience, University of Turin, Via Cherasco 15, 10126 Turin, Italy.
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.
7. Regional Center of Neurogenetics, AS6, 88046 Lamezia Terme (CZ), Italy.
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.
9. Department of Neurology, Case Western Reserve University, Cleveland, Ohio 44106, USA.
10. Meir Hospital, Kfar Saba and Rappaport Faculty of Medicine, Technion, Haifa, Israel 47441.
11. Department of Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, Martinstrasse 52, 20246 Hamburg, Germany.
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.
13. Department of Biochemistry, Department of Orthopaedic Surgery and The Genome Research Centre, University of Hong Kong, Hong Kong.
14. Department of Molecular Cardiovascular Research, Max Delbrueck Center for Molecular Medicine, Robert Roessle Str. 10, D-13125 Berlin, Germany.
15. These authors contributed equally to this work.

Correspondence to: Richard Mayeux³ e-mail: rpm2@columbia.edu

Correspondence to: Lindsay A Farrer² e-mail: farrer@bu.edu

Correspondence to: Peter St George-Hyslop¹ e-mail: p.hyslop@utoronto.ca

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