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Study Detects a Gene Linked to Alzheimer’s, by NICHOLAS WADE -- Jan 15, 2007 NY Times A variant gene involved in Alzheimer’s disease has been detected through study of Dominican families living in Manhattan, scientists are reporting today. The families have about three times the usual incidence of Alzheimer’s, a finding that led Dr. Richard Mayeux of Columbia University in 1994 to start looking for anything in their environment that could be touching off the disease. Finding nothing, Dr. Mayeux decided to search for a genetic cause, a task that seemed worth trying because the Dominican Republic, where the families came from, is a single, long-isolated population in which variant genes are easier to detect. He enlisted three colleagues who were studying Alzheimer’s in other populations, in a strategy of looking for mutations in a set of seven genes. The genes are known to be involved in directing the traffic of proteins inside cells, and are plausible candidates for contributing to Alzheimer’s because the disease seems to result from an abnormal buildup of protein inside the nerve cell. Having genetically screened some 6,000 people, the researchers found that, in four of their populations, people with Alzheimer’s had distinguishing genetic markers in just one of the seven genes, known as SORL1. Patients with the variant forms of the gene produce less of that gene’s protein than usual, leading to a different traffic pattern and allowing a particular protein in nerve cells, known as the amyloid precursor protein, to be converted into toxic form. The finding is being reported today in the journal Nature Genetics by four teams led by Dr. Mayeux, Dr. Peter St. George-Hyslop of the University of Toronto, Dr. Lindsay Farrer of Boston University and Dr. Steven Younkin of the Mayo Clinic Jacksonville. The researchers have not yet isolated the specific mutation that affects the gene, but they believe it reduces production of the gene’s protein and does not harm the protein itself. That raises the possibility of developing a drug to stimulate extra production of the protein, which would be expected to have a protective effect. Alzheimer’s can be prompted by any of several errant genes. A gene that can carry a very high risk for the disease, the apolipoprotein E gene, was discovered in 1993. Hundreds of reports since then have nominated other possible genes, but many of the claims have not been confirmed. Two geneticists at Massachusetts General Hospital, Lars Bertram and Rudolph Tanzi, have tried to bring order to this confused field by combining the data from many studies. In an article in Nature Genetics earlier this month, they presented a group of 13 genes besides apolipoprotein E that have a statistically significant association with Alzheimer’s. Dr. Tanzi said that he had run the numbers on SORL1 and that it would qualify at present for a place in his canon. “This is another gene worth paying attention to,” he said, “but we really have to wait for more replications.” Dr. Mayeux said he regarded the SORL1 gene as more robustly associated with Alzheimer’s than all the other genes except apolipoprotein E, since it had been checked in four different populations and the variant had been shown to have a biological effect in Alzheimer’s patients. But Dr. Tanzi said that in terms of the burden of disease the gene causes, it would rank 13th on his list. Researchers hope that the more Alzheimer-associated genes they find, the more possible targets will emerge both for drugs and for diagnostic tests that can tell who is at risk for the disease. Published online: 14 January 2007; | doi:10.1038/ng1943 The neuronal sortilin-related receptor SORL1 is genetically associated with Alzheimer disease Ekaterina Rogaeva1, 15, Yan Meng2, 15, Joseph H Lee3, 15, Yongjun Gu1, 15, Toshitaka Kawarai1, 15, Fanggeng Zou4, 15, Taiichi Katayama1, Clinton T Baldwin2, Rong Cheng3, Hiroshi Hasegawa1, Fusheng Chen1, Nobuto Shibata1, Kathryn L Lunetta2, Raphaelle Pardossi-Piquard1, Christopher Bohm1, Yosuke Wakutani1, L Adrienne Cupples2, Karen T Cuenco2, Robert C Green2, Lorenzo Pinessi5, Innocenzo Rainero5, Sandro Sorbi6, Amalia Bruni7, Ranjan Duara8, Robert P Friedland9, Rivka Inzelberg10, Wolfgang Hampe11, Hideaki Bujo12, You-Qiang Song13, Olav M Andersen14, Thomas E Willnow14, Neill Graff-Radford4, Ronald C Petersen4, Dennis Dickson4, Sandy D Der1, Paul E Fraser1, Gerold Schmitt-Ulms1, Steven Younkin4, Richard Mayeux3, Lindsay A Farrer2 & Peter St 15 These authors contributed equally to this work. George-Hyslop1 Correspondence should be addressed to Richard Mayeux [email protected] or Lindsay A Farrer [email protected] or Peter St George-Hyslop [email protected] 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, 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. 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. 5 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. 10 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.