Download The neuronal sortilin-related receptor SORL1 is genetically

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.