An international team of researchers, led by Columbia University Medical Center, Boston University School of Medicine and the University of Toronto, has uncovered a major new gene -- SORL1 -- implicated in late-onset Alzheimer's disease. Replicated in four distinct ethnic groups, SORL1 is only the second genetic variant for late-onset Alzheimer's, the type of Alzheimer's found in 90 percent of people with this devastating disease. ApoE4, the first, was identified in 1993.
In an article published in the Jan. 14 advance on-line edition of Nature Genetics (February print edition), researchers describe how variants in the SORL1 gene were found to be more common in people with late-onset Alzheimer's than in healthy people the same age. The authors believe that these genetic variants alter the normal function of SORL1, sending amyloid precursor protein (APP) down a pathway that increases the production of the toxic amyloid beta (A£]) peptides in the brain resulting in Alzheimer's. When the SORL1 gene works properly, it sends APP along recycling pathways -- preventing it from being cut into toxic A£] forms.
People with these genetic variants may not produce normal amounts of SORL1, suggesting that this gene has protective function when working properly. The researchers believe that the reduction of SORL1 in the brain increases the likelihood of developing Alzheimer's disease.
An important aspect of their findings was that the association between Alzheimer's disease and SORL1 was replicated in four distinct ethnic groups: Caribbean-Hispanics, North Europeans, African-Americans and Israeli-Arabs. Many previous studies on the genetics of Alzheimer's used data from mostly white populations of American and European ancestry. In total, the five-year federally- and internationally-funded study involved DNA samples from 6,000 volunteers.
The research team at Columbia University Medical Center was led by Richard Mayeux, M.D., co-director of the Taub Institute for Research on Alzheimer's Disease and the Aging Brain. The team at the University of Toronto was led by Peter St. George-Hyslop, M.D., director of the Centre for Research in Neurodegenerative Diseases, and the Boston University team by Lindsay Farrer, Ph.D., chief of the Genetics Program. Steven Younkin, M.D., Ph.D., chair of Department of Pharmacology at the Mayo Clinic College of Medicine in Jacksonville, Fla. also provided DNA samples from the Mayo's respective unique populations for the study.
"The importance of the finding is that it opens new pathways to explore the cause and as well as potential targets for treatment of this devastating disease," said Dr. Mayeux. "SORL1 represents another critical piece of the Alzheimer's disease puzzle. This appears to be the fifth Alzheimer's disease gene, and there are likely to be other important genetic variants that need to be identified before the entire picture is complete."
"Instead of scanning all the genes in the entire genome, we had an idea of what an Alzheimer's disease-causing gene would look like based on past discoveries," said Dr. St. George-Hyslop. "We knew that the abnormalities in APP processing and the accumulation of its toxic amyloid beta (AƒÒ) peptide derivative cause Alzheimer's, so we hypothesized that other genes associated with APP regulation might also cause the disease."
Genetic Homogeneity of Dominican Population Tapped for Discovery
In 1994, Dr. Mayeux noticed, upon studying elderly residents of Washington Heights, a predominantly Hispanic neighborhood in Northern Manhattan where Columbia University Medical Center is located, that Dominicans have about three times the rate of Alzheimer's disease compared to individuals of different ethnic backgrounds in the community. Dr. Mayeux decided to find out why this population has such a high incidence of Alzheimer's, so he and his Columbia team began visiting Dominican families living in both Washington Heights and the Dominican Republic to collect blood samples of entire families in order to look for similar gene variations in relatives diagnosed with Alzheimer's.
"The Dominican population is very concerned about the increased frequency of disease and was very helpful in forming the basis of this study. From a genetic perspective, Dominicans are a relatively homogenous population, and follow similar diet and living patterns," said Dr. Mayeux. "Because individuals within families stay in touch and remain close to one another even after migrating to the United States, we were able to identify families in this large population that were very similar genetically."
To confirm their preliminary findings, Drs. Mayeux and St. George-Hyslop, his collaborator of more than 25 years, reached out to other colleagues who tapped genetic records of people of from even more diverse ethnic backgrounds.
In total, the initial discovery group included 350 families (representing a total of 1,800 people, half of whom had Alzheimer's), from Columbia University Medical Center and the University of Toronto. The group was divided into two parts: one that was analyzed to help with the discovery of SORL1, and a second that was analyzed to confirm the role of the gene. To this collection, Dr. Farrer, from Boston University School of Medicine, added 500 African-American sibling pairs (representing a total of 1,000 people), where one sibling was diagnosed with Alzheimer's and the other was not. Farrer also enabled the researchers to reconfirm their findings in an examination of data from Israeli-Arabs, while Younkin's data from mostly white Alzheimer's patients provided by the Mayo Clinic also confirmed the findings. Interestingly, the same variant was found in both the Israeli-Arab and Caribbean-Hispanic groups, which indicates that generations ago these two groups may have been genetically or geographically linked.
Seeking Pathogenesis of SORL1 & Attributable Risk of SORL1 Variants
"Now that we know that variants in SORL1 are associated with late-onset Alzheimer's disease and we know the specific regions of the gene involved, our next step is to determine which of the variants contain the specific disease causing alteration," said Dr. Mayeux.
Another next step is to determine how many cases of late-onset Alzheimer's are caused by these SORL1 variants; it is known that ApoE4 explains approximately 20 percent of all cases of late-onset Alzheimer's. Studies are planned to investigate how many Alzheimer's cases are attributable to SORL1. The hope is that this information will help develop accurate screening for this gene.
This research was funded by the National Institute on Aging of the National Institutes of Health, the Alzheimer's Association of the United States, the Canadian Institutes of Health Research, Howard Hughes Medical Institute, the Alzheimer Society of Ontario, the Canada Foundation for Innovation, the Ontario Research and Development Challenge Fund, Genome Canada and the Banbury Fund.
Facts about Alzheimer's Disease
Alzheimer's disease, which affects 4.5 million Americans, is differentiated as either early-onset or late-onset. The early-onset form is rare and tends to affect those between the ages of 30-60. Most cases of early-onset are genetic, caused by a mutation of the APP gene. The late-onset form is much more common -- accounts for 90 percent of all cases of Alzheimer's -- and tends to affect those aged 65 and older. With aging baby boomers, the prevalence of late-onset Alzheimer's is expected to double in the next 25 years as the population ages.
Interviews with study participants in the Dominican arm of the study and graphics, such as a diagram of the mechanism of SORL1 and a map pinpointing the Dominican families affected by Alzheimer's, are available by contacting Elizabeth Streich, Columbia University Medical Center, 212-305-6535; firstname.lastname@example.org.
The Taub Institute for Research on Alzheimer's Disease and the Aging Brain at Columbia University Medical Center is a multidisciplinary group that has forged links between researchers and clinicians to uncover the causes of Alzheimer's, Parkinson's and other age-related brain diseases and discover ways to prevent and cure these diseases. It has partnered with the Gertrude H. Sergievsky Center at Columbia University Medical Center which was established by an endowment in 1977 to focus on diseases of the nervous system. The Center integrates traditional epidemiology with genetic analysis and clinical investigation to explore all phases of diseases of the nervous system. For more information about these centers visit:
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