New Gene Uncovered for Alzheimer’s Disease

in Health & Medicine, News Releases, School of Medicine
January 14th, 2007

Contact: Gina M. Digravio, 617-638-8491 | gina.digravio@bmc.org

(Boston) – An international effort by researchers led by Boston University School of Medicine (BUSM), the University of Toronto, and Columbia University has uncovered a major new gene – SORL1 – for late-onset Alzheimer’s disease. Replicated in four distinct ethnic groups, SORL1 is only the second gene discovered for late-onset Alzheimer’s. APOE, 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 (Aβ) peptides in the brain resulting in Alzheimer disease. When the SORL1 gene works properly, it sends APP along recycling pathways – preventing it from being cut into toxic Aβ forms.

People with these genetic variants may not produce normal amounts of SORL1, suggesting that this gene has a protective function when working properly. The researchers believe that the reduction of SORL1 in the brain increases the likelihood of developing Alzheimer disease.

An important aspect of their findings was that the association between Alzheimer disease and SORL1 was replicated in four distinct ethnic groups: North American and European Caucasians, African-Americans, Caribbean-Hispanics, and Israeli-Arabs. Previous studies on the genetics of Alzheimer’s used data from mostly Caucasian populations of American and European ancestry. This five-year study involved DNA samples from 6,000 volunteers.

The research team at BUSM was led by Lindsay Farrer, PhD, chief of the Genetics Program. The team at the University of Toronto was led by Peter St. George-Hyslop, MD, director of the Centre for Research in Neurodegenerative Diseases, and the Columbia University Medical Center team was led by Richard Mayeux, MD, co-director of the Taub Institute for Research on Alzheimer’s Disease and the Aging Brain. Steven Younkin, MD, PhD, chair of Department of Pharmacology at the Mayo Clinic College of Medicine in Jacksonville, Fla. provided DNA samples from several populations studied at the Mayo clinic.

“Instead of scanning all the genes in the entire genome, we had an idea of what an Alzheimer disease-causing gene would look like based on past discoveries,” said St. George-Hyslop. “We knew that the abnormalities in APP processing and the accumulation of its toxic Aβ peptide derivative cause Alzheimer’s, so we hypothesized that other genes associated with APP regulation might also cause the disease.”

“The importance of the finding is that it opens new pathways to explore the cause as well as potential targets for treatment of this devastating disease,” said Mayeux. “SORL1 represents another critical piece of the Alzheimer disease puzzle. This appears to be the second late-onset Alzheimer disease gene, and there are likely to be other important genetic variants that need to be identified before the entire picture is complete.”

Farrer cautions that more studies are needed. “While we have identified several variants in SORL1 that show the same pattern of association across multiple ethnic groups with very different genetic makeup and lifestyle characteristics, it is unclear whether these variants influence the disease process directly or merely mark the location in the SORL1 gene of the biologically important variants, which have not yet been tested. SORL1 is a relatively large gene containing at least 500 known variants called single nucleotide polymorphisms (SNPs). We examined a representative sample of about 30 SNPs across SORL1 and, unfortunately, have not yet found a ‘smoking SNP’ for Alzheimer disease.”

Diversity and Uniqueness of Populations Tapped for Discovery

Searches for genes for common disorders such as Alzheimer’s, heart disease, diabetes and asthma often have been frustrated by the lack of positive results and the inability to confirm findings in other populations. To enhance the chances for success, several diverse and unique populations were included in this study.

In 1998, Farrer and his BUSM colleagues began studying elderly residents of Wadi Ara, an Arab community in Northern Israel in which prior studies revealed an extraordinarily high incidence of Alzheimer’s and an absence of the ε4 variant of APOE, the primary genetic risk factor for the disorder in most Caucasian populations. “We reasoned that the high incidence of Alzheimer’s in Wadi Ara, where the residents trace their ancestry to a small group of founders and have similar dietary and life style habits, is likely caused by a few gene variants other than APOE,” said Farrer.

Similarly in 1994 Mayeux noticed, upon studying elderly residents of Washington Heights, a predominantly Hispanic neighborhood in Northern Manhattan, that Caribbean-Hispanics from the Dominican Republic have about three times the rate of Alzheimer disease compared to individuals of different ethnic backgrounds in the community. Mayeux decided to find out why this population has such a high incidence of Alzheimer’s. He and his Columbia team began visiting Dominican families living in both Washington Heights and the Dominican Republic to collect blood samples from entire families in order to look for similar gene variants in relatives diagnosed with Alzheimer’s.

Within a few years following the discovery of the APOE association with Alzheimer disease, several studies suggested that the effect of APOE is much weaker in African-Americans, an ethnic group with a rate of Alzheimer’s similar to that in Caucasians. This observation prompted Farrer in 1998 to add a focus on African-Americans to his large federally-funded multi-center genetic epidemiology study of Alzheimer’s disease (the MIRAGE Study). “Historically, African-Americans have been poorly represented in medical research studies as compared to Caucasian Americans,” Farrer. Approximately 250 African-American MIRAGE Study families including at least one sibling diagnosed with Alzheimer’s and one cognitively normal sibling ascertained primarily at Morehouse School of Medicine in Atlanta and the University of Alabama in Birmingham were included in this study.

The total study 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. The discovery sample included 350 families (representing a total of 1,800 people, half of whom were diagnosed with Alzheimer’s) from Columbia University Medical Center (Caribbean-Hispanics) and the University of Toronto (American and European Caucasians) and 500 Caucasian and African-American families (representing a total of 1,000 people) from the MIRAGE Study. The confirmation sample included the Israeli-Arab group, another group of unrelated Caucasian Alzheimer patients and controls from the University of Toronto, and a large series of mostly Caucasian Alzheimer patients and controls from the Mayo Clinic. 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.

Study Funding

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’s 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 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.

The Genetics Program at Boston University School of Medicine was established in 1998 to foment and provide leadership in human and medical genetics research, and extend and develop new genetics curricula for graduate and medical students and postdoctoral fellows seeking academic research careers. Research programs in the Genetics Program include clinical, epidemiological and basic investigation approaches to explore the genetic basis of a broad spectrum of human diseases and other traits. The Genetics Program also houses the Molecular Genetics Core facility which provides DNA extraction, sequencing and genotyping services and tissue culture services to laboratories on both University campuses as well as to non-University laboratories. For more information about the Genetics Program visit: http://www.bumc.bu.edu

Boston University School of Medicine is a leading academic and research institution, with an enrollment of nearly 630 students and more than 1,100 full and part-time faculty members. It is known for its programs in arthritis, cardiovascular disease, cancer, human genetics, pulmonary disease and dermatology, among others, and is one of the major biomedical research institutions in the United States. The School is affiliated with Boston Medical Center, its principal teaching hospital, and Boston Veterans Administration Medical Center. Along with Boston Medical Center and 15 community health centers, the School of Medicine is a partner in Boston HealthNet.

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