January 16, 2007, Updated September 13, 2012

The five-year study involved DNA samples from 6,000 volunteers.Researchers from the Technion in Haifa, Israel are part of an international team of scientists who have uncovered a major new gene – SORL1 – for late-onset Alzheimer disease.

Alzheimer’s disease, which affects 4.5 million Americans, is differentiated as either early-onset or late-onset. 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.

Replicated in four distinct ethnic groups, SORL1 is only the second gene discovered for late-onset Alzheimer’s. APOE, the first gene, was identified in 1993.

The researchers were led by Dr. Robert Friedland, Professor in the Department of Neurology, and a team of investigators at Case School of Medicine, in collaboration with an international effort by researchers led by Boston University School of Medicine (BUSM), the University of Toronto, Columbia University Medical Center, and the Technion. The Technion’s Dr. Rivka Inzelberg led the study of a community of Arabs in northern Israel.

In an article published in Nature Genetics, the 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. This suggests that these genetic variations alter the normal function of SORL1, resulting in Alzheimer disease. 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 Arabs residing in Israel.

“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,” said Richard Mayeux, M.D., co-director of the Taub Institute for Research on Alzheimer’s disease and the Aging Brain at Columbia University Medical Center.

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.

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 1996, Friedland and colleagues in Israel began studying elderly residents of Wadi Ara, an Arab community in northern Israel in which studies revealed a high incidence of Alzheimer’s and an absence of the E4 variant of APOE, the primary genetic risk factor for the disorder in most populations worldwide.

“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 Boston University School of Medicine chief of genetics Prof. Linday Farrer.

Inzelberg of the Technion joined the study team in 2003 and leads an interdisciplinary group of Arab and Jewish physicians, biostatisticians, nurses, social workers and research assistants in northern Israel who are collaborating with Friedland.

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.

Friedland reports that the work illustrates the value of diverse populations and international collaborations for understanding a complex disease such as Alzheimer’s. He also notes that the discovery of this new gene suggests new ways in which therapies can be developed, which is the ultimate goal of this work.

“Currently available therapies cannot arrest the progress of the disease,” Friedland notes. “Understanding how the forms of the SORL1 gene associated with increase risk alter protein handling will suggest novel pharmacological or lifestyle modifications to slow progression.”

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