New Gene Uncovered for Late-Onset Alzheimer's Disease

Columbia University Medical Center

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 January 14 advance online edition of Nature Genetics, 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 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 amyloid beta 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.

Effect Cuts Across Diverse Ethnic Groups

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 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.  Richard Mayeux, co-director of the Taub Institute for Research on Alzheimer’s Disease and the Aging Brain. “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.”

Columbia University Medical Center provides international leadership in pre-clinical and clinical research, in medical and health sciences education, and in patient care. The medical center trains future leaders and includes the dedicated work of many physicians, scientists, nurses, dentists, and public health professionals at the College of Physicians & Surgeons, the College of Dental Medicine, the School of Nursing, the Mailman School of Public Health, the biomedical departments of the Graduate School of Arts and Sciences, and allied research centers and institutions. 

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