Alzheimer’s disease consortium identifies four new genes for Alzheimer’s disease risk

(Press-News.org) (NEW YORK, NY, April 3, 2011) – In the largest study of its kind, researchers from a consortium that includes Columbia University Medical Center identified four new genes linked to late-onset Alzheimer's disease. Each of these genes adds to the risk of developing this most common form of the disease, and together they offer a portal into the causes of Alzheimer's. Their identification will help researchers find ways to determine who is at risk of developing the disease, which will be critical as preventive measures become available, and to identify proteins and pathways for drug development. The findings appear in the current issue of Nature Genetics.

"A significant aspect of our research is that these genes clarify three new pathways," said Richard Mayeux, MD., MS., one of the lead scientists in the Alzheimer's Disease Genetics Consortium (ADGC) and Chairman of the Department of Neurology of Columbia University Medical Center. "APOE-e4 and the other genes identified earlier are related to the accumulation of amyloid in the brain; these new genes are involved in inflammatory processes, lipid metabolism, and the movement of molecules within cells. Therefore, we may now have four pathways that are critically related to the disease and that could really make a difference in how we study and potentially prevent and treat it."

(Dr. Mayeux is also the Gertrude H. Sergievsky Professor of Neurology, Psychiatry and Epidemiology; Director of the Gertrude H. Sergievsky Center, which is devoted to the epidemiological investigation of neurological diseases; and Co-Director of the Taub Institute for Research on Alzheimer's Disease and the Aging Brain at Columbia University Medical Center).

The study, conducted by the ADGC and led by the University of Pennsylvania School of Medicine, the University of Miami, Boston University School of Medicine and Columbia University, reports genetic analysis of more than 11,000 people with Alzheimer's and a nearly equal number of elderly people with no symptoms of dementia. Three other consortia provided additional, confirming data, bringing the total number of people studied to more than 54,000. The consortium also contributed to identification of a fifth gene, reported by other groups of investigators from the United States, the United Kingdom, France, and other European countries.

The study reflects the collaborative effort of investigators from 44 universities and research institutions in the United States, led by Gerard D. Schellenberg, PhD, at Penn, with primary analysis sites at Miami, led by Margaret A. Pericak-Vance, PhD, and at Boston, led by Lindsay A. Farrer, PhD.

"This is the culmination of years of work on Alzheimer's disease by a large number of scientists, yet it is just the beginning in defining how genes influence memory and intellectual function as we age. We're all tremendously excited by our progress so far, but much remains to be done, both in understanding the genetics and in defining how these genes influence the disease process," Schellenberg said.

Until recently, only four genes associated with late-onset Alzheimer's had been confirmed, with the gene for apolipoprotein E-e4 (APOE-e4) having the largest effect on risk. The Nature Genetics studies add another four: MS4A, CD2AP, CD33, and EPHA1. The studies also contributed to the identification and confirmation of two other genes, BIN1 and ABCA7.

The researchers' ultimate aims are two-fold. First, identification of new Alzheimer's disease genes will provide major clues as to its underlying cause. Genetic studies can also provide new insights into the molecules at the center of the disease. Such knowledge is critical for drug discovery, as currently available treatments are only marginally effective.

Second, gene discovery of the type highlighted in the Nature Genetics article will contribute to the ability to predict who is at greatest risk of developing Alzheimer's disease; this will be important as preventive measures become available. Identification of these risk genes will also help researchers to determine the disease-initiating steps that begin in the brain long before any symptoms of memory loss or intellectual decline are apparent. Eventually, it is hoped that researchers will be able to describe the events that lead to the destruction of large parts of the brain and, ultimately, complete loss of cognitive abilities.

Alzheimer's genetics researchers are currently joining forces for an even larger study. The Alzheimer's Association in the U.S. and the Fondation Plan Alzheimer in France have funded the formation of the International Genomics of Alzheimer's Project, whose members met for the first time in November 2010 in Paris.

### The research published in Nature Genetics was supported by the National Institute on Aging, part of the National Institutes of Health, which includes 29 Alzheimer's Disease Centers, the National Alzheimer's Coordinating Center, the NIA Genetics of Alzheimer's Disease Data Storage Site, the NIA Late Onset Alzheimer's Disease Family Study, and the National Cell Repository for Alzheimer's Disease. Together, they collect, store, and make available to qualified researchers DNA samples, datasets containing biomedical and demographic information about participants, and genetic analysis data.

About Alzheimer's Disease
Alzheimer's disease is a progressive neurodegenerative disorder for which there is currently no prevention. Available drugs only marginally affect disease severity and progression, making the disease effectively untreatable. Alzheimer's invariably progresses to complete incapacitation and death over a period of several years; and although the average length of time from onset of symptoms to death is 4 to 8 years, a person can survive 20 years or more after diagnosis. The risk for Alzheimer's rises exponentially with age, increasing from 3 to 5 percent for 65 to 69 years to ~30 to 40 percent for 85 to 89 years. There are 35 million people with Alzheimer's disease worldwide. In the U.S., 3 to 5 million people have Alzheimer's, costing $24.6 billion per year for health care and an additional $36.5 billion per year for lost productivity, worker absenteeism, and replacement. As the population ages, in the U.S., Alzheimer's cases will increase to 8 to 16 million by 2050, affecting 1 in 45 Americans and adding enormously to future health care costs. The cost in human suffering is, of course, incalculable. Identification of genes that contribute to Alzheimer's disease risk and that influence other characteristics of Alzheimer's disease may reveal basic pathogenic mechanisms, identify proteins and pathways for drug development, and provide genetic methods for determining people at greatest risk for when preventive measures become available.

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 among researchers and clinicians to uncover the causes of Alzheimer's, Parkinson's, and other age-related brain diseases and to 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:
http://www.cumc.columbia.edu/dept/taub/
http://www.cumc.columbia.edu/dept/sergievsky/

Columbia University Medical Center provides international leadership in basic, 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, public health professionals, dentists, and nurses at the College of Physicians and Surgeons, the Mailman School of Public Health, the College of Dental Medicine, the School of Nursing, the biomedical departments of the Graduate School of Arts and Sciences, and allied research centers and institutions. Established in 1767, Columbia's College of Physicians and Surgeons was the first institution in the country to grant the M.D. degree and is among the most selective medical schools in the country. Columbia University Medical Center is home to the largest medical research enterprise in New York City and State and one of the largest in the United States. For more information, please visit www.cumc.columbia.edu.