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

In the largest study of its kind, researchers from a consortium that includes Columbia University Medical Centre 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 Centre. '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 Centre, 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 Ageing Brain at Columbia University Medical Centre).

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 centre 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.