July 16, 2008
Researchers have identified four new genes that may play a role in late-onset Alzheimer's, the most common form of the memory-ravaging illness that afflicts some five million Americans. The findings arose out of improved gene analysis technologies and may lead to new understanding and possible new treatments for the disabling brain disease.
"Only over the past five years have we had the tools necessary to identify the full set of genes influencing susceptibility to late-onset Alzheimer's, which probably involves gene-to-gene and gene-to-environment interactions," said study author Rudolph Tanzi, Ph.D., director of the Massachusetts General Hospital's MassGeneral Institute for Neurodegenerative Disease.
Dozens of genes are under investigation as possible contributing factors to Alzheimer's disease. Only one, called the APO-E4 gene, has been confirmed as a strong risk factor for late-onset disease, though not everyone who inherits this gene ends up with Alzheimer's. About 40 percent of those who develop late-onset Alzheimer's carry the APO-E4 gene.
Several other genes have been linked to early-onset Alzheimer's disease, which can occur in a person's 40s or even younger but that accounts for only about 5 to 10 percent of Alzheimer's cases.
"Virtually all current research into therapies is based on the Alzheimer's genes that we already know about; so each new gene we find not only enhances our ability to predict and diagnose the disease, but also provides valuable new clues about biochemical events and pathways involved in the disease process," Dr. Tanzi said.
Adds Lars Bertram, Ph.D., of MGH-MIND, co-lead author of the study: "The emergence of gene chips, which identify markers from the entire genome, along with databases provided by the Human Genome Project and huge advances in genetic analysis give us the means to identify genes that previously would not have been considered candidates."
In the study, the researchers tested around a half million DNA markers, covering most of the human genome, from more than 400 families in which at least three members were Alzheimer's patients. They found five markers exhibiting genetic association with Alzheimer's, one of which corresponds to the gene for APO-E4. The remaining four genes were novel genes that may be linked to Alzheimer's.
To confirm the four novel sites, the researchers analyzed samples from over 900 additional families. The strongest marker was located on chromosome 14. Their results were further supported by an independent analysis comparing 1,400 Alzheimer's patients with healthy controls.
"The genetic association of Alzheimer's with this novel chromosome 14 gene, which like APO-E4 appears to influence age of onset, is sufficiently strong to warrant intensive follow-up investigations into its role in the process of nerve cell death in this disease," Dr. Tanzi said. "This gene also is in the general vicinity of the presenilin-1 gene, which we know is an early-onset Alzheimer's disease gene. We don't know if that proximity is a coincidence, and we currently don't know what the new gene does, although there is some indication it may control the activity of other genes."
The researchers hope that continued study of genes that may contribute to Alzheimer's will lead to better understanding of the disease. It may also allow for the development of new drugs that may be able to halt or reverse the memory and behavior problems of the disease.
The findings may help to explain some of the hereditary aspects of Alzheimer's disease. A study in March, for example, found that people whose parents both had Alzheimer's disease were more than twice as likely to develop the disease themselves. [See the article, "Risk of Alzheimer's Increases When Both Parents Have the Disease."]
But Alzheimer's is a complex disease that researchers are only now beginning to understand. In addition to genetic factors, lifestyle factors like diet and exercise, mental and social stimulation, advancing age, and other environmental components may all play a role in its onset. It will likely take years of continued research to understand the roles of these and other genes in memory and Alzheimer's.
Source: American Journal of Human Genetics, October 31, 2008.