Bob DeMarco Alzheimer's Reading Room

Monday, January 15, 2007

New Gene Linked to Alzheimer's


"It fits into what we believe is the main mechanism of Alzheimer's already," Gandy said. "This reinforces the idea that we're on the right track with therapies already in the pipeline, while also suggesting a totally new strategy that could be used to target entirely new classes of drugs."




New Gene Linked to Alzheimer's


Source Forbes and

Nature Genetics




SUNDAY, Jan. 14 (HealthDay News) -- Scientists has discovered a major new gene and linked it to the development of late-onset Alzheimer's disease. The researchers found that faulty versions of the gene --known as SORL1 -- are more common among those with the disease than among healthy people of a similar age. The finding is significant, the researchers said, because the study included more than 6,000 people from a wide range of racial and ethnic groups -- white Europeans, blacks, Caribbean-Hispanics and Israeli-Arabs.

Abnormal SORL1 genes seem to set in motion a neurological chain of events that promotes the production of amyloid plaque in the brain -- a development integral to the onset of Alzheimer's.

People with these gene variants also appear to have fewer normal SORL1 genes overall, a dip that the researchers believe could also raise the risk for developing late-onset Alzheimer's.

But, the researchers added that not all people with the faulty SORL1 gene will develop Alzheimer's.

"There are multiple genes and maybe some environmental factors [involved], and it may be that some people carry a risk gene but don't get the disease," explained study co-author Dr. Richard Mayeux, co-director of the Taub Institute for Research on Alzheimer's Disease and the Aging Brain in New York City.

"So, until we map out all of (the) genes involved we're not going to understand exactly how to calculate risk for this disease," he said.

The findings are published in the Jan. 14 online issue of Nature Genetics.

Mayeux made his remarks during a news conference prior to the study's release. He was joined by his co-lead collaborators: Dr. Peter St. George-Hyslop, director of the University of Toronto's Centre for Research in Neurodegenerative Diseases; Lindsay Farrer, chief of Boston University's Genetics Program; and Dr. Steven Younkin, chairman of the department of pharmacology at the Mayo Clinic College of Medicine, in Jacksonville, Fla.

The researchers pointed out that three other genetic variants have been previously tied to the development of early onset Alzheimer's, a relatively rare form of the illness that typically strikes between the ages of 30 and 60.

However, only one other genetic variant has been previously linked to late-onset Alzheimer's, which typically strikes people over the age of 65 and accounts for 90 percent of all cases of the disease. This other variant -- known as ApoE4, and first isolated in 1993 -- is thought to account for about 20 percent of all late-onset Alzheimer's cases. ApoE4 is believed to elevate the risk of disease by between 30 percent and 40 percent, the researchers said.

As for the SORL1 variant, the study authors said it probably accounts for fewer cases of Alzheimer's than the ApoE4 variant.

The researchers based their SORL1 finding on a five-year genetic analysis of blood drawn from 6,000 people from around the globe. They included 500 black sibling pairs with one sibling who had Alzheimer's; 350 families in New York City, Toronto and the Dominican Republic -- totaling 1,800 people -- half of whom had the disease; and elderly residents of a northern Israeli-Arab community.

The researchers divided the entire pool into two groups -- one to establish the presence of SORL1 and the other to establish the gene's role. Describing SORL1 as a "big gene" that may contain as many as 500 variants, the researchers focused on the activities of just 29 -- leaving lots of gene turf yet to till.

None of the 29 variants so far appears to be directly related to an Alzheimer's chain of events.

But, when tallying the overall presence of both normal SORL1 and SORL1 with abnormal variants, the researchers found that in each of the racial and ethnic groups, SORL1 with variants was more common among the Alzheimer's patients than among the healthy men and women. And normal SORL1 was less common among those with the disease.

The researchers concluded that SORL1 clearly plays a role in the late-onset Alzheimer's.

While enthusiastic about the finding, Mayeux said it doesn't represent a smoking gun. "Alzheimer's disease is caused by a complex genetic puzzle, and the finding about SORL1 explains a section of the puzzle," he said. "It is not the entire story."

Mayeux and his colleagues stressed that much more work needs to be done.

Dr. Sam Gandy is chairman of the Alzheimer's Association's Medical and Scientific Advisory Council, and director of the Farber Institute for Neurosciences at Thomas Jefferson University in Philadelphia. He agreed that the new finding is just one step down a long and complicated research road, but he said it could be an important step.

"It fits into what we believe is the main mechanism of Alzheimer's already," Gandy said. "This reinforces the idea that we're on the right track with therapies already in the pipeline, while also suggesting a totally new strategy that could be used to target entirely new classes of drugs."

An estimated 4.5 million people in the United States have either early or late-onset Alzheimer's disease, a number that's expected to double during the next 25 years as the population ages.