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Another Risk Factor for Alzheimer’s?

Newly discovered variants in a key gene may indicate a modest risk for late-onset Alzheimer’s disease.
January 16, 2007

Scientists who have studied the genetic makeup of several large and ethnically diverse populations have discovered another gene that may be a modest risk factor for Alzheimer’s disease. The gene, called SORL1, may be involved in the development of late-onset Alzheimer’s, the most common form of the disease, which occurs after age 65 and accounts for 90 percent of Alzheimer’s cases today. Researchers say determining how SORL1 and other genes cause or influence Alzheimer’s disease could open up new avenues for diagnosis and treatment.

“Ultimately, one wants to be able to profile an individual for genes and variants within genes … that may give an understanding of the disease process,” says Lindsay Farrer, chief of the genetics program at Boston University. “And secondly … therapies can be tailored to an individual’s profile. We’re still in the early days of filling in the pieces of that puzzle.”

Farrer and his colleagues zeroed in on the gene SORL1 thanks to previous studies that revealed a key biological pathway in Alzheimer’s. Today, most researchers agree that the disease is caused by a buildup of amyloid plaque in the brain. The chain of events that produces this plaque begins with a normal protein, amyloid precursor (app). When this protein comes in contact with a certain type of enzyme called presenilin, that enzyme cuts, or cleaves, app into a more toxic peptide, amyloid-beta. This sticky protein fragment clumps together to form amyloid plaques, killing nerve cells. For years, scientists have looked for ways to stem this cascade. SORL1, according to Farrer, could play a pivotal role in the disease’s pathway.

Through previous cellular experiments, Farrer and other research groups found that SORL1 is essentially a trafficking molecule. Under normal conditions, SORL1 directs app away from what researchers call the “forbidden zone”–where the enzyme presenilin resides–thus preventing the protein from being sliced apart to form toxic plaque.

“It’s like a delivery boy or carrier protein that delivers the amyloid precursor to various parts of the cell,” says Samuel Gandy, director of the Farber Institute of Neurosciences and vice chair of the Alzheimer’s Association’s Scientific Advisory Council. “It sits at the crossroads of a cell and tells proteins where to go.”

In a five-year study, published in the February edition of Nature Genetics, Farrer, along with colleagues from the University of Toronto, Columbia University, and the Mayo Clinic, analyzed DNA samples from 6,000 people across nine different groups. These groups included Northern-European Caucasians, Caribbean Hispanics, Israeli Arabs, and African Americans. Some groups were selected based on family history: two or more members had the disease. Others were selected based on sibling pairs: one sibling had Alzheimer’s, the other didn’t. The rest had no family linkage to the disease. All cases were compared with controls: genotypes of people without Alzheimer’s.

After analyzing 29 areas along the SORL1 gene that may harbor variations, normal or otherwise, scientists found two specific locations where variations were particularly present in those with late-onset Alzheimer’s. They hypothesize that these variations may be suppressing SORL1’s normal ability to steer app away from the forbidden zone.

“One of the reasons we’re encouraged by our findings is that we have observed the association in a large number of data sets,” says Farrer. “When you see it coming up again and again, we all get more heartened.”

Farrer’s next step is determining exactly how much of a risk these genetic variations pose for developing Alzheimer’s. Identifying genetic risk factors could help in early detection and treatment of the disease. To date, only one gene, apoe-4, has been singled out as a genetic risk factor for Alzheimer’s. People who inherit one copy of apoe-4 have an increased risk of developing the disease, while people who inherit two copies have an even higher risk, although the presence of apoe-4 does not guarantee that the disease will manifest.

Rudolph Tanzi, professor of neurology at Massachusetts General Hospital, recently coauthored a meta-analysis with Harvard colleague Lars Bertram comparing every study in the scientific literature having to do with genetics and Alzheimer’s. Their results confirmed that apoe-4 is the strongest known risk factor. As for other possible genes, he found that most that have been associated with Alzheimer’s tend to have much smaller effects, including Farrer’s recently studied SORL1.

“If apoe-4 is a major leaguer, these [other genes] would be in the minor leagues,” says Tanzi.

Still, many researchers believe Alzheimer’s disease may be caused by a complex interaction of these minor-league genes. People who have one kind of gene may develop Alzheimer’s, while others with the same risk gene may not, based on the presence of other genes that might protect against the disease.

“None of these genes are in a vacuum,” says Farrer. His colleague Steven Younkin, chair of the pharmacology department at the Mayo Clinic in Jacksonville, FL, echoes the need to identify genetic markers.

“It’s always hard to know which avenue is going to prove more fruitful,” says Younkin. “We need a diverse portfolio to influence this disease.”

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