A Second Risk Factor for Alzheimer's

Researchers led by Howard Hughes Medical Institute (HHMI) international research scholar Peter St George-Hyslop have identified a new genetic risk factor associated with the most common form of Alzheimer's disease. The research implicates a gene called SORL1 in late-onset Alzheimer's, which usually strikes after age 65.

In an advance online publication in Nature Genetics on January 14, 2007, St George-Hyslop and colleagues connected the gene to the disease in six different groups of people, although they did not pinpoint the exact genetic mutations in SORL1 responsible for Alzheimer's. In their studies, the researchers used databases that include genetic information about people with and without Alzheimer's disease. More than 6,800 individuals - 45.8 percent of them affected with the disease - were included in the analysis, which is considered a large data set in the field, said St George-Hyslop..

"We looked for variations of SORL1 in nine different groups of people and found those variations to be associated with an increased risk of Alzheimer's in six of them," St George-Hyslop said. "That implies that SORL1 is not the only cause of Alzheimer's, but it's one of several. Some people with the disease will have a SORL1-related cause, and some won't." St George-Hyslop is a professor in the department of medicine and director of the Center for Research in Neurodegenerative Disease at the University of Toronto and an HHMI international research scholar. Through its international research scholars program, HHMI supports leading scientists in 28 countries outside the United States.

The researchers studied several groups of Caucasians, one group of African Americans, one group of Hispanics from the Dominican Republic, and a group of Israeli Arabs. They tracked the SORL1 genes via single nucleotide polymorphisms, or SNPs, which are single-letter changes in a gene's sequence. They found that the Caucasians with Alzheimer's displayed a certain SNP signature at one end of the gene, while the African Americans, Hispanics, and Israeli Arabs with the disease displayed another SNP signature. "This implies that there are at least two, and possibly more, gene variants at work here," said St George-Hyslop. "That's not unusual - in many diseases you see multiple variations that all impact a specific gene."

The team used the SNP databases to track the SORL1 gene in the populations studied, but did not actually pinpoint the precise changes in the gene that contribute to disease. "Now we need to go back and look in the regions around the clusters of SNPs that we tracked and see if we can find additional genetic changes that are either unique or enriched in the individuals with Alzheimer's," said St George-Hyslop. "Then we'll have the actual genetic variations that lead to the disease."

After linking SORL1 to late-onset Alzheimer's, the team investigated the gene's function. Using cell culture studies, they discovered that decreasing the amount of SORL1 increased cells' production of amyloid-beta, a toxic fragment of another protein that destroys neurons. Production of amyloid-beta is the key event in the progression of Alzheimer's disease.