Three Genes Linked to Alzheimer's Disease Risk

Genome studies highlight gene variants that may give new directions to studies of the disorder.

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By Tina Hesman Saey, Science News

Scientists have a new lead on genes that contribute to the risk of developing Alzheimer’s disease.

Comparing subtle genetic spelling variations in nearly 12,000 Alzheimer’s patients with almost 19,000 other people revealed three genes associated with the disease, two international teams of researchers report online September 6 in Nature Genetics.

These genes are the first to be implicated in the risk of getting the common form of Alzheimer’s since the variant of the apolipoprotein E gene APOE4 was identified in 1993. That gene’s influence may explain about 20 percent of cases of Alzheimer’s disease, says Philippe Amouyel of the French health research agency INSERM in Lille and coauthor of one of the new studies. But researchers knew other genes must be involved since 60 to 80 percent of the risk of developing the disease is genetic.

“If there were another gene that had the large effect like APOE, we would have seen it already,” says John C. Morris, director of the Alzheimer’s research center at Washington University in St. Louis. Since no other genes stood out, scientists decided to take a statistical approach and look for common variants of genes that could have subtle influence on the development of the disease. 

Both groups found single “letter” differences, called single nucleotide polymorphisms or SNPs, in the DNA surrounding the gene for clusterin. Also known as CLU or APOJ, clusterin is thought to help remove the plaque-forming molecule amyloid-beta from the brain. Amyloid-beta molecules clump together and somehow kill neurons in a process that isn’t fully understood (SN: 8/16/08, p. 20). 

The two studies “are remarkably consistent with each other,” says Caleb Finch, a neuroscientist at the University of Southern California in Los Angeles who was not involved in either of the studies. Finch predicts that the new studies will kindle more interest in the neurobiology of clusterin, a protein that his previous work has suggested may be important. It’s still not clear exactly how the new variant affects levels of the protein in the brain, he says.

“I’m open-minded about further complexities in the clusterin story and about further gene candidates,” he says.

In one of the new studies, a group led by Julie Williams of Cardiff University in Wales also discovered variants near a gene encoding the PICALM protein, short for phosphatidylinositol-binding clathrin assembly protein. That protein is involved in “controlling what gets into the cells and how it is transported to the rest of the cell,” Williams says. PICALM may help regulate the entry of a precursor to amyloid-beta into neurons, and also participates in regulating communications between neurons. 

Amouyel’s group identified a third gene variant linked to a reduced risk of Alzheimer’s disease. Called CR1, the complement component receptor gene codes for an immune system protein that punches holes in invading bacteria and plays a role in inflammation. Inflammation has been fingered as a probable culprit in the development of Alzheimer’s, but studies of inflammation have produced mixed results. On one hand, inflammation is necessary to clear amyloid-beta and other toxic debris from the brain. But too much inflammation damages tissues, Williams says. The form of CR1 identified in the study seems to have a protective effect against developing Alzheimer’s disease, but the researchers don’t yet know if the variant increases or decreases inflammation, she says.

Editor's Note: This story refers to the common (that is, late-onset) form of Alzheimer's disease. Other established mutations related to Alzheimer's have been for the risk of the rare early-onset form. Other reports of genetic links to Alzheimer's risk have not been replicated. As the researchers state in their paper: "More than 550 other genes have been proposed as candidates for Alzheimer's disease susceptibility, but thus far none have been confirmed to have a role in Alzheimer's disease pathogenesis."