Another Path to Alzheimer's
BU geneticists help uncover new gene for the debilitating disease
By Chris Berdik
Lindsay Farrer, School of Medicine
chief of genetics, is leading BU
researchers in the hunt for the genes
behind Alzheimer’s.
Photo courtesy of MetroWest Daily News
About a decade ago, scientists discovered the first genetic link to Alzheimer’s disease, which afflicts more than four million Americans. Now, Boston University geneticists, collaborating with an international team of researchers, have uncovered a second major genetic association with the deadly disease.
The BU scientists, along with researchers from the University of Toronto and Columbia University, analyzed the DNA of some 6,800 individuals from nine populations, representing four main ethnic groups (Caucasians, African-Americans, Caribbean Hispanics, and Israeli Arabs). They found that variants of the SORL1 gene were more common in people with late-onset Alzheimer’s, the most common form of the disease.
Lead BU researcher Lindsay Farrer, a School of Medicine professor and chief of the genetics program, describes the protein produced by SORL1 as a kind of “traffic cop” in human cells, directing other proteins and molecules where they can and can’t go. One of the key pieces of this intercellular traffic pattern is amyloid precursor protein (APP). When SORL1 is functioning normally, Farrer and his team believe, its protein shuttles APP down a pathway where it metabolizes harmlessly. But, they believe, the genetic variants of SORL1 either reduce the amount of this traffic cop protein or they lead to an altered variety that allows APP to stray into a region of the cell where it degrades into its toxic form, leading to plaques that, in Farrer’s words, “gunk up the brain.”
At this point, that biological scenario remains a hypothesis. What the researchers have found is an association between gene variants and Alzheimer’s disease. The replication of this finding across several populations gives the association strength and scientific validity, but, Farrer notes, “people should not be thinking they can go get their SORL1 gene analyzed and then make a prediction that they will or won’t get Alzheimer’s based on it.”
Fully understanding the biological mechanism that underlies these associations is complicated by the unusually large size of SORL1, which contains at least 500 known variants. So far, researchers have examined only about thirty. Further discoveries, says Farrer, will most likely require the same kind of multi-institution effort that produced this result.
BU geneticists are already engaged in several collaborative efforts. The Alzheimer’s researchers, for example, have been contributing their data and DNA specimens (with subjects’ consent) to a national repository that can be used by other researchers. And in September 2006, the MED department of genetics and genomics launched a Genetic Medicine Database, a searchable collection of prepublication results from BU researchers’ genetic analysis of 320 families from the Framingham Heart Study, the long-running epidemiological study begun by the National Heart, Lung, and Blood Institute in 1948 and run by BU since 1971.
Farrer and his fellow researchers plan to continue investigating the SORL1 gene to zero in on the “biologically causal variants.” They’ll also begin investigations of related genes “to see if SORL1 has any coconspirators.” Farrer says that it’s an “attractive therapeutic target” because of its genetic association with Alzheimer’s and its role in APP processing. Eventually, he says, “we will begin working with others who have greater pharmacological and cell biological expertise than us, in order to try to translate this finding into a possible treatment.