In the March 3 New England Journal of Medicine they report that specific changes in the gene for a protein called ubiquilin-1 are associated with an increased incidence of Alzheimer's in two large study samples. The discovery could lead to improved understanding of the disease mechanism and a new target for the development of preventive and treatment strategies.
"We believe this variant moderately but significantly raises the risk of Alzheimer's disease," says Lars Bertram, MD, of the Genetics and Aging Unit at MIND, lead author of the study. "We now have to pinpoint the biological defects that accompany this finding, which also needs to be independently replicated in other Alzheimer's sample groups." Bertram is an assistant professor of Neurology at Harvard Medical School (HMS).
Mutations that raise the risk of Alzheimer's have been found in four genes. Three of these – involving the amyloid precursor, presenilin 1 and presenilin 2 proteins – cause rare, inherited, early-onset forms of the devastating disorder. The only genetic variation associated with the more common late-onset form is ApoE4, which increases risk but does not directly cause the disease. Researchers expect that several additional genes that affect the risk of developing Alzheimer's may be found.
In 2003, the same research team published results of a full-genome screen of Alzheimer's patients and their affected siblings in a sample of 437 families compiled by the National Institute of Mental Health (NIMH). That study identified several potential chromosome "hotspots" that could be associated with increased risk, one of the strongest on chromosome 9. Since the gene for ubiquilin-1, which is known to interact with the presenilins, resides in the same area of chromosome 9, the researchers chose to test it as a candidate gene.
For the current study the investigators analyzed several sequence variations in ubiquilin-1 and two other candidate genes located nearby on chromosome 9. With the assistance of colleagues from Neurogenetics, Inc., the MIND researchers used a technique called family-based genetic association analysis to evaluate 19 sequence changes in these three genes, searching for alterations more likely to appear in patients with Alzheimer's. After first screening families from the same NIMH study group examined in the 2003 full-genome screen, they retested potential associations in a separate group of 217 sibling pairs. The results confirmed that particular changes in the ubiquilin-1 gene sequence occurred more frequently in individuals with Alzheimer's than in their unaffected siblings.
"The same variants of this gene conferred increased risk for Alzheimer's in both of these large study groups," says Rudolph Tanzi, PhD, director of the Genetics and Aging Unit and senior author of the study. "It was very encouraging to have the results confirmed in so many families."