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."
The researchers then studied brain tissue from Alzheimer's patients and controls to see if the identified gene variants actually change the production of ubiquilin-1. In both groups, the same gene variants that increased the risk of Alzheimer's also led to increased production of a shorter form of ubiquilin-1, an overproduction that was even more pronounced in the patients. "Now we need to figure out what's wrong with too much ubiquilin-1 and with this different form," says Tanzi. "We need to look at how this variant interacts with the presenilins and what effect that may have on the production of A-beta," the protein that accumulates in the amyloid plaques found in the brains of Alzheimer's patients. Tanzi is a professor of Neurology at HMS.
The MGH researchers estimate that the increased risk accompanying these ubiquilin-1 gene variants is less than half that conferred by ApoE4. They and other research groups expect that 4 to 7 additional gene variants may be found that confer similar levels of risk.
Co-authors of the NEJM report are Mikko Hiltunen, PhD, Michelle Parkinson, Martin Ingelsson, MD, Karunya Ramasamy, Kristina Mullin, Rashmi Menon, Andrew Sampson, Monica Hsiao, Thomas Moscarillo, Bradley Hyman, MD, and Deborah Blacker, MD, ScD, all of the MGH; Christoph Lange, PhD, Harvard School of Public Health; and Kathryn Elliott, Gonul Velicelebi, PhD, Steven Wagner, PhD, and David Becker, PhD, Neurogenetics, Inc. The study was supported by grants from NIMH, the National Institute on Aging, the Alzheimer Association, the Deutsche Forschungsgemeinschaft, the Harvard Center for Neurodegeneration and Repair, and the National Alliance for Research on Schizophrenia and Depression.