March 11, 2005

MIND study identifies potential Alzheimer's risk gene

Researchers from the MassGeneral Institute for Neurodegenerative Disorders (MIND) have identified a gene variant that may increase the risk of late-onset Alzheimer's disease. In the March 3 New England Journal of Medicine, they reported 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 and 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."

Mutations that raise the risk of Alzheimer's have been found in four genes. Three of these cause rare, inherited, early-onset forms of the devastating disorder, and only one has been associated with the more common late-onset form. Ubiquilin-1 is known to interact with proteins coded by two of the early-onset genes and is located on part of chromosome 9 previously identified as a potential gene "hotspot." By analyzing sequence variations in ubiquilin-1 genes from members of two large groups of Alzheimer's patients and their siblings, the study confirmed that particular changes in the gene sequence occurred more frequently in Alzheimer's patients. The variant forms also were found to lead 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 Rudolph Tanzi, PhD, director of the Genetics and Aging Unit and senior author of the study. The MGH researchers estimate that the increased risk accompanying these ubiquilin-1 gene variants is less than half that conferred by ApoE4, the other identified late-onset gene.