Researchers from the MassGeneral Institute for Neurodegenerative Disorders ( MIND ) in Charlestown have identified a gene variant that may increase the risk of late-onset Alzheimer's disease.

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.
The investigators analyzed several sequence variations in ubiquilin-1 and two other candidate genes located nearby on chromosome 9.

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.
The results indicated that particular changes in the ubiquilin-1 gene sequence occurred more frequently in individuals with Alzheimer's than in their unaffected siblings.

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.

The 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.

Source: The New England Journal of Medicine, 2005

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