Researchers have identified a gene that appears to play a role in late-onset Alzheimer's disease. The findings may provide insights into how the disease progresses and clues to new therapeutic targets.
To date, researchers have found 72 genes that possibly contribute to the risk of late-onset Alzheimer's disease (mutations in another three cause Alzheimer's in middle-aged adults). Of the 72, only one has been shown unequivocally to put people at risk for the disease late in life: The ε4 variant of ApoE, a gene involved in fat metabolism that increases people's chance of acquiring Alzheimer's by 3 to 15 fold.
In pursuit of other such genes, neuroscientists Lars Bertram and Rudy Tanzi at Harvard Medical School and colleagues examined the DNA of families in which at least two people developed Alzheimer's. The team focused on a region of chromosome 9 containing genetic variations they had previously associated with the disease. In addition, other scientists had shown that a gene in this region called UBQLN1 expressed a protein, ubiquilin, that could interact with presenilin—a protein implicated in Alzheimer's.
Putting these facts together, the researchers compared UBQLN1 in a group of Alzheimer's patients with a group of their healthy relatives, a total of 1439 people. According to results published today in the New England Journal of Medicine, a variation of UBQLN1 called 8i was about 1.5 to 2 times more common in people with Alzheimer's. The researchers then extracted UBQLN1 messenger RNA (which encodes ubiquilin) from the brains of 25 people who had died with Alzheimer's and 17 people who had died without the disorder. Alzheimer's brains contained slightly more of a short version of UBQLN1 messenger RNA than the normal brains, indicating that the 8i variation affects the size of the messenger RNA and thus could disrupt the interaction between ubiquilin and presenilin.
Experts agree that the results need to be replicated before they can gauge the risk that UBQLN 8i confers. Geneticist Margaret Pericak-Vance at Duke University in Durham, North Carolina, says the genetic association isn't very strong, but the messenger RNA data bolsters the researcher's case. But she adds that she and her collaborators previously looked for a link between UBQLN1 and Alzheimer's and came up empty. This may suggest that the contribution of the variant to disease may be very small, she says.