US researchers have identified a gene mutation linked to an increased risk of Alzheimer's disease. The team, based at the Massachusetts General Hospital, say that it is only the second gene ever to be linked to the late-onset form of the disorder. The results, published in the New England Journal of Medicine, are based on a study of 437 affected families.
Alzheimer's disease is caused by the gradual death of certain brain cells, especially in the areas involved in memory. Researchers have already identified mutations in four other genes that raise the risk of the disease. Three of these, which make the amyloid precursor, presenilin 1 and presenilin proteins, are involved in the rare, inherited form of Alzheimer's disease. The symptoms of early onset Alzheimer's appear before the age of 65, usually when someone is in their fifties, but sometimes sooner. The fourth gene variant, ApoE4, is linked to an increased risk of the more common, late onset form of the disorder.
In the latest study, the scientists focussed on a gene called ubiquilin-1, which makes a protein that interacts with presenilin 2. They found that in families with two affected relatives, variants of the ubiquilin-1 gene are significantly associated with late-onset Alzheimer's disease. The team, lead by Rudolph Tanzi, then looked at 217 pairs of siblings, in which one sibling had the disease but the other did not. The results confirmed that particular ubiquilin-1 variants occur more often in Alzheimer's disease patients than their unaffected siblings.
The researchers then studied brain tissue from both Alzheimer's patients and controls. They found that the gene variants linked to the disease resulted in increased production of a shorter form of the ubiquilin protein. 'Now we need to figure out what's wrong with too much ubiquilin-1 and with this different form', said Tanzi. It seems that the ubiqulin-1 variants raise the risk of Alzheimer's by about half as much as the ApoE4 variant does. The scientists say that there are probably another 4-7 additional gene variants to be found, each of which confers a similar level of risk.
Tanzi says his team already know that ubiquilin may have links to the slow build-up of 'plaques' - hallmark structures found in the brains of people with Alzheimer's disease. The plaques are clumps of a protein called beta-amyloid. 'I like to use a kitchen sink metaphor - you either make too much of it or you can't clear it away fast enough', said Tanzi, who thinks ubiquilin-1 may be involved in both processes. An article accompanying the study comments 'the role of the environment cannot be ignored', adding 'most disease is caused by a combination of genetic and environmental factors'.