2nd Gene for Late-Stage Alzheimer's

Scientists have found a gene that, when mutated, appears to increase the risk of developing Alzheimer's disease later in life. No one knows how many Alzheimer's cases might be linked to the mutation, but experts say the number could be large, given that an estimated 30% of the population carries the mutation. The discovery, reported today in Amsterdam at the Sixth International Conference on Alzheimer's Disease and Related Disorders, could provide a better understanding of what causes late-onset Alzheimer's--by far the most common form of the disease.

Gene Chromosome Age of Onset % of Early-Onset Cases % of All Cases
APP 21 45 to 66 <1 <0.1
Presenilin 1 14 28 to 62 40 1 to 2
Presenilin 2 1 40 to 85 <1 <0.1
ApoE4 19 >60 --- >50 (Risk factor)
A2M 12 >70 --- ? (Risk factor)

A team led by neurogeneticist Rudy Tanzi of Harvard's Massachusetts General Hospital in Boston first became interested in the gene because of a possible connection to the b amyloid protein, which has been implicated in Alzheimer's. Work by other researchers suggests that the normal version of the newly discovered protein, called a2-macroglobulin (a2M), acts like a cleanup crew for neurons by binding to and removing b amyloid and several other potentially toxic proteins that might otherwise accumulate outside nerve cells.

One way that a2M might perform this custodial chore is by carrying the bound b amyloid into cells where it can be degraded--a step that requires that it bind to the very same receptor that another protein, called apoE, uses to enter cells. Because a particular apoE variant, called apoE4, had previously been shown to be a risk factor for late-onset Alzheimer's, Tanzi and his colleagues reasoned that the mutant form of this other receptor-binding protein, a2M, might be as well.

To test this idea, the team compared the frequencies of the mutant A2M gene in late-onset Alzheimer's patients and their unaffected siblings. The analysis showed a highly significant association between the mutation and the presence of Alzheimer's disease. For instance, when the researchers removed the possible confounding influence of ApoE4 by looking only at families lacking that ApoE variant, they found that the frequency of the mutant A2M gene in Alzheimer's patients was four times greater than in their siblings who did not have the disease. "I think that [the mutation] is probably the strongest risk factor for whether you get Alzheimer's late in life--as strong as or stronger than ApoE4," says Alzheimer's expert Sam Sisodia of the University of Chicago. The findings will be reported in the August issue of Nature Genetics.

While this linkage will need to be confirmed in other populations, researchers are already beginning to focus on how A2M mutations might lead to Alzheimer's. One possibility is that they interfere with a2M's cleanup operation. This might also be the case with apoE4, which might prevent a2M and its associated proteins from binding to their mutual receptor. If so, that that could also explain how apoE4 spurs the development of Alzheimer's. Those kinds of possibilities are what make the new work "very, very interesting," says Steven Moldin of the National Institute of Mental Health. "It offers a set of very explicit hypotheses that can be tested."