By Dean A. Haycock

Special To BioWorld Today

The destination is unfortunately the same but there are many routes to dementia.

Genetic mutations are responsible for familial Alzheimer's disease (AD), which represents approximately 10 percent of all cases. But what about the other 90 percent of AD cases, the sporadic ones?

Mutations in genes that encode the amyloid precursor protein (APP) or two presenilin proteins have been identified in selected families at risk for AD. APP is the source of the abnormal amyloid peptide that accumulates in the brains of AD patients in the form of amyloid plaques. Presenilins also have been linked to plaque formation.

Several years ago a version of the apolipoprotein E gene (APOEE4) was identified as a risk factor for sporadic AD. (Apolipoproteins help transport cholesterol.) APOEE4, however, does not account for all AD cases.

Now a new study in the March 1998 issue of Nature Genetics points to a new gene that may increase the risk of developing sporadic AD.

The gene encodes an enzyme called bleomycin hydrolase. Bleomycin is an anticancer drug. The enzyme's only known function is to break down and so detoxify bleomycin.

Initial Enzyme Studies Targeted Drug Side Effects

For at least a decade, researchers have been studying the enzyme in hopes of learning how they could activate it in healthy tissue to counter side effects of bleomycin. In the lungs, for example, bleomycin can produce a life-threatening condition called fibrosis. Increasing bleomycin hydrolase activity might prevent the development of this condition.

Robert Ferrell, professor of human genetics at the University of Pittsburgh, and his colleagues studied how the enzyme detoxifies bleomycin. After hearing that enzymes similar to bleomycin hydrolase break down APP, the researchers obtained tissue samples from two separate groups of AD victims and control patients. Comparisons between and within these groups suggested the gene for bleomycin hydrolase represents a new susceptibility locus for developing sporadic AD.

The scientists studied 357 AD cases and 320 controls. They correlated the link between inheritance of one of two forms of the bleomycin hydrolase gene, the A form and the G form, with the presence of AD. Because humans have two copies of the gene, they can be typed as G/G, A/A or A/G.

Individuals inheriting the A/A or the A/G genotypes had no increased risk for developing AD. Pooling all cases, the scientists found that nearly 13 percent of the AD cases had the G/G form of bleomycin hydrolase, while less than 7 percent of the controls did.

Inexplicably, in the subpopulation of subjects who lacked the APOEE4 gene, approximately 16 percent of the AD cases expressed the G/G form of the enzyme, while only 5 percent of those in the control group did. This could mean that persons dealt a genetic hand that includes G/G and excludes APOEE4 have four times the chance of developing Alzheimer's.

If confirmed, this finding would represent the first gene to be linked to increased risk of developing sporadic AD since the connection with APOEE4 was established years ago.

"At this stage, this just provides a possible target for understanding Alzheimer's disease. This is a susceptibility gene. It is not necessary nor is it sufficient to cause disease," Ferrell cautioned.

The paper is definitely of interest in the Alzheimer's community, according to Kenneth Kosik, professor of neurology at the Harvard Medical School, in Boston.

"We are searching very much for genetic risk factors exactly like this. The identification of another one is a very important observation," Kosik said. "We need now to find out if these observations hold up in other populations, other ethnic groups, and then we might be in a position where the bleomycin hydrolase polymorphism becomes as strong a genetic risk factor as we now know APOEE4 is."

Another, larger study is rumored to have found no difference between Alzheimer's risk in persons with the G/G variant of the bleomycin hydrolase gene.

"I'm aware through the grapevine that a group in Boston in collaboration with people at Duke have apparently typed a population for bleomycin hydrolase. The problem is it is not published and I don't know the definition of the population that they looked at or how they analyzed the data," Ferrell said.

Noting that he and his coworkers describe a rather modest increase in risk, Ferrell said it would be possible for methodological differences to account for a difference in results. The difficulty of confirming two- to fivefold increases in risk is one of the reasons the Pittsburgh group looked at two independent populations of AD cases, one from Pittsburgh Alzheimer's Disease Research Center and the other from the Indiana Alzheimer's Disease Center Cell Repository.

Efforts Aimed At Learning Enzyme's Functions

In the meantime, the Pittsburgh researchers are following up their finding with experiments designed to reveal more about the bleomycin hydrolase gene and its possible link to disease.

"We would like to know if the G/G genotype is responsible for the increased risk or is it simply a marker for either other variations within the bleomycin hydrolase itself or a nearby gene. It is not easy to distinguish those two possibilities," Ferrell told BioWorld Today.

Ferrell and his colleagues are screening the gene for variations that may be more strongly associated with increased risk of AD than the G/G variation. At the same time, the group remains interested in the question of why individuals show variations in their response to bleomycin treatment.

Attempts to understand the role the enzyme plays in the absence of bleomycin are under way at the University of Pittsburgh and other laboratories, according to Ferrell.

Zaven Khachaturian, director of the Alzheimer's Association Ronald & Nancy Reagan Research Institute, issued a press release in which he described the report in Nature Genetics as "intriguing, though preliminary."

Ferrell and other researchers interviewed for this article agreed that the bleomycin gene cannot be used to predict if someone will develop Alzheimer's disease. *