By Dean Haycock

Special To BioWorld Today

It may not be a flood of information, but the barriers to understanding the causes of Alzheimer's disease (AD) have sprung some significant leaks since the early 1990s. The first breaks revealed three genes that influence the development of familial Alzheimer disease (FAD), which accounts for perhaps 5 percent of AD and differs from the majority of cases by appearing during middle age.

Then, a variant of a gene called APOE was identified as a risk factor for developing the most common form of the disease, late-onset Alzheimer's disease (LOAD). This impressive progress, however, still left researchers uninformed about the factors that might influence the onset of LOAD, the disease most people think of when they refer to AD.

Now, scientists using a promising new methodological approach, have found a new gene that appears to be associated with LOAD. The advance is described in "Alpha-2 macroglobulin is genetically associated with Alzheimer's disease," which appears in the August issue of Nature Genetics. The senior author of the paper is Rudolph Tanzi, associate professor of Neurology at Harvard Medical School and director of the Genetics and Aging Unit at Massachusetts General Hospital, in Charlestown, Mass.

Up To 30 Percent Of Population Has Mutation

The latest AD gene encodes a protein called alpha-2 macroglobulin (alpha-2M). The mutation may be present in up to 30 percent of the population.

"It could have a major impact," said Steve Wagner, director of protein biochemistry at Sibia Neurosciences Inc., of La Jolla, Calif. "It is probably one of the most important risk factors at this stage." Alpha-2M makes a promising suspect in the list of suspects that might influence the onset or progression of AD.

"The finding is potentially highly significant because it could point us in some clear directions about developing new drug targets," said Steven Moldin, acting chief of the Genetics Research Branch of the National Institutes of Mental Health, in Bethesda, Md.

The protein interacts, for example, with cytokines. These molecules might contribute to damage caused by inflammation in the brains of people with AD. And research from several labs suggests alpha-2M may play a role in cleaning up potentially damaging debris that can accumulate in spaces between brain cells. This debris might include amyloid beta protein, a major component of the amyloid plaques that define the disease.

Alpha-2M may have a significant link to the other known risk factor for LOAD, APOE. The APOE gene product associated with AD is known as ApoE4. Alpha-2M (carrying peptides to be disposed) and ApoE4 (carrying lipids) may use the same receptor to gain access to brain cells. This receptor is called low-density lipoprotein receptor-related protein (LRP). Anything that interferes with alpha-2M's job of cleaning up unwanted peptides from intercellular spaces, including excess ApoE4, could contribute to the disease. This model suggests targets for intervening in the progression of AD and for identifying additional AD genes.

"LRP is probably the next best candidate gene on the horizon," Tanzi said. "Given that LRP serves as the receptor for both ApoE4 and alpha-2M, I think we are seeing a convergence point around LRP as an important scavenger receptor which, based on our data, is siting in the synapse."

He suggests that targeting molecules that contribute to the clearance of excess proteins in synapses might be a valuable approach for developing AD treatments.

"My guess is that most, if not all, of Alzheimer's has genetic component," Tanzi told BioWorld Today. "What we will be looking at in the future is probably accumulations of susceptibility genes, alterations that confer overall risk for the disease. Each one may have a modest effect. My guess is the APOE and alpha-2M will be pretty heavy hitters but there may be a whole slew of genes with smaller, more modest effects that confer risk," Tanzi said.

The three genes associated with FAD appear to cause the disease, whereas the two genes (so far) associated with LOAD appear to increase susceptibility to the disease. The is a good chance other genes will be identified using the same methods Tanzi and his colleagues used to identify the alpha-2M gene as a risk factor for LOAD. This modification of a "family based association" method was devised by co-author Nan Laird, chairman of biostatistics at the Harvard School of Public Health.

"Instead of looking at parents of affected people as controls, they actually used siblings of affected people as controls," Moldin said. "You need to do that in Alzheimer's because the parents are typically dead."

Researchers Compared Sibling Genes In 350 Families

The method looks at pairs of siblings in many different families and compares affected to unaffected siblings. Harvard researchers studied approximately 350 families. For comparison, they looked at other genes proposed, but not proven, to be associated with LOAD. Their results indicated that, besides the gene encoding alpha-2M, only the APOE gene variant — which is accepted as a true risk factor — was associated with AD.

Traditional genetic analysis techniques remain useful and preferable for determining which chromosome a gene is on, according to Tanzi. "But once you are in your region of interest, and you want to quickly go through the candidate genes, the family-based association method has revolutionized the very critical endgame strategy in gene cloning attempts," Tanzi said.

Used this way, the new method produces an "all-or-none" indication of genetic association, avoiding the ambiguity of most traditional methods. Tanzi believes the most important next step is for another group of researchers to replicate the Harvard findings in a separate, independent set of families.

"I think in the next five years this is going to lead to a tremendous outpouring of risk factors for complex age-related disorders," he said. *