New findings debunk theory about so-called Alzheimer's gene
The news last summer that a gene on chromosome 12 was associated with increased risk of developing Alzheimer's disease was hailed as a breakthrough.
In the May issue of Nature Genetics, however, a multi-center team including Vanderbilt's Program in Human Genetics reports that the findings cannot be replicated.
Alzheimer's disease is the most common cause of senile dementia and afflicts more than four million people in the United States. Patients suffer a progressive decline in cognitive, neural, and muscular functions.
Relatively few genes have been linked to this devastating disease, the causes of which remain largely unknown. In fact, before last summer's report, only the gene encoding a variant of apolipoprotein E had been associated with elevated risk of late-onset Alzheimer's, the most common form of the disease. The identification of another genetic risk factor, a variant of the alpha-2-macroglobulin gene (A2M-2), was considered a major step forward.
"The increase in risk for Alzheimer's disease caused by A2M-2 was suggested to be equal to or greater than that of the epsilon 4 variant of apolipoprotein E, the strongest risk factor for Alzheimer's known to date," said Jonathan L. Haines, Ph.D., associate professor of Molecular Physiology and Biophysics and director of the Program in Human Genetics.
Alpha-2-macroglobulin was a logical suspect in the hunt for Alzheimer's culprits. It can act as a kind of molecular "bouncer," escorting potentially toxic proteins out of the synapse – the space between neurons. Since one of the proteins it removes is beta amyloid, a hallmark component of the plaques and tangles that characterize Alzheimer's disease, a defective alpha-2-macroglobulin might allow beta amyloid buildup and toxicity.
In addition, the alpha-2-macroglobulin gene (A2M) is located in the broad region of chromosome 12 that was linked to Alzheimer's disease susceptibility by Haines and colleagues in 1997. So the association made sense, but it needed to be confirmed in other groups of families.
The current study evaluated the A2M gene in more than 100 Alzheimer's families, consisting of multiple members afflicted with the disease. The study also included nearly 400 cases of sporadic Alzheimer's disease and 320 age-matched cognitively normal controls.
"There was no evidence for an association between the A2M-2 variant and increased Alzheimer's risk in any patient sample," Haines said. "We also showed that there were no detectable biochemical defects in the mutant alpha-2-macroglobulin protein encoded by the A2M-2 variant."
Despite negating the link between A2M-2 and Alzheimer's, the researchers maintain that there is still strong and reproducible evidence for a genetic defect on chromosome 12 that does elevate risk of Alzheimer's.
"It's pretty clear that the search for the chromosome 12 Alzheimer's gene must continue. There are several other genes in this region that we are looking at now," Haines said. "Identifying this gene will provide the potential for improved diagnosis as well as better understanding of the mechanisms causing Alzheimer's disease."
The multi-center effort included researchers at Boston University School of Medicine, Duke University Medical Center, and the University of Toronto. The studies were supported by the NIH, the Medical Research Council of Canada, the Alzheimer Society of Ontario, and the Alzheimer Association.