Researchers believe it's not enough to look for disease risk genes -- understanding expression levels of genes is important, too
Using sophisticated techniques that scan the genomes of patients, researchers at the Mayo Clinic campus in Florida have found that a gene appears to either help protect against development of Alzheimer's disease, or promote the disorder depending on the level of gene in the brain.
In two research studies published almost simultaneously in the journals Neurology and PLoS ONE, the scientists found strong evidence for the role of the gene, insulin-degrading enzyme (IDE), in influencing risk of Alzheimer's disease. The Mayo researchers were one of the groups that first found an association between IDE and Alzheimer's several years ago, but these new findings now offer a novel theory about how the gene could be involved in the disease process.
"We found a new mechanism of action for this Alzheimer's disease susceptibility gene, that acts by altering gene expression levels," says neuroscientist and neurologist Nilufer Ertekin-Taner, M.D., Ph.D., the lead investigator on the Neurology study and contributor to the PLoS ONE research.
Fanggeng Zou, Ph.D., and Minerva Carrasquillo, Ph.D., are the joint first authors of the Neurology study. Drs. Carrasquillo and Zou, Olivia Belbin, Ph.D., and Ph.D. candidate Mariet Allen are the joint first authors of the PLoS ONE study. Both studies were published online in early 2010.
IDE is known to break apart amyloid beta, the protein that clumps together in the brains of Alzheimer's patients. The Mayo researchers say their findings suggest that too little expression of IDE may promote development of the disease, while increased expression appears to protect against the disorder.
"It is an issue of the level of the normal gene, not whether a gene is in a mutant form that is not acting properly," says Dr. Ertekin-Taner. "We believe this is a novel and potentially powerful approach to understanding the complex biology behind development of Alzheimer's disease."
Until these studies, scientists have searched for Alzheimer's disease genes by looking to see if patients had different variations in genes from non-patients - variations that increased the risk for disease development. Apolipoprotein E-4 (APOE-4) - the only major Alzheimer's disease susceptibility gene discovered to date - also was found that way. Humans can inherit three different forms of APOE, and researchers found that people who had one or two copies of APOE-4 have a substantially increased risk of developing Alzheimer's.
The Mayo researchers took a different tack in this research. In the Neurology study, spearheaded by Dr. Zou, they measured messenger RNA (mRNA) expression levels of 12 genes in an unaffected area of the brain in 200 people with Alzheimer's disease. These 12 genes were previously identified as potential risk genes for Alzheimer's by this group and others in the literature. They then identified genetic variations within and around these 12 genes, from among the hundreds of thousands of variations measured as part of the whole genome screen for Alzheimer's disease. That work was spearheaded by Dr. Carrasquillo in the laboratory of Steven Younkin, M.D., Ph.D., George M. Eisenberg Professor of Neuroscience at the College of Medicine, Mayo Clinic.
Measuring mRNA is a way to quantify gene expression. Genes that are activated produce more mRNA in order to make protein.