Researchers at the Translational Genomics Research Institute (TGen), Banner Alzheimer's Institute, Kronos Science Laboratory and their collaborative partners, suggests that the gene — called GAB2 — modifies an individual's risk for Alzheimer's disease when associated with other genes, including APOE4.
Alzheimer's disease is the most common form of disabling memory and thinking problems in older people. The progressive neurological disorder afflicts an estimated 5 million Americans, a number expected to triple by 2050.
"We have entered a new era in medical research. Today's technologies permit us to survey a sufficient number of letters throughout the human genome to provide a clearer picture of how life works and ultimately allow better clinical management of patients," said Dr. Dietrich Stephan, Director of TGen's Neurogenomics Division and the paper's senior author, "These new, robust tools may eventually allow us to improve our ability to diagnose Alzheimer's disease, even before it strikes"
To date, the most significant gene found to predispose an individual to late onset Alzheimer's (LOAD) has been APOE4. In this latest study, researchers from seven organizations contributed to the genome-wide scan using Affymetrix microarray technology. The team screened the DNA from 1,400 individuals who had been clinically assessed with Alzheimer's prior death, and simultaneously examined more than 500,000 SNPs or genetic variations to characterize and confirm additional LOAD susceptibility genes. The search revealed GAB2.
Based on the genetics of this and other neuroscientific findings, researchers suggest the healthy form of the GAB2 gene may protect brain cells from developing tangles, one of the hallmarks of Alzheimer's disease. If the findings are confirmed, this discovery could provide a target for future Alzheimer's therapeutic drugs.
"We hope that this study, along with the genome-wide genetics studies to come, will contribute to the clarification of Alzheimer's risk factors and disease mechanisms, the discovery of promising new disease-slowing and prevention therapies, and the identification of patients and at-risk people most likely to benefit from those treatments," said Dr. Eric Reiman, the study's first author and Executive Director of the Banner Alzheimer's Institute.
After finding an association between a form of the GAB2 gene and Alzheimer's disease in three separate groups, the researchers showed that the GAB2 gene is unusually active in vulnerable brain cells from Alzheimer's patients and that the GAB2 protein produced by this gene is present in those brain cells containing tangles. When the researchers silenced GAB2 in preliminary studies it increased a molecular process thought to play an important role in the development of tangles. Based on these findings, the researchers hypothesize that GAB2 might function under normal conditions to compensate for the harmful effects of APOE4 and other genes in older people and that the GAB2 risk gene lacks this protective effect.
"This discovery allows us to accelerate the development process for creating a new diagnostic test that is capable of detecting the presence of GAB2, and may ultimately help millions of individuals reach a more informed decision regarding the most appropriate type and timing of treatment," said Dr. Chris Heward, President of Kronos Science Laboratory.
Until recently, researchers lacked the technology to examine the genetic components of a disease at such a high-level of detail. By utilizing the Affymetrix 500K Arrays, the study's researchers rapidly produced a genetic map of each brain tissue sample and isolated the GAB2 gene relatively quickly.
"This Alzheimer's disease breakthrough is another powerful example of a fundamental life science discovery made by an Affymetrix customer. Our latest microarray technology continues to accelerate research at an unprecedented pace by enabling scientists to better identify the specific genetic variations associated with complex diseases," said Kevin King, President of Life Sciences Business and Executive Vice President at Affymetrix.
In addition to surveying an unprecedented number of genetic markers in each person's DNA, the researchers capitalized on extremely rigorous criteria to determine whether or not their volunteers had Alzheimer's. For instance, the study included more than 1000 brain donors confirmed to either have Alzheimer's disease or be free of the disorder at autopsy. This study resulted in a comprehensive set of high-quality data to be made publicly available to the research community.
The researchers believe that deposition of this data set in the public domain will open a new era in Alzheimer research. When a scientist suspects a particular gene or pathway maybe implicated in Alzheimer's disease, they will use these data to see if there is genetic evidence supporting their idea. Reviewing these data in an hour will permit them to save months of work and thousands of dollars to achieve the same result.
Moreover, it paves the way for even more advanced studies using larger sample populations, more powerful array chips that can distinguish more genetic markers, and more sophisticated methods of analyzing the data.