News Release

Genetic 'fellow traveler' discovered in Alzheimer's

Peer-Reviewed Publication

Cell Press

A new gene that influences susceptibility to late-onset Alzheimer’s disease (LOAD) has been identified by an international research team that analyzed the genomes of more than a thousand people with and without the disorder. The researchers identified the gene, called GAB2, as one that appears to influence the risk of Alzheimer’s in people with a version of a gene called APOE, which is the best established genetic risk factor for LOAD.

LOAD is expected to become an overwhelming medical problem in the next few decades as the population ages, since it afflicts about 10% of people over 65 and almost half of people over 85.

The research team from 15 institutions, led by Eric Reiman and Dietrich Stephan, published their discovery in the June 7, 2007, issue of the journal Neuron, published by Cell Press. The researchers were supported by 20 of the National Institute on Aging's Alzheimer's Disease Centers.

Although the variant version of APOE, called epsilon 4, was well known to be associated with increased Alzheimer’s susceptibility, there were also hints that variants of other genes modified APOE’s effects, said the researchers. However, detecting the infinitesimal genetic differences that would reveal Alzheimer’s susceptibility genes has been extremely difficult because of their subtle effects.

To identify such “fellow traveler” genes, the research team performed comparative analyses of the entire genomes of 1,411 people who were either Alzheimer’s-affected carriers of APOE epsilon 4 or unaffected controls. They searched for tiny genetic variations, called single-nucleotide polymorphisms, that would reveal other susceptibility genes in the carriers who had Alzheimer’s.

The researchers identified variations in the GAB2 genes that were highly associated with cases of LOAD. Further genetic analyses of LOAD cases and nonaffected people revealed that the gene was highly expressed in neurons that are vulnerable to the pathology of Alzheimer’s.

Studies of the GAB2 gene have indicated that the protein it produces controls a biochemical pathway that protects against the abnormal formation of protein “tangles” that kill brain cells, said the researchers. To explore the gene’s role, they experimentally “silenced” the gene in neurons, observing an increase in the form of a key protein that contributes to such tangles.

“Discovery of this novel LOAD susceptibility gene provides new opportunities to investigate LOAD pathogenesis, predisposition, treatment, and prevention,” concluded the researchers.

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The researchers include Eric M. Reiman of Translational Genomics Research Institute (TGen) and Banner Alzheimer’s Institute in Phoenix, AZ, University of Arizona in Tucson, AZ, and Arizona Alzheimer’s Consortium in Phoenix AZ; Jennifer A. Webster, Travis Dunckley, Victoria L. Zismann, Keta D. Joshipura, John V. Pearson, Diane Hu-Lince, Matthew J. Huentelman, David W. Craig, Winnie S. Liang, and RiLee H. Herbert of Translational Genomics Research Institute (TGen) and Arizona Alzheimer’s Consortium in Phoenix, AZ; Amanda J. Myers of University of Miami, Miller School of Medicine in Miami, FL and National Institute on Aging, National Institutes of Health in Bethesda, MD; John Hardy of National Institute on Aging, National Institutes of Health in Bethesda, MD and Institute of Neurology in Queen Square, London; Keith D. Coon of St. Joseph's Hospital and Medical Center in Phoenix, AZ; Thomas Beach, Andrew Grover, and Joseph Rogers of Sun Health Research Institute in Sun City, AZ and Arizona Alzheimer’s Consortium in Phoenix AZ; Kristen C. Roher, Alice S. Zhao, Doris Leung, Leslie Bryden, Lauren Marlowe, and Mona Kaleem of National Institute on Aging, National Institutes of Health in Bethesda, MD; Diego Mastroeni of Sun Health Research Institute in Sun City, AZ; Christopher B. Heward of Kronos Science Laboratory in Phoenix, AZ; Rivka Ravid of Netherlands Institute for Neurosciences, Dutch Royal Academy of Arts and Sciences in Amsterdam; Michael L. Hutton and Stacey Melquist of Mayo Clinic in Jacksonville, FL; Ron C. Petersen of Mayo Clinic in Rochester, MN; Gene E. Alexander of Arizona State University in Tempe, AZ and Arizona Alzheimer’s Consortium in Phoenix AZ; Richard J. Caselli of Mayo Clinic in Scottsdale, AZ and Arizona Alzheimer’s Consortium in Phoenix AZ; Andreas Papassotiropoulos of Translational Genomics Research Institute (TGen) in Phoenix, AZ and Biozentrum, University of Basel, Switzerland; Dietrich A. Stephan of Translational Genomics Research Institute (TGen), Arizona Alzheimer’s Consortium, and Banner Alzheimer’s Institute in Phoenix, AZ.

These studies were supported by Kronos Life Sciences Laboratories, the National Institute on Aging (Arizona Alzheimer’s Disease Center P30 AG19610, RO1 AG023193, Mayo Clinic Alzheimer’s Disease Center P50 AG16574, and Intramural Research Program), the National Alzheimer’s Coordinating Center (U01 AG016976), and the state of Arizona.

Reiman et al.: “GAB2 Alleles Modify Alzheimer’s Risk in APOE e4 Carriers.” Neuron 54, 713–720, June 7, 2007. DOI 10.1016/j.neuron.2007.05.022. www.neuron.org.


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