Sep. 16, 2008 Investigators at the Translational Genomics Research Institute (TGen) announced a link between the brain protein KIBRA and Alzheimer's disease, a discovery that could lead to promising new treatments for this memory-robbing disorder.
The new discovery builds on a previous TGen-led study published in the journal Science, which showed a genetic link between KIBRA and memory in healthy adults.
In the new study, TGen researchers found that carriers of a memory-enhancing flavor of the KIBRA gene had a 25 percent lower risk of developing Alzheimer's disease.
The findings were reported September 13 in the online edition of Neurobiology of Aging, a Philadelphia-based peer-review journal that generally focuses on how aging affects the nervous system.
"This research suggests that KIBRA, and possibly some of the proteins with which it interacts, may play a role in Alzheimer's disease,'' said Dr. Matthew Huentelman, an investigator in TGen's Neurogenomics Division and the paper's senior author.
The critical difference found in KIBRA, a protein so named because it is commonly found in the kidneys and brain, was that those individuals with the T-allele gene were less likely to develop Alzheimer's than those with the C-allele. Alleles are those genetic markers – A, C, G or T – that determine such inherited traits as eye and hair color, or susceptibility to disease.
"We are now beginning to dig deeper regarding the genetic sequence of KIBRA in individuals carrying, and not carrying, the T-allele. We believe this variation causes a potential lifelong difference in the total levels of KIBRA in the brain, and that this may influence one's risk for Alzheimer's," said Huentelman, who led a team that worked with several Arizona institutions, as well as other national and international universities and research institutions.
Dr. Eric Reiman, clinical director of TGen's Neurogenomics Division and executive director of the Banner Alzheimer's Institute, said, "This study suggests a link between the inherited genes involved in normal human memory and the predisposition to Alzheimer's disease.
"It provides promising new targets at which to aim new treatments to stave off Alzheimer's and improve memory," said Reiman, who also is director of the Arizona Alzheimer's Consortium and a contributor to the study.
The findings announced today are built on a 2006 study led by collaborative teams from Arizona and Zurich, Switzerland, and published in the journal Science. That pioneering TGen research revealed a link between KIBRA and memory, in which healthy adults with the KIBRA T-allele performed better on memory tests than those without this gene.
In the most recent analysis, Huentelman's team confirmed a link between KIBRA and Alzheimer's in three different ways:
Using TGen's powerful analytic tools to find a genetic association between the KIBRA gene and Alzheimer's disease, comparing more than 1,700 living and deceased people, with and without the disorder.
Using gene expression tools to find that KIBRA, and genes for other molecules that interact with KIBRA, were significantly altered in the neurons of people who had Alzheimer's disease, but not in individuals without the disorder.
Using a brain imaging technique called positron emission tomography (PET) to find that cognitively-normal, late-middle-aged people lacking the protective T-allele gene had reduced activity in parts of the brain usually affected by Alzheimer's.
Genetic association study
In a study of 702 deceased persons diagnosed with Alzheimer's, and 1,026 living and deceased persons with and without Alzheimer's, researchers found that non-carriers of the KIBRA T-allele had increased risk of late-onset Alzheimer¹s.
The genotyped samples came from five centers, including three European organizations representing German, Dutch and Norwegian populations.
Gene expression study
The gene expression study examined tissues from six regions of the brain among 47 deceased individuals. The brain tissue samples were provided by three Alzheimer's disease centers: Washington University in St. Louis, Mo.; Duke University in Durham, N.C.; and Sun Health Research Institute in Sun City, Ariz.
KIBRA, and a subset of other molecules directly interacting with it, were significantly altered in regions of the brain involved in Alzheimer's disease pathology. The regions investigated included the hippocampus, entorhinal cortex, posterior cingulate cortex, middle temporal gyrus, and superior frontal gyrus. However, they were not altered in a region of the brain typically unaffected by the disease¬ -- the primary visual cortex.
Positron Emission Tomography scans
PET scans of 67 non-carriers of the KIBRA T-allele, and 69 carriers -- all with close relatives diagnosed with Alzheimer's -- showed that non-carriers exhibited, on average, similar alterations in the metabolic activity of key brain regions known to be altered in the earliest stages of the disease. All 136 individuals were mentally-normal, late-middle-aged Phoenix-area volunteers solicited from newspaper advertisements. They ranged in age from 47 to 68, with an average age of 55.
Scans showed that individuals without the KIBRA T-allele --¬ those with only KIBRA C-alleles from their mother and from their father -- had less metabolic brain activity when compared to those individuals carrying the T-allele -- from either their mother or father, or both. These differences were found in the precuneus and posterior cingulated regions of the brain affected in the earliest stages of Alzheimer's.
Previous work led by Reiman illustrated a similar finding when individuals were grouped according to whether they carried the most powerful genetic indicator for Alzheimer's -- the epsilon 4 allele of apolipoprotein E. In the current study, the effects of this allele were controlled for, yet similar observations were made. This suggests that KIBRA may play a role in a convergent biological risk pathway for the disease.
TGen's Jason Corneveaux and Dr. Winnie S. Liang were the paper's first authors.
Other Arizona participants in the study were: Arizona Alzheimer's Consortium, Banner Alzheimer's Institute, Sun Health Research Institute, St. Joseph's Hospital, Arizona State University, Mayo Clinic Arizona, and the University of Arizona's departments of Psychiatry, Radiology, and its Evelyn F. McKnight Brain Institute.
Other U.S. participants included: University of Miami, the National Institute on Aging, and the Mayo Clinic Rochester.
International collaborators included: the Netherlands Institute for Neurosciences, Netherlands; the Norwegian University of Science and Technology, and St. Olav's Hospital, Norway; the University of Bonn, Germany; and the University of Basel, Switzerland.
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