Evidence for an association between KIBRA and late-onset Alzheimer's disease

• Published in: Neurobiology of aging Vol. 31; no. 6; pp. 901 - 909
• Main Authors: Corneveaux, Jason J., Liang, Winnie S., Reiman, Eric M., Webster, Jennifer A., Myers, Amanda J., Zismann, Victoria L., Joshipura, Keta D., Pearson, John V., Hu-Lince, Diane, Craig, David W., Coon, Keith D., Dunckley, Travis, Bandy, Daniel, Lee, Wendy, Chen, Kewei, Beach, Thomas G., Mastroeni, Diego, Grover, Andrew, Ravid, Rivka, Sando, Sigrid B., Aasly, Jan O., Heun, Reinhard, Jessen, Frank, Kölsch, Heike, Rogers, Joseph, Hutton, Michael L., Melquist, Stacey, Petersen, Ron C., Alexander, Gene E., Caselli, Richard J., Papassotiropoulos, Andreas, Stephan, Dietrich A., Huentelman, Matthew J.
• Format: Journal Article
• Language: English
• Published: London Elsevier Inc 01.06.2010; Elsevier
• Subjects: Aged; Aged, 80 and over; Alzheimer Disease - complications; Alzheimer Disease - diagnostic imaging; Alzheimer Disease - genetics; Alzheimer Disease - pathology; Apolipoproteins E - genetics; Biological and medical sciences; Brain - diagnostic imaging; Brain - enzymology; Brain - pathology; Brain Mapping; Cognition Disorders - etiology; Cognition Disorders - genetics; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Development. Senescence. Regeneration. Transplantation; Expression profiling; Female; Fundamental and applied biological sciences. Psychology; Gene Expression Profiling - methods; Genetic Predisposition to Disease; Genetics; Genome-Wide Association Study - methods; Genotype; Glial Fibrillary Acidic Protein - metabolism; Humans; Imaging; Internal Medicine; Intracellular Signaling Peptides and Proteins; Male; Medical sciences; Memory; Neurology; Neurons - metabolism; Neurons - pathology; Neuropsychological Tests; Oligonucleotide Array Sequence Analysis - methods; Phosphoproteins; Polymorphism, Single Nucleotide - genetics; Positron-Emission Tomography - methods; Proteins - genetics; Vertebrates: nervous system and sense organs; Genetics; Expression profiling; Imaging; Memory; Nervous system diseases; Senescence; Alzheimer disease; Central nervous system disease; Degenerative disease; Cerebral disorder
• ISSN: 0197-4580; 1558-1497; 1558-1497
• DOI: 10.1016/j.neurobiolaging.2008.07.014

We recently reported evidence for an association between the individual variation in normal human episodic memory and a common variant of the KIBRA gene, KIBRA rs17070145 (T-allele). Since memory impairment is a cardinal clinical feature of Alzheimer's disease (AD), we investigated the possibility of an association between the KIBRA gene and AD using data from neuronal gene expression, brain imaging studies, and genetic association tests. KIBRA was significantly over-expressed and three of its four known binding partners under-expressed in AD-affected hippocampal, posterior cingulate and temporal cortex regions (P<0.010, corrected) in a study of laser-capture microdissected neurons. Using positron emission tomography in a cohort of cognitively normal, late-middle-aged persons genotyped for KIBRA rs17070145, KIBRA T non-carriers exhibited lower glucose metabolism than did carriers in posterior cingulate and precuneus brain regions (P<0.001, uncorrected). Lastly, non-carriers of the KIBRA rs17070145 T-allele had increased risk of late-onset AD in an association study of 702 neuropathologically verified expired subjects (P=0.034; OR=1.29) and in a combined analysis of 1026 additional living and expired subjects (P=0.039; OR=1.26). Our findings suggest that KIBRA is associated with both individual variation in normal episodic memory and predisposition to AD.