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

Abstract

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.

Introduction

We recently capitalized on genome-wide association, brain gene expression and brain imaging studies to characterize an association between a common variant of the KIBRA gene and individual variation in normal human memory. KIBRA rs17070145 T-allele non-carriers had lower scores than carriers of this allele on episodic memory tests in a pooled genome-wide association study (GWAS) of normal young adults, a replication study of young adults, and another replication study of middle-aged adults (Papassotiropoulos et al., 2006). KIBRA was expressed in human and murine brains, supporting its potential relevance to the biology of memory and related behaviors. After controlling for their memory scores in a functional magnetic resonance imaging (fMRI) study, KIBRA T-allele non-carriers had greater hippocampal activation than non-carriers during an episodic memory task, suggesting that the hippocampus had to work harder to perform the task in those with the poor memory allele.

Since memory impairment is a cardinal clinical feature of Alzheimer's disease (AD), we decided to investigate the possibility of an association between AD and KIBRA using data from neuronal gene expression, brain imaging, and genetic association studies. We initially tested the hypothesis that the KIBRA biomolecular pathway would exhibit dysregulation at the transcriptional level in the brains of AD patients. We compared expression of the KIBRA gene and its four known binding partners PRKCZ (protein kinase C zeta), DYNLL1 (dynein light chain 1), ESR1 (estrogen receptor), and KIAA0513 using data from a microarray study of non-tangle-bearing neurons laser-capture microdissected from AD cases and matched elderly controls. For this microarray study, neurons were extracted from six brain regions shown to be differentially affected by AD, including the hippocampus and entorhinal cortex [which are vulnerable to early neurofibrillary pathology in persons clinically affected by or at risk for AD (Du et al., 2003, Frisoni et al., 1999)], the posterior cingulate cortex [which is associated with unusually early hypometabolism and fibrillar amyloid pathology in persons clinically affected by or at risk for AD (Mirra et al., 1991, Small et al., 2000)], the middle temporal gyrus [associated with amyloid pathology in persons affected by AD (Grupe et al., 2007, Jack et al., 1998, Mirra et al., 1991)], superior frontal gyrus [which demonstrates metabolic changes with regards to aging (Loessner et al., 1995)], and primary visual cortex [which is relatively spared in persons with AD (Metsaars et al., 2003)].

Next, we used data from a fluoro-deoxyglucose (FDG) positron emission tomography (PET) study to test the hypothesis that cognitively normal, late-middle aged KIBRA rs17070145 T-allele non-carriers have lower cerebral glucose metabolism than carriers of this allele in brain regions known to be metabolically affected by AD. We have previously reported an association between apolipoprotein E (APOE) ɛ4 gene dose (i.e. the number of ɛ4 alleles in a person's APOE genotype) and lower cerebral glucose metabolism in each of the precuneus, posterior cingulate, parietotemporal and prefrontal regions known to be progressively affected by AD (Reiman et al., 2005). Since APOE ɛ4 gene dose is associated with three levels of risk for late-onset AD, we proposed that PET could be used as a presymptomatic, quantitative endophenotype – a measure more closely related to disease-severity than the clinical features themselves – to assess putative modifiers of AD risk.

Since the precuneus and posterior cingulate cortex have been implicated in (i) successful retrieval memory (Buckner et al., 2005), (ii) the “default system” that is preferentially active during the passive “resting” state (Buckner et al., 2005), (iii) the earliest metabolic reductions in persons at genetic risk for late-onset AD (Reiman et al., 2005), (iv) early fibrillar amyloid pathology (Mirra et al., 1991), and (v) preferential rates of gray matter loss in AD patients (Ishii et al., 2005), our PET studies also provide support for the relationship between KIBRA's connection to neurobiological processes involved in both normal episodic memory and predisposition to AD.

Finally, we looked for an association of the KIBRA rs17070145 SNP with AD and found that non-carriers of the T-allele have an increased risk of developing late-onset AD (and explored possible associations with all three KIBRA rs17070145 genotypes) using data from our GWAS association study of 702 clinically characterized and neuropathologically verified expired subjects and in a combined analysis of data from 1026 additional living and expired subjects.