Age-Modulated Associations between KIBRA, Brain Volume, and Verbal Memory among Healthy Older Adults.

Ariana Stickel,Katrin Walther,Lee Ryan,Kevin Kawa,Matt Huentelman,Ryan Richholt,Elizabeth Glisky

doi:10.3389/fnagi.2017.00431

Abstract

The resource modulation hypothesis suggests that the influence of genes on cognitive functioning increases with age. The KIBRA single nucleotide polymorphism rs17070145, associated with episodic memory and working memory, has been suggested to follow such a pattern, but few studies have tested this assertion directly. The present study investigated the relationship between KIBRA alleles (T carriers vs. CC homozygotes), cognitive performance, and brain volumes in three groups of cognitively healthy adults—middle aged (ages 52–64, n = 38), young old (ages 65–72, n = 45), and older old (ages 73–92, n = 62)—who were carefully matched on potentially confounding variables including apolipoprotein ε4 status and hypertension. Consistent with our prediction, T carriers maintained verbal memory performance with increasing age while CC homozygotes declined. Voxel-based morphometric analysis of magnetic resonance images showed an advantage for T carriers in frontal white matter volume that increased with age. Focusing on the older old group, this advantage for T carriers was also evident in left lingual gyrus gray matter and several additional frontal white matter regions. Contrary to expectations, neither KIBRA nor the interaction between KIBRA and age predicted hippocampal volumes. None of the brain regions investigated showed a CC homozygote advantage. Taken together, these data suggest that KIBRA results in decreased verbal memory performance and lower brain volumes in CC homozygotes compared to T carriers, particularly among the oldest old, consistent with the resource modulation hypothesis.

Highlights

Since the initial KIBRA study demonstrating a benefit of the T allele for episodic memory functioning in three separate samples (Papassotiropoulos et al, 2006), multiple studies have supported the notion that the KIBRA T allele provides a small but significant benefit to episodic memory and working memory performance
A single nucleotide polymorphism (SNP) specific comparison detected differential gene expression in T carriers and CC homozygotes: T carriers tended to overexpress genes involved in the MAPK signaling pathway, a pathway involved in learning and memory (Piras et al, 2017)
Our study showed that among a sample of cognitively healthy middle aged, young old, and older old adults, the influence of KIBRA on verbal memory performance increased with age, with differences between T carriers and CC homozygotes evident only among the older old group

Summary

Introduction

The KIBRA gene is located on chromosome 5 and is responsible for producing proteins expressed in the kidneys and brain, from which the name KIBRA is derived (Schneider et al, 2010). The interaction between KIBRA and protein kinase C zeta, which is expressed in the hippocampus and is implicated in long term potentiation (Johannsen et al, 2008; Sacktor, 2008; Lee et al, 2013; Volk et al, 2013; Vogt-Eisele et al, 2014), may be the mechanism by which KIBRA affects memory functioning (Büther et al, 2004; Schneider et al, 2010). A SNP specific (rs17070145) comparison detected differential gene expression in T carriers and CC homozygotes: T carriers tended to overexpress genes involved in the MAPK signaling pathway, a pathway involved in learning and memory (Piras et al, 2017)

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Results