Investigating the influence of KIBRA and CLSTN2 genetic polymorphisms on cross-sectional and longitudinal measures of memory performance and hippocampal volume in older individuals
Introduction
Episodic memory declines with age (Rönnlund et al., 2005) and yet our current understanding of the underlying biological processes is rudimentary. Heritability estimates of 30–60% for memory suggest that genetics plays a major role in memory performance (McClearn et al., 1997, Papassotiropoulos and de Quervain, 2011). Despite significant heritability, only a small number of genes have consistently been associated with memory performance and the diversity of the results is striking. The first GWAS of episodic memory function resulted in the identification of KIBRA, kidney and brain expressed protein (also known as WW and C2 domain containing 1, WWC1), as a candidate gene affecting memory performance as well as functional brain activity based on three separate cohorts within the age range of 18–81 years (Papassotiropoulos et al., 2006). From this study a single nucleotide polymorphism (SNP) leading to a substitution of C→T (rs17070145) in KIBRA was identified which positively affects memory performance. Further, it was shown that non T-carriers over-recruit hippocampal regions during episodic memory retrieval. Following this initial study, several studies have replicated the findings in samples with ages between 30 and 89 years (e.g. Almeida et al., 2008; Schaper et al., 2008; Vassos et al., 2010), although the results have not always been consistent using similar samples ranging in age from 18 to 77 years (e.g. Nacmias et al., 2008, Need et al., 2008). For example, in a large-scale attempt to replicate the association of the KIBRA SNP to episodic memory, including participants between 35 and 85 years of age, Kauppi et al. (2011) confirmed that the T-allele was associated with improved memory performance when using an immediate free recall word task, an effect that was augmented with increasing age. However, in contrast with the original findings, T allele carriers showed increased hippocampal activity instead of the non-carriers. There are also other studies that have failed to find any association with the KIBRA SNP and memory (e.g. Need et al., 2008). One study even found that carriers of the T-allele performed more poorly on long-term memory tests (Nacmias et al., 2008) and that the T-allele is associated with increased risk of developing Alzheimer's disease (Rodríguez-Rodríguez et al., 2009). Even when examining past studies that exclusively investigated the effect in older samples (>50 years of age) the results are mixed with studies in favor of the positive association of KIBRA T-allele and episodic memory (Almeida et al., 2008, Schaper et al., 2008) and against such association (Nacmias et al., 2008, Rodríguez-Rodríguez et al., 2009). Moreover, KIBRA-status was not able to predict whether individuals would decline or maintain episodic memory function over 15 years (Josefsson et al., 2012). Thus, the effect of the KIBRA SNP, rs17070145, on memory performance is still unclear, as indicated by a recent meta-analysis (Milnik et al., 2012) and review (Schwab et al., 2014).
Another polymorphism identified by the Papassotiropoulos et al. (2006) memory GWAS was a CLSTN2 (calsyntenin 2) SNP (rs6439886), however, this association was not confirmed in the replication sample. Subsequently this association has been replicated in two other independent studies in both adolescents and older adults (Jacobsen et al., 2009, Laukka et al., 2013).
The mechanisms by which these two polymorphisms (KIBRA rs17070145, CLSTN2 rs6439886) may influence episodic memory functioning is unclear. KIBRA encodes a phosphoprotein, which binds to many proteins including those implicated in neuronal and synaptic plasticity, cell migration, vesicular transport, mitosis and tumorigenesis (Zhang et al., 2014). It has been proposed that KIBRA regulates AMPA receptors, the major excitatory synaptic receptors of the brain, suggesting KIBRA may be involved in synaptic plasticity and transmission (Makuch et al., 2011, Zhang et al., 2014). CLSTN2 is part of the components of the postsynaptic membrane and is located predominately in excitatory synapses giving CLSTN2 a role in intracellular postsynaptic signaling, potentially mediating specific responses in excitatory synaptic transmission (Hintsch et al., 2002).
Interactions between genes may also contribute to memory performance. However, few studies have appraised gene–gene interactions and memory performance. In 2010, Preuschhof et al. observed an interaction between two SNPs, located in the KIBRA and CLSTN2 genes (rs17070145, rs6439886), on episodic memory performance in young adults. Individuals who were both KIBRA T and CLSTN2 C-carriers had the highest performance compared to KIBRA C homozygotes/CLSTN2 C-carriers who had the lowest performance. However, a recent study failed to replicate previous results (Sédille-Mostafaie et al., 2012).
One major limitation with previous attempts to understand the effects of KIBRA or CLSTN2 on memory is that prior investigations have been cross-sectional. Notably, it has been suggested that the genetic influence on cognition is magnified at older ages (Lindenberger et al., 2008, Papenberg et al., 2013) as well as playing an important role in the cognitive changes associated with increased age (Mattay et al., 2008). This implies that it is important to investigate cognitive change over time in relation to specific genetic polymorphisms in order to better understand the complex relationships between genetics and age-related memory performance.
Both KIBRA and CLSTN2 are highly expressed in the medial temporal lobe (Zhang et al., 2014, Schneider et al., 2010, Hintsch et al., 2002), a brain region important for episodic memory (Squire et al., 2004). Moreover, it has been shown that in the Older Australian Twins Study and other cohorts that ~53–65% of the variance in hippocampal volume can be attributed to genetic influences (Blokland et al., 2012, Mather et al., 2015). In the original paper by Papassotiropoulos et al. (2006) there was no KIBRA genotype difference in hippocampal volume. However, a recent study by Palombo et al. (2013) showed that KIBRA T-allele carriers had larger total hippocampal volume compared to non-carriers. It should be noted that both these studies investigated younger participants, were cross-sectional and used small sample sizes (N≤32). Thus, the association between certain memory-related genetic polymorphisms, such as KIBRA and CLSTN2, and memory-related brain structures, such as the hippocampus, should also be investigated in larger samples using older participants and measuring longitudinal change.
The aim of the present study was to investigate the effect of these previously described KIBRA and CLSTN2 polymorphisms and their interaction on memory performance both cross-sectionally and longitudinally in two independent studies of older adults. Additionally, we aimed to assess the effect of these SNPs on hippocampal volume and hippocampal atrophy.
Section snippets
Sydney MAS
The Sydney Memory and Ageing Study (Sydney MAS) is a longitudinal community-based study of non-demented older adults aged 70–90 years at baseline (Wave 1). Participants were excluded if they had a previous diagnosis of dementia, schizophrenia or bipolar disorder, multiple sclerosis, motor neuron disease, developmental disability, progressive malignancy or any other medical or psychological conditions that may prevent from completing the assessments; if they scored <24 on the Mini-mental State
Cross-sectional analysis
Table 2 shows memory domain scores and hippocampal volume, including statistics, split by the KIBRA SNP T-carrier status for the two cohorts, Sydney MAS and OATS. When comparing memory domain scores at Wave 1 from the Sydney MAS cohort there was no beneficial effect of being a KIBRA T-carrier on any of the variables: General memory domain p=.79; Verbal memory domain p=.72. Nor were there any significant main effects for CLSTN2 carrier status (general memory domain p=.62, verbal memory domain p
Discussion
In the present study, by using both cross-sectional and longitudinal data, we investigated if genetic polymorphisms in KIBRA and CLSTN2 were associated with memory performance and hippocampal volume in two independent samples of older adults. This is the first study to also examine change of hippocampal volume in relation to KIBRA and CLSTN2 polymorphisms longitudinally. We failed to replicate the initial reported association of the KIBRA T-allele with better long-term memory performance (
Acknowledgments
We would like to acknowledge and thank the Sydney MAS and OATS participants, their supporters and the respective research teams. The studies are supported by a National and Health Medical Research Council (NHMRC)/Australian Research Council (ARC) Strategic Award 401162 and the NHMRC Program Grants 350833 and 568969. OATS was facilitated by access to the Australian Twin Registry, which is funded by the NHMRC Enabling Grant 310667. DNA was extracted by Genetic Repositories Australia, an Enabling
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