Gene by neuroticism interaction and cognitive function among older adults

Chronological age is often taken as a risk factor for cognitive decline associated with neurobiological aging. Yet age does not represent a causal mechanism itself—rather, it is a crude proxy for the accumulations of pathogenic processes occurring with age (MacDonald et al., 2011). The search for mechanisms that drive age-related diseases would therefore benefit from more refined analyses based on elements such as genetic predispositions, environmental influences, and psychosocial factors. Although there is a virtual scientific consensus that complex human phenomena involve interactive genetic and psychosocial processes (Institute of Medicine, 2006), research has traditionally focused on only one of these, seldom applying the interactive level of analysis (Dar-Nimrod and Heine, 2011). The present study is part of an increasing focus on the interactive approach to the study of cognitive function (e.g., Lee et al., 2011; Sachs-Ericsson et al., 2010). Genes have been implicated in aging-related cognitive decline. Specifically, a number of studies identified an association between presence/absence of the apolipoprotein (ApoE) e-4 allele on chromosome 19 and cognitive function in healthy adults (Reed et al., 1994; Woodard et al., 2010), with a meta-analysis (Small et al., 2004) indicating that the presence of the allele is associated with cognitive decline. The physiological mechanisms by which the presence of ApoE e-4, an allele associated with elevated risk for cardiovascular diseases (Song et al., 2004) and Alzheimer’s disease (Hardwood et al., 2010), may affect cognitive function remain unknown. The apparently modest effect size indicated by the meta-analysis (Small et al., 2004) highlight the variability in the magnitude of the association between ApoE e-4 and cognitive decline and generate interest in potential moderators that affect the magnitude of this association. The physiological mechanisms, in which causal genetic indicators of complex phenotypes (such as cognitive function) affect phenotypes, are usually unknown (McCarthy and Hirschhorn, 2008). To address this weakness one must take into account that much of the expression of specific genes is dependent on environmental conditions (Johnson et al. 2009). More specifically, the cognitive-related, phenotypic expression of ApoE e-4 has been shown to be affected by environmental stimuli in transgenic mouse models (Levi and Michaelson, 2007) and psychosocial elements have been shown to moderate the association between the presence of the allele and cognitive function among older adults (Lee et al. 2011). This study explores the moderating role of personality phenotypes. Individuals’ personality affects much of their psychosocial environment (McAdams and Pals, 2006). Personality characteristics have also been linked to cognitive performance and function (Robinson and Tamir, 2005; Williams et al. 2010). In research on personality and health, the Five Factor Taxonomy of personality (FFT) has been utilized extensively (Smith and Williams, 1992; Chapman et al., 2009). The FFT enumerates primary domains of personality, the Big 5 (neuroticism, extraversion, openness to experience, agreeableness, and conscientiousness), which emerge in a variety of populations, languages and cohorts (McCrae and Costa, 2008). These personality dimensions are considered to be phenotypes shaped by a combination of environmental and genetic input (Institute of Medicine, 2006). Increased neuroticism, the propensity to experience anxiety, distress, and negative affect, is predictive of cognitive decline associated with age (Chapman et al. in press; Crowe et al., 2006; Wilson et al., 2005). To the extent that Neuroticism is a phenotypic marker of an underlying process that drives age-related cognitive decline, older individuals with elevated neuroticism who are also carriers of ApoE e-4 would be expected to be characterized by a distinct pattern of cognitive aging, characterized by more precipitous decline. From a physiological perspective, an allostatic load framework supports the prediction that neuroticism moderates the association between ApoE e-4 and cognitive function. It is well-established that increased HPA axis activity is associated with cognitive function (Lupien et al., 1998). Previous findings indicate increased HPA axis activity among individuals with ApoE e-4 (Peskind et al., 2001) and among individuals high on neuroticism (Mangold et al., 2006). Double-dysregulation of the HPA axis resulting from a combination of the presence of ApoE e-4 and increased neuroticism may exacerbate cognitive decline. Empirical findings are also consistent with the moderation prediction. Caselli et al. (2004) showed that trait anxiety, a facet subsumed by neuroticism, moderated associations between the presence of ApoE e-4 homozygous genotype and a specific cognitive function (problem solving) among healthy adults. Several additional studies found that depression moderated the association between the presence of ApoE e-4 and cognitive function among older adults. These studies identified interactions between depression and the presence of ApoE e-4 affecting cognitive decline (Niti et al., 2009) and increased incidence of Mild Cognitive Impairment (MCI: Geda et al., 2006). As neuroticism is considered a strong predictor of depression (Duberstein et al. 2008) these findings may have portrayed a narrow picture focusing on particular symptoms and overlooking the broader phenomenon encompassed by neuroticism. To provide a direct test of the hypothesized moderating influence of neuroticism, we conducted a primary analysis of data collected in the Ginkgo Evaluation of Memory (GEM) study (Dekosky et al., 2008). In addition, as empirical research indicated associations between cognitive function and other personality dimensions such as openness to experience (Chapman et al., in press; Wilson et al., 2005), extraversion (Chapman et al., in press; Crowe et al., 2006), and conscientiousness (Chapman et al., in press; Wilson et al., 2007) we included the interactions between ApoE genotype and these personality dimensions in the analysis for exploratory purposes. We also included an interaction term for ApoE e-4 by agreeableness, which represents the last main facet of personality for which no previous research indicates association with age-related cognitive function.