The role of the APOE gene in cognitive recovery following traumatic brain injury : an exploration of direct effects and interactions with age and sex

Traumatic brain injury (TBI) is frequently associated with cognitive impairment, which can be either transient or lifelong. Despite this, the ability to predict who will experience poorer cognitive outcomes remains challenging. The APOE gene, which has three alleles; APOE ɛ2, ɛ3, and ɛ4, has recently attracted attention as a biomarker that may be of prognostic value, as the resultant protein is believed to facilitate post-injury repair. The protein derived from the APOE e4 allele is less structurally sound than that of the e2 or e3 alleles and as such, it has been proposed that APOE e4 carriers may have impaired recovery of cognitive function after injury. Although there is growing literature exploring this hypothesis, the findings to date have been inconclusive. This ambiguity may be due in part to methodological limitations, such as the small sample sizes typically associated with genetic studies in clinical populations, and also may be due to moderating factors being overlooked. For example, it has been proposed that APOE e4 may have an antagonistic pleiotropic effect whereby it confers beneficial effects during the reproductive phase of life, and becomes detrimental during the post-reproductive life phase. Furthermore, there is evidence that female sex hormones enhance the expression of APOE, but that this may not occur for female APOE e4 carriers due to the structural nature of the protein. However, the possible effects of age and sex are yet to be investigated in relation to post TBI cognitive function. The aims of the current thesis are twofold; firstly, to provide a more integrative and in-depth investigation of the relationship between APOE e4 and TBI by conducting a meta-analysis of the literature to date, and secondly, to investigate whether factors such as age and sex may interact with the expression of APOE e4 in relation to post-TBI cognitive function. This thesis comprises four studies: Firstly, a meta-analysis was conducted to provide a more comprehensive interpretation of the extant literature. This revealed no significant differences between APOE e4 carriers and non-carriers, either in terms of general cognitive function or within specific cognitive domains known to be commonly impacted by TBI. Limitations of the literature to date were identified and attempts were made to redress these in the following two studies, which both assessed the processing speed, working memory and executive function of participants who had sustained a TBI. One study assessed these functions during the acute recovery period by exploring the contribution of all three APOE alleles separately (N = 142; APOE e4 = 37, APOE e3 = 92, APOE e2 = 13), and also considering whether injury severity influenced the expression of APOE ɛ4. This revealed that possession of APOE genotype was unlikely to contribute to differences, regardless of injury severity. The following study employed a longitudinal design, and measured outcomes at 3, 6 and 12 months post injury (N = 119; APOE e4 = 30, APOE e3 = 77, APOE e2 = 12). In this study, as well as considering the general effect of APOE ɛ4, age and/or sex differences were evaluated to determine whether there was an interaction between these factors and APOE ɛ4. There was tentative evidence that APOE ɛ4 was associated with impaired executive function, but this was inconsistent. There was no evidence of an interaction between age and APOE ɛ4, and little evidence of an interaction between sex and APOE e4. In an adjunct methodological study, the effect of missing data was explored in the sample and a number of traditional and more recently developed techniques used to compensate for missingness were applied to determine the ability of each to provide the best estimate of the true sample parameters. This thesis has a number of strengths, including the separate categorising of all three alleles, and the consideration of potential interactions between age, sex and APOE ɛ4. The key finding of this thesis is that APOE ɛ4 is unlikely to have a pervasive effect on cognitive recovery after TBI, but that further investigation of the interaction between APOE status and age and sex is needed.