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The role of the APOE gene in cognitive recovery following traumatic brain injury : an exploration of direct effects and interactions with age and sex
thesisposted on 2023-05-27, 11:20 authored by Christine PadgettChristine Padgett
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 ‚Ä¶vµ2, ‚Ä¶vµ3, and ‚Ä¶vµ4, 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 ˜í¬µ4 allele is less structurally sound than that of the ˜í¬µ2 or ˜í¬µ3 alleles and as such, it has been proposed that APOE ˜í¬µ4 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 ˜í¬µ4 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 ˜í¬µ4 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 ˜í¬µ4 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 ˜í¬µ4 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 ˜í¬µ4 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 ˜í¬µ4 = 37, APOE ˜í¬µ3 = 92, APOE ˜í¬µ2 = 13), and also considering whether injury severity influenced the expression of APOE ‚Ä¶vµ4. 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 ˜í¬µ4 = 30, APOE ˜í¬µ3 = 77, APOE ˜í¬µ2 = 12). In this study, as well as considering the general effect of APOE ‚Ä¶vµ4, age and/or sex differences were evaluated to determine whether there was an interaction between these factors and APOE ‚Ä¶vµ4. There was tentative evidence that APOE ‚Ä¶vµ4 was associated with impaired executive function, but this was inconsistent. There was no evidence of an interaction between age and APOE ‚Ä¶vµ4, and little evidence of an interaction between sex and APOE ˜í¬µ4. 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 ‚Ä¶vµ4. The key finding of this thesis is that APOE ‚Ä¶vµ4 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.
Rights statementCopyright 2016 the Author Chapter 2 appears to be the equivalent of a post-print version of an article published as: Padgett, C. R., Summers, M. J., Skilbeck, C. E., 2016. Is APOE ‚Ä¶vµ4 associated with poorer cognitive outcome following traumatic brain injury?: A meta-analysis, Neuropsychology, 30(7), 775-790. This chapter may not exactly replicate the final version published in the APA journal. It is not the copy of record. Chapter 3 appears to be the equivalent of a post-print version of an article published as: Padgett, C. R., Skilbeck, C. E., Summers, M. J., 2014. Missing data: the importance and impact of missing data from clinical research, Brain impairment, 15(1), 1-9 Chapter 5 appears to be the equivalent of an Accepted Manuscript of an article published by Taylor & Francis in Journal of clinical and experimental neuropsychology on 22/2/16, available online: http://www.tandfonline.com/10.1080/13803395.2015.1137557