Apolipoprotein E4 Polymorphism and Outcomes from Traumatic Brain Injury: A Living Systematic Review and Meta-Analysis

Abstract

The mortality of traumatic brain injury (TBI) has been largely static despite advances in monitoring and imaging techniques. Substantial variance exists in outcome, not fully accounted for by baseline characteristics or injury severity, and genetic factors likely play a role in this variance. The aims of this systematic review were to examine the evidence for a link between the apolipoprotein E4 (APOE4) polymorphism and TBI outcomes and where possible, to quantify the effect size via meta-analysis. We searched EMBASE, MEDLINE, CINAHL, and gray literature in December 2017. We included studies of APOE genotype in relation to functional adult TBI outcomes. Methodological quality was assessed using the Quality in Prognostic Studies Risk of Bias Assessment Instrument and the prognostic studies adaptation of the Grading of Recommendations Assessment, Development and Evaluation tool. In addition, we contacted investigators and included an additional 160 patients whose data had not been made available for previous analyses, giving a total sample size of 2593 patients. Meta-analysis demonstrated higher odds of a favorable outcome following TBI in those not possessing an ApoE e4 allele compared with e4 carriers and homozygotes (odds ratio 1.39, 95% confidence interval 1.05 to 1.84; p = 0.02). The influence of APOE4 on neuropsychological functioning following TBI remained uncertain, with multiple conflicting studies. We conclude that the ApoE e4 allele confers a small risk of poor outcome following TBI, with analysis by TBI severity not possible based on the currently available published data. Further research into the long-term neuropsychological impact and risk of dementia is warranted.

Role of Sulfonylurea Receptor 1 and Glibenclamide in Traumatic Brain Injury: A Review of the Evidence

“…It follows that the host-response is a key factor in regulating secondary injury processes such as cerebral edema and contusion expansion that significantly influence outcome after TBI. Genetic variation is increasingly recognized as an important contributor to variability in post-traumatic host response [28,[115][116][117][118][119][120][121][122][123][124]. adjacent gene KCNJ11 (encoding KIR6.2).…”

Genetics of Chronic Traumatic Encephalopathy

“…Although all of the tauopathies display these tau deposits, the tauopathies are differentiated by the tau isoforms and anatomic distribution. 32 Rare mutations in MAPT cause an autosomal dominant tauopathy (FTDP-17), which may manifest as several clinical phenotypes including frontotemporal dementia COMT, 54,55 ANKK1, 55,56 IL1A, 57 IL1B, 26,58 IL1RN, 59 DRD2, 55,56 TNF, 60 BDNF, [61][62][63] BCL2, 64 mtDNA haplotypes H, J, T, U, 65 mt-ND3, 66 p53, 67 ACE, 68 NGB, 69 ABCB1, 70,103 AQP4, 71 CYP19A1, 72 PARP1, 73 IL6, 74,75 VMAT2 76,77 Genes/loci implicated in poor chronic c outcomes after TBI b APOE4, [78][79][80][81] TMEM106B, 50 BDNF, [61][62][63] mt-ND3, 66 NGB, 69 PPP3CC 105 Genes/loci implicated in AD Early-onset AD: APP, 82 PSEN1, 82 PSEN2, 82 Late-onset AD: CR1, 83,84 INPP5D/SHIP1, 83,84 UNC5C, 85 HBEGF/PFDNI1, 86,87 MEF2C/TMEM161B, 83 TREM2, 88,89 CD2AP/ADGRF2, 83,84 HLA-DRB/HLA-DQB1,…”

Apolipoprotein E regulates the maturation of injury-induced adult-born hippocampal neurons following traumatic brain injury

“…Neurogenesis is affected in an ApoE isoform-dependent manner after both ischemic stroke [39] and controlled cortical impact [17] in mouse models but not after concussion [40]. Recently a large meta-analysis in humans concluded that outcome following TBI occurs in an ApoE isoform-dependent manner thus validating its importance in overall TBI, but the underlying mechanism remains entirely unknown [41].…”