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The apolipoprotein E (apoE) gene (APOE) is polymorphic with three alleles, ε2, ε3, and ε4, which give rise to three isoforms, E2, E3 and E4. Many reports have now described a strong association between the ε4 allele and risk of developing late onset Alzheimer's disease as the result of the E4 isoform binding to β-amyloid protein and accelerating the deposition of amyloid, which is the main constituent of senile plaques.1 The APOE ε4 allele also appears to be associated with deposition of β-amyloid after traumatic brain injury, which is also accompanied by increased APOE expression in the central and peripheral nervous systems.
Neurological and cognitive decrements are well documented complications of coronary artery bypass grafting (CABG) surgery. Given that APOE ε4 is associated with deposition of β-amyloid after traumatic brain injury, and poor neurological outcome after subarachnoid haemorrhage and stroke, it may also adversely influence neurocognitive outcome after CABG surgery. In a preliminary report, Tardiff and colleagues2 found that the APOE ε4 allele was associated with greater risk of cognitive impairment, especially in those patients with lower educational levels. More recently, Steed and colleagues3 were unable to replicate the findings in a larger study. However, both of these studies had low incidences of APOE ε4 allele, and thus its role remains equivocal.
Previously, we have reported that palpable aortic atheroma and a preoperative neurological deficit are risk factors for a decline in cognition after CABG surgery.4 Here we report the effect of the APOE ε4 allele in 86 patients who formed a subgroup in that study.
The day before and three months after CABG surgery, a battery of cognitive tests and a structured neurological examination were completed. Factor analysis of the cognitive test battery found that 52% of the test score variance before surgery on these six tests was explained by one component, validating the use of a General Cognitive Factor. The cognitive tests' z scores were summed to obtain an overall General Cognitive Score, which was shown to have a very high correlation (r=0.998) with the General Cognitive Factor.
Blood (2.7 ml) was collected into potassium/EDTA (1.2 mg/ml) at the three month follow up appointment, and DNA was extracted for APOE genotyping.
Fifty two patients were APOE ε4 negative and 34 were APOE ε4 positive. The allele frequencies for APOE ε2, APOE ε3, and APOE ε4 were 0.07 (12/172), 0.72 (123/172), and 0.21 (37/172) respectively. The incidence of palpable aortic atheroma (χ2=0.536, p=0.464) and preoperative (χ2=0.124, p=0.724) and postoperative (χ2=2.44, p=0.118) neurological deficits were not significantly affected by the APOE ε4 allele.
We tested the hypothesis that people with one or more APOE ε4 alleles would have a worse cognitive outcome after CABG surgery. Thus, using analysis of covariance, follow up cognitive score was the outcome variable, preoperative cognitive score was controlled by entering it as a covariate, and APOE ε4 status was a between subjects factor. With α set at 0.05 and the use of a two tailed test, the power of this study to detect different sized effects (in standard deviation units) in the primary outcome (General Cognitive Score) between the APOE ε4 positive and APOE ε4 negative groups was as follows: 61% at SD difference of 0.5; 76% at 0.6; 88% at 0.7; 94% at 0.8.
Verbal fluency was adversely affected after CABG surgery by the presence of the APOE ε4 allele (F=6.31, p=0.014). However, possession of the APOE ε4 allele had no significant influence on the General Cognitive Score (F=0.261, p=0.611) or any of the other cognitive tests (table 1).
We have not shown any association between APOE ε4 and general cognitive or neurological change after CABG surgery. Verbal fluency was adversely affected by the presence of the APOE ε4 allele, but this finding should be interpreted cautiously as it may be a type I statistical error.
The younger mean age of our study population (59 compared with 612 and 643 years) may limit the expression of APOE ε4 and cognitive change but heighten the association of APOE ε4 with coronary artery disease. This may account for our greater APOE ε4 allele frequency (0.21 compared with 0.132 and 0.173) and failure to show an association with a decline in general cognitive ability.
Our cognitive test battery included verbal fluency, a measure of executive function, which was not specifically tested in the other studies. Deficits in executive functions influence a person's ability to work, function appropriately at home, and maintain social relationships.5 These are often the changes that patients complain about after CABG surgery, and this cognitive domain has not been extensively investigated to date.
We assessed cognitive performance at 12 weeks as compared with six weeks in the other studies.2,3 The longer follow up time may unmask the interaction of APOE ε4 and brain injury after CABG surgery in the cognitive domains related to executive function. Long term follow up at one or two years may show a greater affect of APOE ε4 on general cognitive performance.
We found no association between APOE genotype and cognitive scores before surgery, which is in agreement with previous studies.2,3 In terms of recognised risk factors for cognitive decline, we found no association between APOE genotype and the presence of palpable aortic atheroma or neurological deficit before surgery.
In conclusion, this study does not support the hypothesis that the APOE ε4 allele confers additional risk of general cognitive or neurological decline after CABG surgery. Rather, it implies a specific effect on long term outcome of verbal fluency that warrants further investigation.
This work was supported by Welcome Trust Grant 050190.
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