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Ann Thorac Surg 2008;86:841-847. doi:10.1016/j.athoracsur.2008.04.085
© 2008 The Society of Thoracic Surgeons
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Original Articles: Adult Cardiac

The Apolipoprotein E {epsilon}4 Allele is not Associated With Cognitive Dysfunction in Cardiac Surgery

Brendan S. Silbert, MB, FANZCAa,b,*, Lisbeth A. Evered, BS, MBiostata, David A. Scott, PhD, FANZCAa,b, Tiffany F. Cowie, BS, MBAc

a Centre for Anaesthesia and Cognitive Function, Department of Anaesthesia, St. Vincent's Hospital, University of Melbourne, Melbourne, Australia
b Department of Surgery, St. Vincent's Hospital, University of Melbourne, Melbourne, Australia
c Department of Pathology, University of Melbourne and the National Neuroscience Facility, Melbourne, Australia

Accepted for publication April 24, 2008.

* Address correspondence to Dr Silbert, Department of Anaesthesia, St. Vincent's Health, PO Box 2900, Fitzroy, VIC, 3065, Australia (Email: brendan.silbert{at}svhm.org.au).


   Abstract
Top
 Abstract
Introduction
 Material and Methods
 Results
 Comment
 Acknowledgments
 References
 
Background: The plasma protein apolipoprotein E (APOE) is a risk factor for degenerative cognitive decline manifested by mild cognitive impairment and later by Alzheimer's disease. Patients undergoing coronary artery bypass grafting (CABG) are known to have a high prevalence of preexisting cognitive impairment and postoperative cognitive dysfunction. Because both mild cognitive impairment and Alzheimer's disease generally occur in elderly individuals, the age group that commonly present for CABG, we investigated if the APOE {epsilon}4 allele was associated with patients manifesting preexisting cognitive impairment and postoperative cognitive dysfunction.

Methods: The DNA of 282 patients who had undergone neuropsychologic testing before and 3 and 12 months after CABG was analyzed for APOE genotype. Patients were classified as having preexisting cognitive impairment if cognitive function was decreased in two or more tests compared with a healthy control group. Postoperative cognitive dysfunction was defined as a decrease in two or more tests compared with the group mean baseline score.

Results: The APOE {epsilon}4 allele was found in 83 (29.4%) patients. Although preexisting cognitive impairment was present in 105 (37.2%) and postoperative cognitive dysfunction in 33 (12%) and 31 (11%) at 3 and 12 months postoperatively, there was no relationship with the presence of the APOE {epsilon}4 allele or any of the six genotypes.

Conclusions: Preexisting cognitive impairment and postoperative cognitive dysfunction are not associated with APOE {epsilon}4 genotype, suggesting that cognitive impairment both before and after CABG may not be associated with degenerative cognitive decline.


   Introduction
Top
 Abstract
 Introduction
Material and Methods
 Results
 Comment
 Acknowledgments
 References
 
The most common neurologic complication after cardiac operations is cognitive dysfunction, which has a reported incidence of 53% at discharge, 36% at 6 weeks, 24% at 6 months, and 42% at 5 years [1]. A number of presurgical and surgical factors have been implicated in the genesis of cognitive dysfunction [2], as have several aspects of cardiopulmonary bypass management [3].

The plasma protein apolipoprotein E (APOE) plays a key role in the metabolism of lipids [4]. APOE has been implicated in Alzheimer's disease (AD) because it is found in plaques and neurofibrillary tangles and is known to bind to amyloid-β, an important component of AD pathology [5]. It plays a role in neuronal repair, a function that also implicates it in the maintenance of cerebral function. Genetic studies have shown that a specific genotype of the APOE gene, the {epsilon}4 allele, is associated with AD [6].

Mild cognitive impairment (MCI) is believed to be a prodrome of AD or even an early stage of the same disease. It is characterized by subtle deterioration in cognition without dementia or impairment of acts of daily living [7]. The APOE {epsilon}4 allele has been linked to MCI, supporting the concept of MCI progressing to or being an early stage of AD [8]. Both MCI and AD are considered degenerative cognitive disorders because the primary pathology is degeneration in the central nervous system. This contrasts with vascular cognitive disorders in which the primary pathology is vascular but may lead to deterioration in cognition that is clinically indistinguishable from degenerative cognitive disorders [9].

Patients undergoing coronary artery bypass grafting (CABG) procedures are susceptible to cognitive impairment both before and after the operation. Recent allusions to cognitive impairment before operation have used the term "preexisting cognitive impairment" (PreCI) to describe this entity. PreCI is similar to MCI, but unlike MCI, does not require a subjective complaint from the patient or relative and is defined solely by an objective deterioration in cognitive function. PreCI occurs in up to 45% of patients [10].

Cognitive dysfunction after operation is known as postoperative cognitive dysfunction (POCD) [11, 12]. It is unknown whether the pathology involved in poor cognition both before and after CABG shares mechanisms with MCI or AD. A relationship between APOE alleles and cognition either before or after CABG would support a common mechanism for cognitive decline in surgical and nonsurgical subjects.

Two studies have investigated a link between APOE {epsilon}4 and POCD. Tardifff and colleagues [13] studied 65 patients and Steed and colleagues [14] studied 111 patients. The former study suggested that the APOE {epsilon}4 genotype was associated with POCD, but the second study was unable to verify this finding. Interestingly, Gaynor and colleagues [15] reported an association between the APOE {epsilon}2 allele and neurodevelopmental sequelae after infant cardiac surgery. The APOE {epsilon}2 allele has been linked to cardiovascular disease and abnormal blood lipids [16] and is reportedly protective in dementia [17]. Although not the focus of this study, all genotypes of the APOE gene were evaluated to control for such secondary genotype effects.

The present study was undertaken to investigate the association between APOE {epsilon}4 genotype and PreCI and to further elucidate any relationship between the APOE {epsilon}4 genotype and the development of POCD.


   Material and Methods
Top
 Abstract
 Introduction
 Material and Methods
Results
 Comment
 Acknowledgments
 References
 
Study Participants
The study group consisted of 282 patients from the 291 patients at two of the three hospitals that participated in the AustraliaN Trial Investigating PostOperative cognitive Deficit, Early extubation and Survival (ANTIPODES), a prospective, randomized controlled trial [18]. Institutional Ethics Committee approval was granted, and written informed consent was obtained from all patients. Eligible patients were aged 55 years or older, scheduled to undergo elective first-time on-pump CABG, and were randomized to receive either high- or low-dose opioid anesthesia. Because there was no difference in cognitive outcome between patient groups (regardless of opioid dose) when tested at 3 months and 12 months postoperatively, all patients were treated as a single group for the purpose of POCD at these testing times. Blood was not drawn or analyzed for logistic reasons in 9 patients at the two sites participating in the study.

PreCI was defined by using the cognitive test results from 170 control subjects without cardiovascular disease. Ninety controls free of cardiovascular disease consisted of friends and family members of patients undergoing CABG at one hospital [12], and the remaining 80 patients had responded to general advertisements to be involved in a study of healthy aging [19]. The control participants completed the same neuropsychologic test battery as the CABG group, with the exception of one test, as noted subsequently.

Neuropsychologic Testing
All patients completed a battery of eight neuropsychologic tests administered by a trained interviewer. The tests used for the purpose of this study were administered at baseline (during the week before CABG) and at 3 and 12 months after. The test battery consisted of the Auditory Verbal Learning test from CERAD (Consortium to Establish a Registry for Alzheimer's Disease), Digit Symbol Substitution test, Trail Making test parts A and B, Controlled Oral Word Association Test (COWAT), Semantic Fluency test, and the Grooved Pegboard test (dominant and nondominant hands) [12].

Absolute test scores were reversed for timed tasks so that a decrease relative to an earlier assessment implied cognitive decline for every test. Preoperatively, decreased cognitive function for each test was defined if the test score was 2 standard deviations (SD) or more below the mean of the healthy control group for that test [10]. Only 2.5% of the normative control group was outside 2 SD, and thus cognitive function was considered severely compromised when defined in this manner [20]. Because the Semantic Fluency test was not administered to the control group, preoperative cognition was assessed on seven tests. PreCI was defined for individual patients when decreased cognitive function was present in two or more tests of the seven measures of performance [21]. Although the derivation of PreCI differs from that of MCI, both constructs imply a level of cognition that is below normal [22]. The intelligence quotient (IQ) was derived from the results of the National Adult Reading Test (NART) [23].

Postoperatively, decreased cognitive function for each test was defined as a decrease of an individual's score of at least 1 SD of the baseline mean for all patients for the relevant test (after adjusting for systematic factors such as learning and practice effects). This was done by calculating the change in population score at each testing time from baseline (systemic population change) and subtracting this value from each individual's change score [20]. POCD in each patient was defined as decreased postoperative function on two or more test results. The process of testing and the analysis of the results has been described in detail elsewhere [12].

There are few data on the prevalence of PreCI and its association with APOE {epsilon}4 in patients presenting for CABG. Assuming an APOE {epsilon}4 prevalence of approximately 30% [8], the 282 patients in our data set would enable detection of a PreCI frequency of 50% greater in those patients with the APOE {epsilon}4 allele compared with those without ({alpha} = 0.05, β = 0.8; assuming PreCI occurs in 40% of patients).

In addition to analyzing cognition as a categoric variable, we also analyzed preoperative cognition as a group using a composite z score (sum of the individual z scores for all the tests) or a z change score for postoperative cognitive change [14].

Apolipoprotein E Analysis
Venous blood was taken before induction of anesthesia and stored at 4°C before processing. Genomic DNA (50 ng) which had been extracted using the Blood Mini-Kit (Qiagen, Hilden, Germany), was amplified with 200nM primer (APOE-F 5'-GCCTACAAATCGGAACTGGA and APOE-R 5'-ACCTGCTCCTTCACCTCGT), in the presence of 1 unit of Platinum Taq polymerase (Invitrogen, Carlsbad, CA), 1.5mM magnesium chloride, and 200uM deoxyribonucleotide triphosphate with denaturation at 94°C for 7 seconds and 30 cycles of 94°C for 30 seconds, 55°C for 30 seconds, and 72°C for 30 seconds. The product was sequenced with BDV3.1 (Applied Biosystems, Foster City, CA) using the APOE-F primer on an ABI 3130-xl genetic analyser, and the APOE genotype of each sample was determined.

Statistical Analyses
Genotype was analyzed as a category based on the presence or absence of {epsilon}4 allele. In addition analysis was undertaken using all six genotypes ({epsilon}2/2, {epsilon}3/3, {epsilon}4/4, {epsilon}3/2, {epsilon}4/2, {epsilon}4/3).

Group comparisons were made using unpaired t tests for continuous variables, the Mann-Whitney U test for ranked data, and {chi}2 square or Fisher exact test for dichotomous variables. Incidence analysis was used to examine cognition after patients were classified as having PreCI or POCD [24, 25].

Associations were determined using univariable and multivariable logistic regression with a value of p < 0.2 set for entry into the multivariable regression models. APOE was entered because it was the primary outcome variable. Significance was set at p < 0.05.


   Results
Top
 Abstract
 Introduction
 Material and Methods
 Results
Comment
 Acknowledgments
 References
 
Table 1 reports the demographics, clinical risk factors, and medication use. There was no difference between those patients with and without the APOE {epsilon}4 allele. There were two postoperative strokes, with one presenting as hemianopia and the other as mild hemiparesis. Both patients were still able to complete all cognitive assessments. Five patients died, four of whom completed cognitive assessments at 3 months after operation.


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  		Table 1 Patient Demographics, Cardiovascular Risk Factors, and Medications
 
The distribution of the six APOE genotypes, together with the presence or absence of PreCI for each genotype, is reported in Table 2. The APOE {epsilon}4 allele was present in 83 patients (29.4%), which included 75 heterozygotes (26.6%) and 8 homozygotes (2.8%).


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  		Table 2 Prevalence of APOE Genotype and Preexisting Cognitive Impairment
 
PreCI was defined in 105 (37.2%) of the 282 patients. There was no significant difference between any APOE genotype and the prevalence of PreCI. There was no difference in the prevalence of PreCI in patients with the APOE {epsilon}4 allele compared with those without an APOE {epsilon}4 allele (Table 3). The demographic, cardiovascular risk factors, and medications (Table 1) were entered into univariable analysis but did not reveal any variables that met the criteria for entry into multivariable analysis (p < 0.02). Multivariable analysis therefore included those risk factors known to be associated with cognition (age and IQ) together with APOE because this was the primary outcome variable. Multivariable analysis showed a relationship between PreCI and age (odds ratio [OR], 1.1; 95% confidence interval [CI], 1.06 to 1.14), and IQ (OR, 0.92; 95% CI, 0.89 to 0.95), but not the presence of the APOE {epsilon}4 genotype (OR, 0.61; 95% CI, 0.31 to 1.18). There was no difference in the results of any individual preoperative test of cognition when analyzed according to the presence or absence of an APOE {epsilon}4 allele (Table 4).


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  		Table 3 APOE {epsilon}4 Allele and Preexisting Cognitive Impairment
 

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  		Table 4 Results of Individual Cognitive Tests Preoperatively and Presence of APOE {epsilon}4 Allele
 
POCD was present in 33 of patients (12%) at 3 months and 31 of patients (11%) at 12 months after CABG. There was no difference between any APOE genotype and the incidence of POCD at either 3 or 12 months (Table 5). The presence of an APOE {epsilon}4 allele was not associated with POCD at either time (Table 6). There was no significant difference in the results in any the of individual cognitive tests between those patients with or without an APOE {epsilon}4 allele at either 3 or 12 months (Table 7).


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  		Table 5 Prevalence of Genotype of APOE and Postoperative Cognitive Dysfunction
 

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  		Table 6 Prevalence of an APOE {epsilon}4 Allele and Postoperative Cognitive Dysfunction
 

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  		Table 7 Results of Individual Cognitive Tests at 3 Months and 12 Months After Operation
 
Multivariable analysis at 3 months and 12 moths showed only a relationship between POCD and age at 3 months (OR, 1.05; 95% CI, 1.00 to 1.11). There was no association with the presence of APOE {epsilon}4 at either time.

When preoperative and postoperative cognition were analyzed using continuous z scores instead of categoric classification to measure cognition, there was still no significant relationship identified between the APOE {epsilon}4 genotype or the presence of an APOE {epsilon}4 allele.


   Comment
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
Acknowledgments
 References
 
Despite the identification of PreCI in 37.2% of patients, we were unable to identify any association with the presence of the APOE {epsilon}4 allele or with a particular APOE genotype. This lack of association was also present for POCD at both 3 and 12 months postoperatively. These findings indicate that the APOE {epsilon}4 allele is not associated with cognitive impairment either before or after CABG.

The primary aim of this investigation was to examine the association of PreCI and the APOE {epsilon}4 allele on the basis that cognitive impairment preoperatively may share some of the characteristics of MCI. This important, because it is now recognized that 37% to 45% of patients presenting for CABG may have PreCI [10, 21]. The exact nature of this cognitive impairment is unknown; however, an association with the APOE {epsilon}4 allele would indicate some commonality with MCI and AD. The failure to identify this association implies that PreCI may involve differing pathophysiology from cognitive impairment in subjects who have not been selected for the presence of cardiovascular disease. This supports the hypothesis that the cognitive impairment seen before operation in this group may derive from cardiovascular disease rather than degenerative disease. Because the risk the factors for coronary artery disease in patients presenting for CABG are also known risk factors for degenerative cognitive impairment [5], the failure to implicate the APOE {epsilon}4 allele may be a key factor in differentiating vascular from degenerative cognitive decline.

Another approach in distinguishing vascular from degenerative cognitive impairment is related to the cognitive domains affected. Although MCI is now subclassified according to which cognitive domains are impaired, amnestic impairment is a common feature of degenerative dementia [26, 27]. The presence of the APOE {epsilon}4 allele did not affect the results of the CERAD Auditory Verbal Learning test, which specifically tests for memory, further supporting that cognitive impairment in this setting is unlikely to be solely of degenerative origin.

The neuropsychologic testing in this study was designed to detect subtle changes in cognition in contrast to the presence of frank dementia. In the Canadian Study of Health and Aging, APOE {epsilon}4 was not associated with cognitive impairment in the early stages but became associated at the time when dementia was detected [28]. Thus, extended follow-up is needed to fully discount any possibility that the presence of the APOE {epsilon}4 allele does not lead to dementia in the longer term despite the lack of association with cognitive decline up to 12 months postoperatively.

A negative finding may be due to a type II error as a result of inadequate numbers. However, there was an insignificant trend for the prevalence of PreCI to be increased in those patients without the APOE {epsilon}4 allele making it unlikely that our finding was a false-negative. The study was not powered to detect significant changes in POCD. The low incidence of POCD overall at 3 and 12 months makes it unlikely that a difference due to the presence of the APOE {epsilon}4 allele would have been detected in this study.

Although there are no previous reports linking PreCI to APOE {epsilon}4, there have been several attempts to investigate the association of POCD and APOE {epsilon}4 after—rather than before—CABG. Tardiff and colleagues [13] studied 65 patients 6 weeks after CABG and measured cognition as both a categoric variable defined as cognitive decline (20% decrement in 20% of tests) and as a continuous cognitive impairment index (defined as an average percentage decline over all the tests). Genotype was analyzed as either the presence or absence of the APOE {epsilon}4 allele because the patient numbers were too small to examine all the APOE alleles. The APOE {epsilon}4 allele was present in 13% of patients. Both logistic and linear regression models for cognitive decline and the cognitive impairment index showed a significant relationship to the presence of the APOE {epsilon}4 allele. The authors suggested that the cognitive changes after CABG share similarities with AD. However, the study was limited by small numbers, incomplete follow-up, and no cognitive testing beyond 6 weeks. There was no difference between preoperative test scores between the APOE {epsilon}4 group and those without the APOE {epsilon}4 allele, but no attempt was made to define preoperative cognition.

A more recent study used the Mini Mental State Examination as a crude index of POCD at 6 days after CABG, and also suggested that the APOE {epsilon}4 allele is associated with early cognitive decline [29].

Steed and colleagues [14] attempted to replicate the Tardiff study using a larger sample of 111 patients to enable the analysis of individual APOE genotypes. Cognitive decline was calculated using a continuous measure (z change score) and two categoric methods (a decline of ≥ 1 SD on two or more tests; 20% decrement in 20% of tests). At the 6-week follow-up, no association with the presence of the APOE {epsilon}4 allele was found between change in cognitive function for the z-based change scores or any of the individual neuropsychologic tests. Categoric measures of change in cognition also failed to show an association with the APOE {epsilon}4 allele. This lack of association held for individual genotype groupings. Again, no attempt was made to classify cognition preoperatively, although it was also noted that there was no difference in preoperative cognition between patients with the APOE {epsilon}4 and those without it.

The APOE {epsilon}4 allele has also been studied in relation to cognition and delirium after noncardiac procedures. Abildstrom and colleagues [30] failed to show any association with POCD measured as a categoric variable (z score for each test or summary z score) in 976 patients [30]. In contrast, Leung and colleagues [31] identified a significant association between postoperative delirium and the presence of the APOE {epsilon}4 allele.

The present study addresses several shortcomings in the previous studies of POCD and APOE {epsilon}4 in relation to CABG. First, the prevalence of PreCI has been addressed by using an appropriate control group to define preoperative cognitive status. Second, the number of patients greatly exceeds that of all previous studies of APOE {epsilon}4 after CABG. Third, the study group is confined to elderly CABG patients, a group which is known to have a high prevalence of PreCI and POCD. Fourth, follow-up was continued for 12 months rather than limited to 6 weeks, allowing for the detection of late-onset cognitive decline.

When classified as APOE {epsilon}4 present or absent, our results did not differ significantly from results for Australian volunteers without cognitive deficits [32] or those studied by Abildstrom and colleagues [30] for noncardiac operations. There was also no significant difference in the distribution of individual alleles with these studies. However, our numbers may have been too low for sufficient power to detect a difference in the distribution of the APOE alleles in patients with cardiovascular disease and control patients. The frequency of {epsilon}4/{epsilon}4 in patients undergoing CABG reported by Steed and colleagues [14] was significantly higher than this study (2.8% vs 7.2%; p = 0.05), and they claimed this was representative of patients with coronary heart disease. Our results suggest that the frequency of APOE {epsilon}4 alleles may be lower than that suggested by Steed and colleagues.

Patients with coronary artery disease are known to have a higher prevalence of the APOE {epsilon}4 allele. In a meta-analysis of APOE alleles and coronary artery disease, the odds associated with having one {epsilon}4 allele were 38% higher than APOE {epsilon}3/{epsilon}3 [33]. The biochemical mechanism is related to dysfunction of the {epsilon}4 isoform in lipoprotein metabolism and an increased concentration of serum cholesterol and triglycerides. It has been suggested that the role of the APOE {epsilon}4 allele in lipid metabolism may explain both the association with cardiovascular disease and AD [5].

In conclusion, in patients presenting for CABG, the presence of PreCI was defined in 37.2% of patients and POCD in 12% at 3 months and 11% at 12 months. No association was detected between any APOE allele or the APOE {epsilon}4 isoform, either before or at any time after the procedure. These results indicate that PreCI and POCD in patients for CABG do not share a link with APOE {epsilon}4 found in MCI or AD, supporting a vascular rather than a degenerative origin of cognitive impairment in these patients.


   Acknowledgments
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
 Acknowledgments
References
 
This work was funded by the National Health and Medical Research Council, Canberra, Australian Capital Territory, Australia (Project Grant #140510). We would like to thank Stavroula Kanellakis, BS, the Department of Pathology, University of Melbourne for helping with the genotyping.


   References
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
 Acknowledgments
 References
 

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L. A. Evered, B. S. Silbert, D. A. Scott, P. Maruff, K. M. Laughton, I. Volitakis, T. Cowie, R. A. Cherny, C. L. Masters, and Q.-X. Li
Plasma Amyloid {beta}42 and Amyloid {beta}40 Levels Are Associated With Early Cognitive Dysfunction After Cardiac Surgery
Ann. Thorac. Surg., November 1, 2009; 88(5): 1426 - 1432.
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P. A. Thistlethwaite
Invited Commentary
Ann. Thorac. Surg., September 1, 2008; 86(3): 848 - 848.
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