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(Stroke. 1998;29:1882-1887.)
© 1998 American Heart Association, Inc.

Original Contributions

The Apolipoprotein E 4 Allele and Outcome in Cerebrovascular Disease

M. O. McCarron, MA, MRCP; K. W. Muir, MSc, MRCP, MD; C. J. Weir, PhD; A. G. Dyker, MRCP; I. Bone, FRCP; J.A.R. Nicoll, MD, MRCPath; K.R. Lees, MD, FRCP

From the Departments of Neuropathology (M.O.M., J.A.R.N.) and Neurology (K.W.M., I.B.), Institute of Neurological Sciences, Southern General Hospital; and Acute Stroke Unit, Department of Medicine and Therapeutics, Gardiner Institute, Western Infirmary (C.J.W., A.G.D., K.R.L.), Glasgow, Scotland.

Correspondence to Dr James A.R. Nicoll, Department of Neuropathology, Institute of Neurological Sciences, Southern General Hospital, Glasgow G51 4TF, UK. E-mail JARN1H{at}clinmed.gla.ac.uk

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Background and Purpose—Polymorphism of the apolipoprotein E gene (APOE) may influence outcome after traumatic brain injury and intracerebral hemorrhage, with the 4 allele being associated with poorer prognosis. We investigated APOE allele distribution in acute stroke and the effect of the 4 allele on outcome.

Methods—APOE genotypes were determined in 714 stroke patients: 640 ischemic stroke and 74 intracerebral hemorrhage patients. The survival effect of the 4 allele was assessed with the use of a stratified log-rank test. A Cox proportional hazards regression model was used to estimate the independent effect of 4 dose (0, 1, or 2) on survival, and logistic regression was used to determine the effect on 3-month outcome (good if alive at home, poor if in care or dead).

Results—Allele distribution matched the general population with no difference between the ischemic and hemorrhagic groups. Survival in the entire cohort was unaffected by 4 dose. Improved survival with increasing 4 dose was found in the ischemic group (relative hazard=0.76 per allele; P=0.04). If transient ischemic attacks were excluded, a trend for improved survival persisted (P=0.06). With intracerebral hemorrhage, a trend was seen toward reduced survival with 4 (P=0.07, log-rank test). Three-month outcome in the ischemic group was unaffected by 4 dose, and a trend toward poorer outcome with 4 was seen for intracerebral hemorrhage (P=0.10).

Conclusions—The APOE 4 allele had divergent effects on survival and outcome in ischemic and hemorrhagic strokes in this population. The reported adverse effect on patients with intracerebral hemorrhage was supported. The favorable survival effect on ischemic stroke patients requires further study.

Key Words: apolipoproteins • stroke outcome

	Introduction

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Apolipoprotein E is a polymorphic glycoprotein (apo E for protein, APOE for gene) that mediates the binding of lipid particles to specific lipoprotein receptors. It is synthesized predominantly in liver but is also expressed in significant amounts in brain, where apo E is the major mediator of cholesterol and lipid transport. This is important in membrane maintenance and repair.¹ Apo E is encoded by a 4-exon gene located on the long arm of chromosome 19. Three major isoforms, E2, E3, and E4, result from different amino acid substitutions at positions 112 and 158 in the 299–amino acid protein and are encoded from separate alleles, denoted by 2, 3, and 4, respectively.

The 4 allele is a dose-dependent risk factor for Alzheimer's disease.² It is also associated with higher total serum cholesterol and LDL cholesterol levels,³ atherosclerosis, and ischemic heart disease.⁴ Studies to date have produced apparently conflicting results on the influence of APOE alleles on predisposition to ischemic stroke.^{5 6 7 8 9 10 11 12 13} In small case-control or cross-sectional studies, 2,⁵ 4,^{6 7} or both alleles⁸ have been significantly overrepresented, while others have found no influence of APOE polymorphisms.^{9 10 11 12} The excess of both 2 and 4 alleles in a form of hemorrhagic stroke due to cerebral amyloid angiopathy(CAA)^{14 15 16} is now thought to play an important etiologic role.^{17 18}

In addition, interest has focused on the role of APOE in the response to and recovery from acute central nervous system (CNS) injury. Possession of the 4 allele has been implicated as a poor prognostic factor in head injury^{19 20 21} and in intracerebral hemorrhage.²²

We studied the distribution of APOE alleles in both acute ischemic and hemorrhagic cerebrovascular disease in a cohort of unselected patients admitted to an acute stroke unit (Western Infirmary, Glasgow). We also examined the effect of the APOE 4 allele on survival and 3-month outcome in all patients as well as in the ischemic and hemorrhagic subgroups to test the hypothesis that the 4 allele is associated with an adverse outcome.

	Subjects and Methods

Top Abstract Introduction Subjects and Methods Results Discussion References

 
This retrospective study represents a series of unselected admissions between June 1990 and December 1995 to the acute stroke unit of the Western Infirmary, Glasgow. Patients were admitted who presented with an acute onset of a focal neurological deficit. Clinical data and investigation results were recorded prospectively. All patients had their deficit categorized on the basis of clinical features according to the Oxfordshire Community Stroke Project (OCSP) classification.²³ Patients were included who had a clinical diagnosis suggestive of stroke and compatible imaging findings (CT and MR) along with follow-up information. Only patients with missing blood samples or unconfirmed APOE genotypes were of necessity excluded from study. The study had local ethics committee approval.

APOE Genotyping
APOE genotypes were determined with the use of frozen whole blood samples, blind to outcome and stroke classification. Leukocyte DNA was extracted and amplified by a polymerase chain reaction method with appropriate primers.²⁴ The product was digested with the use of the restriction enzyme HhaI, separated on a 10% polyacrylamide gel, stained with ethidium bromide, and visualized by ultraviolet light.

Outcome Measurements
Survival and placement follow-up were by record linkage²⁵ to the Scottish deaths register and to a national database of hospital discharge records. Record linkage is a validated method for monitoring end points in clinical studies.^{26 27 28 29} Although reliable, the method does not detect admissions to non–National Health Service hospitals or institutions outside Scotland. As a marker for functional outcome, we used the 3-month data (a common end point in therapeutic stroke trials^{30 31} ) to define good outcome as being alive at home and poor outcome as alive in care or dead.

Statistical Analysis
The effect of the 4 allele on survival was first assessed with the use of a stratified log-rank test. A stratification variable with 5 levels, based on clinical presentation and CT scan, was used. The 5 levels of the variable were as follows: total anterior circulation infarction, partial anterior circulation infarction, posterior circulation infarction, lacunar infarction (from the OCSP classification²³ ), and primary intracerebral hemorrhage.

A Cox proportional hazards regression model³² was used to estimate the effect of the 4 allele dose (absent, heterozygous, and homozygous) on survival following an acute cerebrovascular event after adjustment for other prognostic factors. A similar model was used for the ischemic subgroup with and without patients with a transient (<24 hours) neurological deficit. Potential prognostic factors that were considered were age, history of hypertension, diabetes, duration of neurological deficit (transient ischemic attack or clinical stroke), ischemic heart disease, previous stroke, smoking, hematocrit level, plasma glucose, and serum cholesterol. Since the OCSP classification would not satisfy the proportional hazards assumption, the same 5-level stratification variable as was used in the log rank test was included. The proportional hazards assumption was tested for each prognostic factor to be considered for the model. In the hemorrhagic stroke group an unstratified log-rank test was used.

Differences in the distributions of potential prognostic variables between the 2 outcome categories at 3 months were assessed with a ² test (categorical variables) or a Mann-Whitney test (continuous variables). The presence or absence of the 4 allele, age, hypertension, diabetes, clinical diagnosis (stroke or transient ischemic attack), ischemic heart disease, previous stroke, smoking, hematocrit level, plasma glucose level, serum cholesterol, clinical presentation according to the OCSP classification, and stroke type were examined. Variables that had a value of P<0.1 in the univariate test were then considered in a stepwise logistic regression model along with the presence of the 4 allele. This analysis was repeated in the ischemic group. In the hemorrhagic group a ² test was used to assess any association between presence of 4 allele and 3-month outcome.

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Of 714 patients included from the database, 640 (89.6%) had an acute ischemic event and 74 (10.4%) had suffered an intracerebral hemorrhage. The baseline characteristics in both groups are shown in Table 1. The allele frequency was in Hardy-Weinberg equilibrium. Table 2 shows the APOE allele distribution among patients in the ischemic, hemorrhagic, and both categories. There was no statistically significant difference between the allele distribution in the ischemic and hemorrhagic groups (2: ²=0.437, 1 df, P=0.51; 3: ²=0.012, 1 df, P=0.91; 4: ²=0.74, 1 df, P=0.61). In anterior circulation disease there was no difference in APOE allele frequency between lacunar and cortical (total and partial anterior circulation syndromes) ischemic events. The allele distribution in both ischemic and hemorrhagic strokes was similar to that in a previous sample of the Scottish population.³³

View this table: [in this window] [in a new window]   Table 1. Medical Histories and Baseline Characteristics of the Patients

View this table: [in this window] [in a new window]   Table 2. Distribution of APOE Alleles in 714 Patients With an Acute Cerebrovascular Insult

Survival
The dose of the 4 allele assessed in the entire cohort was not associated with a survival effect (P=0.11, stratified log-rank test). However, a planned subgroup analysis showed a nonsignificant association of the 4 allele dose with improved survival among ischemic patients (P=0.052, stratified log-rank test) (Figure 1). An analysis of the hemorrhagic group with and without the 4 allele showed an opposite nonsignificant trend toward an adverse association with survival (P=0.07, log-rank test) (Figure 2).

View larger version (18K): [in this window] [in a new window]   Figure 1. Kaplan-Meier survival curves for patients with ische mic cerebrovascular disease carrying 0, 1, or 2 APOE 4 alleles.

View larger version (16K): [in this window] [in a new window]   Figure 2. Kaplan-Meier survival curves for patients with primary intracerebral hemorrhage with and without the APOE 4 allele.

In the Cox proportional hazards regression, all of the clinical factors considered satisfied the proportional hazards assumption. Age (P<0.0001, relative hazard=1.04 per year) and the clinical diagnosis (stroke versus transient ischemic attack, P=0.03, relative hazard=2.13) were the only variables that were significant in addition to the stratification variable. After these had been included in the model, 4 allele dose (4 absent, 4 heterozygous, and 4 homozygous) was not significant (P=0.41) for the whole group of patients. However, in the model for the ischemic subgroup the 4 allele dose had a small significantly favorable effect on survival (P=0.04, relative hazard=0.76). This relative hazard remains virtually unchanged if serum cholesterol evel is forced into the proportional hazards model. Again age (P<0.0001, relative hazard=1.04 per year) and clinical diagnosis (P=0.008, relative hazard=2.58) were the only other significant variables along with the stratification variable. However, in the analysis of ischemic stroke patients (n=556, after exclusion of those with a neurological deficit of <24 hours' duration), the 4 allele dose did not significantly affect survival (P=0.06) after age (P<0.0001) and serum cholesterol level (P<0.02) were included in the model.

Three-Month Outcome
Placement information 3 months after the acute stroke was available on 683 patients. Table 3 shows the univariate test results on different potential prognostic variables for both ischemic and hemorrhagic patients. The 4 allele was not associated with any of these factors. There was also no association between 4 and the prestroke prescriptions of warfarin, salicylic acid, and antihypertensive therapy. Stepwise logistic regression identified OCSP classification, clinical diagnosis of stroke or transient ischemic attack, age, and stroke type (ischemic or hemorrhagic) as independent predictors of 3-month outcome category (Table 4). Total anterior circulation syndrome, increased age, and hemorrhagic stroke each resulted in a greater probability of poor outcome. After these variables were included in the logistic regression model, the 4 allele dose was not significant in the entire group (P=0.09) or in the ischemic subgroup (P=0.13). As with the survival analysis, there was a nonsignificant trend toward an adverse 3-month outcome with the 4 allele among patients with a hemorrhagic stroke (²=2.66, P=0.10; odds ratio for poor outcome, 3.03; confidence interval, 0.77 to 11.98) (Table 5).

View this table: [in this window] [in a new window]   Table 3. Assessment of Univariate Variables on 3-Month Outcome in All Patients

View this table: [in this window] [in a new window]   Table 4. Results of Logistic Regression in All Patients Showing Those Variables That Predicted 3-Month Outcome

View this table: [in this window] [in a new window]   Table 5. Effect of APOE 4 Allele Presence on 3-Month Outcome in Primary Intracerebral Hemorrhage

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
This study shows that the APOE allele distribution does not significantly differ in patients with acute ischemic and hemorrhagic cerebrovascular disease, the distribution being similar to the general white population.³ This finding suggests that APOE polymorphisms do not predispose to the major forms of cerebrovascular disease. APOE has been shown in a smaller study not to be a risk marker of the most common form of hemorrhagic stroke (deep hypertensive or basal ganglia hemorrhages).³⁴ Although cerebral amyloid angio- pathy (CAA)–related hemorrhages have an overrepresentation of the 2 and the 4 alleles,^{14 15 16 17 18 34} this type of hemorrhage is only definitely diagnosed on the basis of a full autopsy showing one or more lobar hematomas with pathological evidence of CAA in the absence of another diagnostic lesion.^{14 35} Because CAA-related hemorrhages only make up 10% of intracerebral hemorrhages,³⁶ it is unlikely that the current clinical study would have been able to detect this APOE polymorphic association.

The negative results of the APOE 4 allele on prognosis when ischemic and hemorrhagic patients are analyzed together conceal divergent subgroup effects associated with possession of the 4 allele. The trend toward worse survival and 3-month outcome in the hemorrhagic stroke patients supports the finding in a previous study of intracerebral hemorrhage²² and is similar to outcome results among head injury patients.^{19 20 21} Although not statistically significant in this relatively small group of patients with intracerebral hemorrhage, those with 4 were twice as likely to be dead at 6 months, a magnitude of difference that is identical to our previous studies in head injury.¹⁹ In addition, the adverse survival association of intracerebral hemorrhage with 4 was early and then plateaued (Figure 2). This may be important because in both intracerebral hemorrhage and head injury a mechanical or shearing force is delivered to brain parenchyma.

Patients with ischemic cerebrovascular disease had a small dose-dependent survival advantage associated with possession of the 4 allele: the 4 homozygotes were associated with an early survival advantage, whereas among 4 heterozygotes, a much larger group, this was a later but sustained effect (Figure 1). The survival effect was more pronounced in the entire group of patients with an ischemic event than in the group with completed ischemic stroke only. However, the absence of a significant effect on placement suggests that, unlike hemorrhagic insults, APOE polymorphisms may not have a major influence on recovery of CNS function after focal ischemia.

The methodology in our study merits some consideration. Potential shortcomings include the retrospective design and use of the OCSP classification instead of a functional classification of stroke. Although the survival association with 4 in the ischemic stroke group is small and could be a chance finding, the size of the study (640 ischemic stroke patients) and the robust nature of the survival end point lend support to our findings. As a second end point, we used the combined outcome at 3 months of death or accommodation in a care facility versus being alive and at home.^{28 37} We used this as a surrogate marker of functional outcome, and although factors other than stroke outcome can influence institutionalization, it represents an important end point for the individual patient after stroke.

Apo E is the primary apolipoprotein in the brain, produced by astrocytes and oligodendrocytes. Animal models have shown increased expression of apo E and increased neuronal uptake after ischemic³⁸ and hemorrhagic insults.³⁹ That apo E is important in neuronal injury has been suggested in APOE-deficient (knockout) mice, in which a larger infarct volume occurs after focal cerebral ischemia.⁴⁰ The mice also have a prolonged intrinsic clotting time and elevated fibrinogen. Although these results suggest that apo E may influence the amount of injury incurred from a CNS insult, it is currently not clear if these properties are important in humans.

Apo E may play a role in CNS repair through different mechanisms, some of which are known to be isoform specific: (1) It helps to maintain the dendritic cytoskeleton, as shown by homozygous APOE-deficient mice that display significant loss of synapses and marked dendritic disruption with age.⁴¹ In vitro work has demonstrated a neurotrophic role of apo E. Although in the dorsal root ganglion the E3 isoform enhances neurite growth more than E4,⁴² this is not the case in rat hippocampal cultures.⁴³ (2) Apo E has an antioxidant effect (E3 is more efficient than E4), which may protect neurons.⁴⁴ (3) The E4 isoform encourages deposition of amyloid ß-protein, which is known to damage endothelial cells by producing superoxide radicals.⁴⁵ (4) Although not known to be isoform specific, apo E is involved in downregulation of the CNS inflammatory response, as shown by suppressed glial secretion of tumor necrosis factor-,⁴⁶ and this decrease in inflammatory mediators may reduce ischemic injury.

A less robust cytoskeleton, oxidative damage, increased edema, and poor mobilization of cholesterol and lipids are all putative mechanisms by which apo E could affect outcome. These or other unknown apo E functions may contribute in an isoform-specific manner, their particular influence depending on the type of CNS insult.

It is not clear how 4 can be associated with a prolonged favorable outcome in ischemic cerebrovascular disease. The survival benefit over several years associated with the 4 allele in these patients is intriguing because epidemiological studies have shown that the 4 allele decreases in frequency with age,^{3 47} presumably because of increased mortality from ischemic heart disease in patients with 4. A previous outcome study in the same population used for the present study found higher cholesterol concentrations to be associated with improved survival over 3 years following stroke.²⁸ Although higher serum cholesterol levels in patients with 4³ may be invoked to explain the beneficial survival association of 4 in cerebral ischemia, cholesterol concentrations were not significantly different in our patients with and without the 4 allele. This is not surprising because only 7% of total serum cholesterol variation is attributed to apo E.³

In conclusion, whereas APOE genotype appears to influence predisposition to CAA-related hemorrhage, it is not associated with the more common forms of acute hemorrhagic and ischemic cerebrovascular disease. This study supports a previous finding that 4 is associated with a poorer outcome in intracerebral hemorrhage. Our findings also demonstrate that the APOE 4 allele is not a poor prognostic factor in ischemic stroke and indeed may be associated with improved survival. Further study of the apparently divergent effects of APOE genotype on outcome after different forms of acute brain injury (ischemic infarct, intracerebral hemorrhage, and trauma) may help to elucidate the relevant mechanisms in which apo E is involved.

	Acknowledgments

 
M.O. McCarron is supported by a Patrick Berthoud Fellowship, and C.J. Weir is an MRC Training Fellow. We wish to thank Janice Stewart and Kathryn Brown for assistance with apo E genotyping, Chris Povey at Scotland (National Health Service) Information and Statistics Division for his assistance with record linkage, and Dr G.T. McInnes, Professor J.L. Reid, and Dr P.F. Semple for permission to study their patients.

Received April 30, 1998; revision received June 12, 1998; accepted June 16, 1998.

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