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Vol. 57 No. 10, October 2000 TABLE OF CONTENTS
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Prospective Study of Apolipoprotein E Genotype and Functional Outcome Following Ischemic Stroke

Mark O. McCarron, MD, MA, MRCP; Keith W. Muir, MD, MRCP, MSc; James A. R. Nicoll, MD, FRCPath; Janice Stewart; Yvonne Currie, BSc; Kathryn Brown, PhD; Ian Bone, FRCP

Arch Neurol. 2000;57:1480-1484.

ABSTRACT

Background  The apolipoprotein E (APOE) {epsilon}4 allele is a marker of adverse outcome following head injury and intracerebral hemorrhage. Transgenic animal data in a focal cerebral ischemia model suggest that the {epsilon}4 allele increases infarct size and functional impairment.

Objective  To determine if APOE genotype is associated with functional recovery from ischemic stroke.

Design  Prospective study.

Setting  Stroke service at a university teaching hospital.

Patients  Patients with clinical and neuroimaging findings (computed tomography or magnetic resonance imaging) compatible with an acute ischemic stroke.

Main Outcome  Functional outcome by Barthel index (BI) and modifed Rankin scale (mRS) was compared for {epsilon}3/{epsilon}3 patients vs {epsilon}4 carriers and vs {epsilon}2 carriers at 1 and 3 months. Univariate predictors of 3-month outcome were examined in a multivariate analysis.

Results  One hundred eighty nine patients were enrolled: 100 women, 89 men (mean ± SD age, 69.4 ± 11.0 years). There were 25 {epsilon}2 alleles (frequency, 0.07), 292 {epsilon}3 alleles (0.77), and 61 {epsilon}4 alleles (0.16). Baseline National Institutes of Health Stroke Scale scores and Oxfordshire Community Stroke Project classifications were similar in all groups ({epsilon}3/{epsilon}3, {epsilon}4, and {epsilon}2 carriers). One-month (BI, P = .64; mRS, P = .59) and 3-month (BI, P = .87; mRS, P = .73) outcomes were not associated with possession of either {epsilon}4 or the {epsilon}2 allele. Baseline National Institutes of Health Stroke Scale scores (P<.001) and age (P = .002) were significant predictors of 3-month BI and mRS outcomes in multivariate analyses.

Conclusions  Although there is a robust influence of APOE polymorphism on functional recovery after some types of brain injury in humans, it does not exert a major influence on injury severity or functional recovery following ischemic stroke.



INTRODUCTION
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ALLELIC VARIATION in apolipoprotein E (APOE for gene; apoE for protein) influences some forms of acute and chronic brain injury.1 Interest in the effects of APOE polymorphism on the central nervous system arose in 1993 with the finding that the APOE {epsilon}4 allele is associated with late-onset familial2 and sporadic Alzheimer disease.3 The {epsilon}4 allele seems to determine not if but when an individual will develop the disease.4 In addition, possession of the {epsilon}4 allele is clearly established as a marker of poorer outcome following acute5-7 and chronic head injury8 as well as intracerebral hemorrhage.9-10 There has been less consistent evidence to demonstrate that the APOE {epsilon}4 allele is associated with a worse outcome following ischemic stroke.

Animal studies with APOE knockout mice have shown larger infarcts in models of focal cerebral ishemia11 and increased neuronal injury in models of global cerebral ischemia.12-13 Homozygous APOE {epsilon}3/{epsilon}3 and {epsilon}4/{epsilon}4 transgenic mice have also been assessed under transient focal cerebral ischemia conditions.14 Mice with the {epsilon}3/{epsilon}3 genotype had significantly smaller infarct volumes and better functional outcome than did {epsilon}4/{epsilon}4 mice. These results yield the testable hypothesis that human {epsilon}4 carriers may have a poorer outcome following ischemic stroke (as occurs in head injury) than non-{epsilon}4 carriers. However, no adverse effect on long-term survival could be demonstrated in a large retrospective study in patients with ischemic stroke10; instead, a modestly improved long-term survival was associated with increasing {epsilon}4 allele dose. This study did not, however, examine functional recovery. Survival after ischemic stroke is influenced profoundly by nongenetic factors. Because the transgenic animal data in transient focal cerebral ischemia have demonstrated such functional differences in {epsilon}3/{epsilon}3 compared with {epsilon}4/{epsilon}4 animals, we sought to determine if APOE genotype influences 1-month or 3-month functional outcome in humans following ischemic stroke.


PATIENTS AND METHODS
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PATIENT SELECTION

Consecutive patients were recruited prospectively from an acute stroke unit between January 1997 and May 1998. Ischemic stroke was diagnosed when patients presented with an acute onset of a focal neurological deficit with no evidence of intracerebral hemorrhage or alternative pathologic characteristics on brain imaging. Prior to enrollment, all patients or a relative gave informed consent for the study. Clinical baseline characteristics including National Institutes of Health Stroke Scale (NIHSS) scores15 and Oxfordshire Community Stroke Project (OCSP) classifications16 were recorded at the time of admission. The study was approved by the hospital ethics committee.

APOE GENOTYPING

Apolipoprotein E genotypes were determined from whole blood samples by physicians blind to stroke classification and outcome. Leukocyte DNA was extracted and amplified by a polymerase chain reaction.17 The product was digested using the restriction enzyme HhaI, separated on a 10% polyacrylamide gel, stained with ethidium bromide, and visualized by UV light.

FOLLOW-UP

Participating patients were observed prospectively. Functional outcome was measured at 1 month and 3 months using the Barthel Index (BI)18 and modified Rankin scale (mRS),19-20 blind to APOE genotype.

STATISTICAL ANALYSIS

Differences in stroke severity using OCSP classifications and the NIHSS scores among different APOE genotype categories ({epsilon}3/{epsilon}3, {epsilon}2 carrying, and {epsilon}4 carrying patients) were assessed with a {chi}2 test and Mann-Whitney test, respectively. Outcome categories of the BI and mRS were defined as in the National Institute of Neurological Disorders recombinant tissue plasminogen activator trial21: ie, good (mRS, 0-1; BI 95-100); moderate (mRS, 2-3; BI, 55-90); poor (mRS, 4-5; BI, 0-50); and dead (mRS, 6). Outcome was compared between {epsilon}4 carriers and {epsilon}3/{epsilon}3 patients as well as between {epsilon}2 carriers and {epsilon}3/{epsilon}3 patients using the {chi}2 test. The groups were also examined as {epsilon}4 and non-{epsilon}4 carriers with outcome dichotomized as good (mRS, 0, 1, or 2; BI>55) vs all other functional categories. Differences in the distribution of potential prognostic variables (OCSP classifications and NIHSS scores; history of hypertension, stroke or transient ischemic attack, diabetes mellitus, atrial fibrillation, ischemic heart disease, peripheral vascular disease; current cigarette smoker; current infection or hyperlipidemia; use of aspirin, calcium antagonists, angiotensin-converting enzyme inhibitors; age; and possession of the {epsilon}2 or {epsilon}4 APOE alleles) were examined in a linear regression analysis using 3-month BI and mRS scores as categorical values. Variables with P<.05 on univariate analysis were then considered in a multivariate analysis by multiple linear regression.


RESULTS
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One hundred eighty nine patients were enrolled and APOE genotyped. All had follow-up assessments. There were 89 men and 100 women (mean ± SD age, 69.4 ± 11.0 years; range, 28-93 years). The baseline characteristics, including the OCSP classifications are given in Table 1. The median NIHSS score on admission was 6 (interquartile range, 3-10).


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Table 1. Baseline Characteristics of Patients With Ischemic Stroke*

The APOE alleles were in Hardy-Weinberg equilibrium. No patient had the {epsilon}2/{epsilon}2 genotype, as indicated on the tabulation below.


APOE Genotype Distribution Among Patients With Ischemic Stroke

Fifty-eight patients (31%) carried 1 or more {epsilon}4 alleles and 25 (13%) had an {epsilon}2 allele. There was no significant difference in the age of {epsilon}3/{epsilon}3 patients (mean age, 69 years) and {epsilon}4 (mean age, 68 years; P = .56) or {epsilon}2 carrying patients (mean age, 73 years; P = .11) at the time of stroke. The APOE allele frequencies were 0.07 for {epsilon}2 (n = 25 alleles), 0.77 for {epsilon}3 (n = 292), and 0.16 for {epsilon}4 (n = 61), a similar frequency distribution to that found in previously studied Scottish populations.22

STROKE SEVERITY

There was no statistically significant difference in baseline stroke severity among the proportion of patients in different OCSP categories for {epsilon}3/{epsilon}3 vs {epsilon}2 or {epsilon}4 carriers (Table 2). Although patients possessing an {epsilon}4 allele had greater median NIHSS scores on admission to the hospital than {epsilon}3/{epsilon}3 carriers, the difference was also not statistically significant (P = .10).


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Table 2. Stroke Severity and Apolipoprotein E Genotype*

OUTCOME

One-month outcome (Figure 1) was not statistically different in {epsilon}4 carriers and patients with the {epsilon}3/{epsilon}3 genotype for either BI (P = .64) or mRS (P = .59) scores. Similarly, there were no significant differences between {epsilon}2 carriers and {epsilon}3/{epsilon}3 patients (mRS, P = .19; BI, P = .87).



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Figure 1. Outcome at 1 month measured by the modified Rankin scale and Barthel Index. All data are percentages of patients; comparisons are all with {epsilon}3/{epsilon}3 patients.

The results were unchanged at 3 months (Figure 2). In addition, dichotomizing around end points that signify functional independence (mRS<3 and BI>55) yielded no statistically significant differences between {epsilon}4 (n = 58) and non-{epsilon}4 carriers (n = 131) (mRS, P = .37; BI, P = .61) or for {epsilon}2 carriers compared with non-{epsilon}2 carriers (mRS, P = .19; BI, P = .32). Excluding {epsilon}2/{epsilon}4 heterozygotes (in case of divergent functional effects) from the analyses did not alter any of the results.



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Figure 2. Outcome at 3 months measured by the modified Rankin scale and Barthel Index. All data are percentages of patients; comparisons are all with {epsilon}3/{epsilon}3 patients.

Univariate analyses showed that OCSP categories (P<.001), NIHSS scores (P<.001), and age (P = .002) were significantly associated with an adverse 3-month (BI) outcome. Scores for the NIHSS and age remained significant in a multivariate analysis of 3-month BI and mRS outcomes (Table 3).


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Table 3. Predictors of 3-Month Functional Outcome Derived From a Multivariate Analysis*


COMMENT
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Although APOE polymorphism has emerged as an important determinant of outcome following head injury5-8 and intracerebral hemorrhage,9-10 the findings of this prospective outcome study and a previous retrospective survival study in another population10 indicate that the {epsilon}4 allele does not exert a major adverse influence on baseline severity, functional outcome, or survival following ischemic stroke. These contrasting findings from different types of brain injury suggest that the association of the {epsilon}4 allele with outcome may be insult specific.

Previous case-control and cohort studies have examined APOE genotype as a possible genetic predisposition to ischemic stroke.23-31 Some studies have implicated the {epsilon}2 allele,24-25 some the {epsilon}4 allele,25-27 and others have reported neutral findings.28-31 A recent meta-analysis of case-control studies found a small significant overrepresentation of the {epsilon}4 allele in ischemic stroke patients compared with age- and sex-matched controls.32 The {epsilon}4 allele is also overrepresented in coronary heart diseas{epsilon}33 and is thought to be more atherogenic than other APOE alleles.34 Individuals with the {epsilon}3/{epsilon}4 and {epsilon}4/{epsilon}4 genotypes seem to carry excess risk compared with control subjects in both coronary heart diseas{epsilon}33 and ischemic stroke.32 Although the results of the current study demonstrated fewer lacunar infarcts in {epsilon}4 carriers (29% vs 42%) and higher median NIHSS scores compared with {epsilon}3/{epsilon}3 patients (7 vs 5), neither of these was statistically significant, supporting the findings of a larger study that demonstrated no difference in APOE allele frequencies between patients with lacunar and cortical ischemic events.10

Properties of apoE that are potentially relevant to brain injury (neurotrophic,35 antioxidant,36 immunomodulatory,37 and intracellular calcium effects38) have been identified under in vitro conditions. Although some of these are isoform specific (neurotrophic,35 antioxidant,36 and intracellular calcium changes38), the relevance in vivo of differing mechanisms has not been clearly defined. Consequently, in head injury and intracerebral hemorrhage (conditions for which possession of the {epsilon}4 allele seems to almost double the risk of a poor prognosis6, 10), it is not known whether {epsilon}4 carriers incur more severe injury or have defective repair mechanisms compared with non-{epsilon}4 carriers. In the present study, baseline NIHSS scores and OCSP categories were used to assess stroke severity. Similar findings in each of the major APOE genotype groupings ({epsilon}3/{epsilon}3, {epsilon}4, and {epsilon}2 carriers) suggest that ischemic insult severity in stroke is not associated with APOE genotype.

The outcome findings of our study question how reliably one can extrapolate data from animal models of stroke to humans.39 Brain apoE changes have been well described in different animal models of brain injury,1, 40 including cerebral ischemia.41 The results have suggested that injury either causes neuronal expression of apoE or increases neuronal uptake of apoE.41 This has led to the description of apoE as an "injury factor."42 In one focal ischemic model, infarct volume and hemiparesis severity were significantly worse in transgenic {epsilon}4/{epsilon}4 mice compared with {epsilon}3/{epsilon}3 mice.14 It remains unclear if APOE genotype influences the size of human infarct volume in different types of ischemic stroke. Tomimoto et al43 have demonstrated that apoE-immunoreactive axons in humans are accompanied by apoE-positive macrophages in the periphery of infarcts, although APOE genotypes were not examined in this small study. However, a recent semiquantitative assessment of neuronal damage following global ischemia in humans failed to demonstrate an APOE genotype influence.44

The follow-up functional assessments in our study provided a means, albeit crude, of measuring repair. The neutral results suggest that the different apoE isoforms do not reflect major differences in repair mechanisms following cerebral ischemia in humans. A trend toward better functional outcome in {epsilon}2 carriers vs either the {epsilon}3/{epsilon}3 or {epsilon}4+ groups was present, but must be interpreted with caution since only 13% of the population (n = 25 patients) possessed an {epsilon}2 allele. Furthermore, survival and 3-month placement following ischemic stroke in a cohort of 640 patients10 were not associated with the APOE {epsilon}2 allele.

Although ischemic stroke is a heterogeneous condition, the number of patients in our study is much greater than in those studies of head injury5-8 or intracerebral hemorrhage9-10 (equally heterogeneous conditions) that demonstrated an influence of APOE {epsilon}4 on outcome. This supports the conclusion that APOE genotype does not contribute to major clinically significant differences in either injury severity or functional outcome in ischemic stroke. Our results indicate that associations between APOE genotype and outcome in humans may be insult specific.


AUTHOR INFORMATION
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Accepted for publication February 23, 2000.

Mark O. McCarron, MD, MA, MRCP, is supported by a Patrick Berthoud Fellowship, Kent, England.

Reprints: Keith Muir, MD, MRCP, MSc, Department of Neurology, Institute of Neurological Sciences, Southern General Hospital, Glasgow G51 4TF, Scotland (e-mail: k.muir{at}clinmed.gla.ac.uk).

From the Departments of Neurology (Drs McCarron, Muir, and Bone and Ms Currie) and Neuropathology (Drs McCarron, Nicoll, Brown, and Ms Stewart), Institute of Neurological Sciences, Southern General Hospital, Glasgow, Scotland.


REFERENCES
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