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
Methods—APOE genotypes were determined in
714 stroke patients: 640 ischemic stroke and 74
intracerebral hemorrhage patients. The survival
effect of the
Results—Allele distribution matched the general population
with no difference between the ischemic and hemorrhagic groups.
Survival in the entire cohort was unaffected by
Conclusions—The APOE
The
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
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
APOE Genotyping
Outcome Measurements
Statistical Analysis
A Cox proportional hazards regression model32 was
used to estimate the effect of the
Differences in the distributions of potential prognostic variables
between the 2 outcome categories at 3 months were assessed with a
Survival
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,
Three-Month Outcome
The negative results of the APOE
Patients with ischemic cerebrovascular disease had a small
dose-dependent survival advantage associated with possession of the
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
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-
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
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
Received April 30, 1998;
revision received June 12, 1998;
accepted June 16, 1998.
© 1998 American Heart Association, Inc.
Original Contributions
The Apolipoprotein E
4 Allele and Outcome in Cerebrovascular Disease
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. 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). 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). 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. 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 4 allele has been implicated as a poor
prognostic factor in head injury19 20 21 and in
intracerebral
hemorrhage.22 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 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.
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
trials30 31 ) to define good outcome as being
alive at home and poor outcome as alive in care or dead.
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. 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. 
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 a new window]
Table 1. Medical Histories and Baseline Characteristics of
the
Patients
View this table:
[in a new window]
Table 2. Distribution of APOE Alleles in 714
Patients With an Acute Cerebrovascular
Insult
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):
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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 a new window]
Figure 2. Kaplan-Meier survival curves for patients with
primary intracerebral hemorrhage with and
without the APOE 4 allele.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.
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 a new window]
Table 3. Assessment of Univariate Variables on 3-Month
Outcome in All Patients
View this table:
[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 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. 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. 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. 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. 
,46 and this decrease in inflammatory
mediators may reduce ischemic injury. 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 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.
References
Top
Abstract
Introduction
Subjects and Methods
Results
Discussion
References
2 allele
and risk of stroke in the older population. Stroke. 1997;28:2410–2416.4 and cerebral hemorrhage
associated with amyloid angiopathy. Ann Neurol. 1995;38:254–259.[Medline]
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2 allele in haemorrhage due to cerebral amyloid
angiopathy. Ann Neurol. 1997;41:716–721.[Medline]
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2 allele is specific for patients with
cerebral amyloid angiopathy-related hemorrhage. Neurosci
Lett.. 1998;247:45–48.[Medline]
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4 associated with chronic traumatic
brain injury in boxing. JAMA. 1997;278:136–140.[Abstract]
4 is associated
with the presence and earlier onset of hemorrhage in cerebral
amyloid angiopathy. Stroke. 1996;27:1333–1337..
J Neuroimmunol. 1997;76:70–74.[Medline]
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