(Stroke. 2000;31:53.)
© 2000 American Heart Association, Inc.
Original Contributions |
Incidence of Dementia in Relation to Stroke and the Apolipoprotein E 
4 Allele in the Very Old
Findings From a Population-Based Longitudinal Study
From the Stockholm Gerontology Research Center and Department of Geriatric Medicine, Karolinska Institute, Stockholm, Sweden.
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Abstract |
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 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
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Background and Purpose—Both stroke and the apolipoprotein E (APOE)
4 allele increase the
risk of dementia. However, the interaction between stroke and APOE on
dementia is still unclear. We addressed this topic by using a
longitudinal design.
Methods—We followed up a community cohort of 1301 subjects aged
75 years, who did not have dementia at baseline. Among them, 92
subjects had a history of stroke (from 3 months to 16 years before
baseline interview). After the 3-year follow-up, 224 dementia cases had
been diagnosed. During the period of follow-up, 91 subjects had a first
occurrence of stroke (incident stroke). The APOE genotype was
known for 985 subjects. Cox proportional hazards regression models were
constructed to estimate the risk for dementia in terms of relative
risks (RRs) for stroke and the APOE 4 allele, with adjustment
for age, sex, education, systolic blood pressure,
antihypertensive medication use, and heart disease.
Results—In the entire study population, RRs for dementia related
to history of stroke and incident stroke were 1.7 (95% CI, 1.1 to 2.6)
and 2.4 (95% CI, 1.6 to 3.5), respectively, after adjustment for all
potential confounders. Subjects with stroke that occurred within 3
years before baseline had RR of 2.4 (95% CI, 1.4 to 4.2), whereas
those with stroke occurring >3 years before baseline had RR of
dementia of 1.1 (95% CI, 0.6 to 2.3). Among those with APOE
information, individuals with only history of stroke (that occurred
within 3 years before baseline) had RR of 3.1 (95% CI, 1.4 to 6.6),
individuals with only the APOE 4 allele had RR of 1.7 (95% CI,
1.1 to 2.5), and individuals with both factors had RR of 5.3 (95% CI,
2.1 to 13.4). The corresponding figures when incident stroke was
examined instead of history of stroke were 2.3 (95% CI, 1.3 to 4.1),
1.7 (95% CI, 1.1 to 2.4), and 4.6 (95% CI, 2.0 to 10.6),
respectively. The RR of interaction term for history of stroke and APOE
4 was 1.1 (95% CI, 0.3 to 3.8; P=0.8). The
corresponding figure was 1.2 (95% CI, 0.4 to 4.4;
P=0.7) for incident stroke and APOE 4. Furthermore,
the RRs of dementia without any stroke and dementia with stroke in
relation to APOE 4 were 1.6 (95% CI, 1.1 to 2.3) and 1.2 (95% CI,
0.6 to 2.4), respectively. In addition, the APOE 4 allele was
not significantly related to the occurrence of stroke (RR=0.8; 95% CI,
0.5 to 1.5).
Conclusions—A relatively fresh stroke is a risk factor for
dementia. APOE 4 increases the risk of dementia without stroke but
not dementia with stroke. Our data do not support a multiplicative
effect of stroke and the APOE 4 allele on the risk of dementia.
However, both factors seem to have an additive effect on the risk of
dementia. The APOE 4 allele does not increase the risk of stroke
in this Swedish elderly population.
Key Words: apolipoproteins • dementia • stroke
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Several studies have shown that the incidence of dementia is higher than expected in ischemic stroke patients compared with controls.1 2 3 4 5 6 The mechanisms underlying the relationship between stroke and dementia may be multiple.5 7 Stroke may be either direct or the main cause of dementia.8 In addition, stroke may act as a precipitating factor for degenerative dementia such as Alzheimer’s disease (AD).9 Furthermore, dementia and stroke may share common risk factors such as hypertension. Special attention has been paid to a genetic risk factor, the apolipoprotein E (APOE) gene,10 11 which has been suggested to carry the susceptibility to both stroke and dementia.
APOE is a plasma protein that plays an important role in the transport
of cholesterol and other lipoproteins.12 13
The APOE has 3 common isoforms in plasma that are encoded by the 3
alleles (2, 3, and 4) of a single gene on chromosome 19.
The 4 allele has been found to be consistently
associated with increased risk of AD, even in very old
populations,14 15 16 17 18 19 although the mechanisms are not quite
understood. In contrast, the relationship between the APOE 4
allele and vascular dementia or dementia with stroke is
controversial.11 17 19 20 21 22 23 24 25 26 27 28 In some studies, the APOE 4
allele has been associated with increased risk of vascular
dementia,11 17 20 21 22 but other studies have failed to
confirm this association.23 24 25 26 27 28 Finally, an ethnic
variation of the APOE effect on dementia has been reported. The APOE
4 allele is not a significant risk factor for AD among blacks
and Hispanics.29
The effect of APOE genotypes on the development of stroke has
also been recently investigated. Compared with the 3 allele, the
4 allele is related to higher levels of serum total
cholesterol and LDL cholesterol,30
and there is evidence of a role of the APOE 4 allele in
atherosclerosis,31 which is a possible
cause of stroke.32 However, inconsistent findings
concerning the relationship between the APOE 4 genotypes and
stroke have been reported. Both the APOE 433 34 and
235 36 alleles have been found to be related to an
increased risk of ischemic stroke, whereas other studies have
not found any association.37 38
There are few studies that examine the effect of interaction between
APOE and stroke on the risk of dementia. In a population-based
prospective study of 353 men aged 69 to 89 years, Kalmijn and
coworkers10 suggested that cerebrovascular disease and the
APOE 4 allele might have a synergistic effect on cognitive
decline.
Few studies have directly focused on people aged 75 years, the age
group that is more often and more severely affected by stroke and
dementia. We investigated the Kungsholmen cohort aged 75 years to
clarify the relations between stroke and the APOE 4 allele for
dementia. Specifically, we tried to distinguish between stroke and APOE
as independent or multiplicative risk factors for dementia.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Study Population
The study population for this analysis is a total of 1301 dementia-free subjects at baseline who participated in the first follow-up of the Kungsholmen Project, which is a longitudinal study of aging and dementia. The details of the study design have been reported previously.39 40 In brief, the study base of the project consisted of all persons who lived in the Kungsholmen district of Stockholm and who were aged
75 years at study entry. The
Mini–Mental State Examination (MMSE)41 was used as a
screening test for dementia. Other information was also collected in
the screening phase that began in October 1987 and ended in December
1989. Of the 2368 eligible persons, 1810 (76.4%) participated in the
screening test (phase I). Among the 385 subjects who were screened
positive (MMSE <24), 71 dropped out. A random sample of 354 subjects
who were screened negative (MMSE score 24, excluding 39 dropouts from
the whole sample of 393) and 314 subjects with an MMSE <24 were then
clinically examined (phase II) to detect prevalent dementia
cases.39 Among these 668 (314 with MMSE <24 and 354 with
MMSE 24) subjects, 110 persons refused to participate in the clinical
examination, 2 persons were affected by mental deficiency, and 225
prevalent dementia cases were identified.42 Of the 1473
participants who were free of dementia at baseline, as diagnosed by
means of the 2-phase design, 172 subjects were excluded because they
refused to participate or moved from Stockholm, and 1301 remained for
the follow-up assessment for incident dementia
cases.42
Identifying Incident Dementia
Of the 1301 subjects, 987 (75.9%) were able to
participate in the follow-up examination, which included physical,
neurological, and psychiatric examinations, neuropsychological
assessment, laboratory tests, and family interview. The examination was
conducted between November 1990 and April 1992. There were 314 persons
who died before the follow-up examination. The medical records and
death certificates of these subjects were extensively reviewed. The
Diagnostic and Statistical Manual of Mental
Disorders, Revised Third Edition (DSM-III-R)
diagnostic criteria43 were used to define
dementia. The cases fulfilling the criteria were defined as clinically
definite dementia. A second category, questionable dementia, was used
when there was evident memory impairment but dysfunction of a second
cognitive ability was questionable. In a preliminary analysis,
we found that both definite and questionable dementia were related to
stroke and APOE 4 in a similar manner. Therefore, both categories
were treated as dementia cases in the final analyses applied in
the present study. Details of the clinical examination,
diagnostic procedure, and primary results of age- and
sex-specific incidence of dementia have been reported
previously.42
History of Stroke and Incident Stroke
Information on stroke (International Classification of
Diseases, Eighth Revision [ICD-8], codes 430 to 438) was derived
from the Stockholm computerized inpatient register, which was started
in 1969. In Sweden, >90% of patients who suffer from a stroke are
admitted to a hospital.44 A previous study that
examined the validity of the register data on stroke reported that 94%
of hospitalized stroke cases were classified correctly.45
The cohort members in our study had lived in the Stockholm area for an
average of 63 years. A subject was considered to have a history of
stroke if he or she had any stroke event recorded in the register
before the baseline interview. During the follow-up period, subjects
with first-ever stroke of the stroke-free cohort were identified. The
whole study population was divided into 3 groups: subjects with a
history of stroke, with incident stroke, and with no stroke. Dementia
with stroke was defined as demented cases with either a history of
stroke or incident stroke.
APOE Genotyping
A standard polymerase chain reaction procedure was used for APOE
genotyping,46 and the DNA was prepared from
peripheral blood samples that were taken at baseline. The
details of the procedure have been reported.38 APOE
genotyping was undertaken for 75.7% (n=985) of the whole study
population. We performed sensitivity analysis47 to
ascertain potential bias due to the missing values of the APOE
genotypes.
Assessment of Other Covariates
Subjects’ educational levels were based on formal schooling.
Arterial blood pressure (systolic Korotkoff phase I
and diastolic phase V) was measured with a mercury
sphygmomanometer and with the subject in a sitting position after
having rested for 5 minutes.48
Information on medication use was collected for the 2 weeks preceding the baseline interview.49 Use of both prescription and nonprescription drugs was queried, and medicine containers and prescription forms were inspected to verify this information. Antihypertensive drugs included all medicines potentially used for lowering blood pressure (Anatomical Therapeutic Chemical classification system50 codes C02, C03, and C07).
History and/or presence of heart disease (myocardial infarction [ICD-8 codes 410 to 412], cardiac dysrhythmia [ICD-8 code 427], and heart failure [ICD-8 code 428]) were detected from the Stockholm computerized inpatient register.
Statistical Analysis
Incidence rates of dementia were calculated by dividing the
number of events by the number of person-years of follow-up. The
follow-up time for nondemented individuals was determined from the date
of the baseline interview to the date of the follow-up examination or
death. For the demented individuals, half of this time was assumed
since dementia is such an insidious disease that it is difficult to
determine the exact date of onset. We used Cox proportional hazards
regression models to calculate the relative risk (RR) of developing
dementia in relation to stroke and APOE genotype. First, only
age (in years) and sex (female versus male) were included in the
models; then all the potential confounders such as education (<8
versus 8 years), systolic pressure (2 dummy variables,
<140 and >160 mm Hg, compared with 140 to 160 mm Hg),
heart disease (yes versus no), antihypertensive medication use (yes
versus no), age, and sex were entered. Since the results did not differ
substantially, we have reported only the RRs from the models in which
all the covariates were taken into account.
When the relationship between history of stroke, APOE 4 allele,
and dementia was analyzed, several Cox models were constructed.
Because of limited numbers, 2/4, 3/4, and 4/4 were
considered 1 group that was labeled 4, which was compared with the
group of subjects without the 4 allele. First, history of stroke
and the APOE 4 allele were included in separate models as
potential risk factors for dementia. Then history of stroke and the
APOE 4 allele were simultaneously included in the
same models to examine the independent effect of these 2 factors on
dementia. Third, 3 indicator variables representing
subjects with only history of stroke, only the APOE 4 allele,
and both history of stroke and the APOE 4 allele were included
in the same model. Finally, to verify whether there was a synergistic
effect of history of stroke and the APOE 4 allele on the risk of
dementia, an interaction term for both factors was included in the
model together with these 2 factors.
All these models were repeated when incident stroke was studied instead of history of stroke. Persons with incident stroke were excluded when the relationship between history of stroke and dementia was studied and vice versa.
To investigate the relationship between the APOE 4 allele and
dementia with and without stroke, 2 separate Cox models were
constructed. Subjects with 3/3 genotype as a reference
group and subjects with any 4 and 2 (2/2, 2/3) were
included in the models.
Finally, sensitivity analysis for the missing values of APOE
genotypes was performed by producing 2 extreme imputations.
This analysis assumed that either all subjects with missing
values of APOE genotypes had the 2 allele (imputation 1)
or that all of them had the 4 allele (imputation 2). All of the
analyses were repeated in these 2 imputations.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The mean age at baseline of the 1301 cohort members was 82.0 years (SD, 5.0); 76.1% were female. The mean baseline MMSE score was 26.6 (SD, 2.7). The mean follow-up interval of the cohort was 36.6 months, with a maximum of 63.1 months. Among the 987 who completed the clinical examination at follow-up, 199 were diagnosed as demented. Among the 314 subjects who died over the follow-up interval, 25 were diagnosed as demented. The availability of APOE genotype was 85% (840/987) in those who completed the follow-up examination and 46% (145/314) in those who died during the follow-up period.
Table 1
shows the baseline
characteristics of the study population according to the occurrence of
stroke.
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History of Stroke and Risk of Dementia
There were 92 subjects with a history of stroke recorded
before baseline interview. These subjects had a significantly increased
incidence of dementia (Table 2). Among
the 92 subjects with a history of stroke, 45.7% (n=42) had had the
stroke within 3 years before baseline, and 54.3% (n=50) had had the
stroke >3 years before baseline. Subjects with stroke that occurred
within 3 years before baseline had RR of 2.4 (95% CI, 1.4 to 4.2),
whereas subjects with stroke occurring >3 years before baseline had RR
of 1.1 (95% CI, 0.6 to 2.3).
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Incident Stroke and Risk of Dementia
There were 91 subjects whose first-ever stroke occurred during the
follow-up period. The risk for dementia in relation to incident stroke
was >2-fold (Table 2
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APOE 4 Allele, Stroke, and Risk of Dementia
From the results reported above, we know that only stroke that
occurred within 3 years before baseline interview was related to higher
risk of dementia. Therefore, we analyzed the relationship among
history of stroke, APOE 4, and dementia in 2 ways: including and
excluding subjects with stroke occurrence >3 years before baseline.
Stroke that occurred within 3 years before baseline and APOE 4
produced RRs of 3.0 (95% CI, 1.7 to 5.5) and 1.7 (95% CI, 1.2 to
2.4), respectively, when they were simultaneously included
in the model together with all other covariables. Table 3 shows that history of stroke and APOE
4 were each significantly related to increased risk of dementia.
Subjects with stroke that occurred within 3 years before baseline and
APOE 4 had heavier risk of dementia than those with either of the 2
factors (Table 3, bottom). When incident stroke was studied
instead of history of stroke, the adjusted RRs were 2.4 (95% CI, 1.5
to 3.9) and 1.7 (95% CI, 1.2 to 2.4), respectively, when they were
simultaneously included in the model. As shown in Table 4, a pattern of the relationship among
incident stroke, APOE 4, and dementia was seen that was similar to
that shown in the bottom part of Table 3. We further
investigated whether there was a synergistic effect between stroke and
APOE 4 on the risk of dementia by including an interaction term in
the Cox models. No significant multiplicative effect was seen when
interaction terms were included in the models. The RRs of interaction
terms for Table 3 (bottom) and Table 4 were 1.1 (95% CI,
0.3 to 3.8; P=0.8) and 1.2 (95% CI, 0.4 to 4.4;
P=0.7), respectively.
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APOE 4 Allele and Risk of Dementia Without Stroke
We further examined the relation between APOE genotype and
dementia according to presence of stroke. Among the 162 dementia cases
identified in those with APOE information, there were 121 patients
without stroke and 41 with stroke. Table 5 shows the incidence and the RR for
dementia with and without stroke in relation to the APOE
genotype. APOE 4 was related to increased incidence of
dementia without stroke but not dementia with stroke.
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APOE 4 Allele and Risk of Stroke
Further analyses focused on subjects with APOE
information, excluding those with stroke at baseline (n=63). Among the
60 patients whose stroke occurred during the follow-up period, 23.3%
had the APOE 4 allele, which was similar to the frequency of the
allele (29.1%) in those without stroke (P=0.3). The
APOE 4 allele was not significantly related to the occurrence of
stroke (adjusted RR=0.8; 95% CI, 0.5 to 1.5).
Additional Analyses
Very mild dementia cases among persons who screened positive (MMSE
<24) still could be missed and therefore were included in the
follow-up cohort. For that reason, all analyses were performed
in the subpopulation of subjects with baseline MMSE 24 (n=1212).
Subjects with only history of stroke (that occurred within 3 years
before baseline), subjects with only APOE 4, and subjects with both
factors had RRs of 3.4 (95% CI, 1.3 to 8.6), 1.7 (95% CI, 1.1 to
2.6), and 3.9 (95% CI, 1.2 to 12.6), respectively. The RR of
interaction term was 0.7 (95% CI, 0.1 to 3.1; P=0.6).
Subjects with only incident stroke, subjects with only APOE 4, and
subjects with both factors had RRs of 2.8 (95% CI, 1.6 to 5.1), 1.7
(95% CI, 1.1 to 2.5), and 5.5 (95% CI, 2.4 to 13.0), respectively.
The RR of interaction term was 1.2 (95% CI, 0.4 to 3.4;
P=0.8).
Since dementia diagnosis was based on information from 2 sources
(clinical examination for those examined at follow-up and medical
records or death certificates for those who died before the
follow-up examination), all the analyses were repeated in the
subpopulation of those who undertook the follow-up clinical examination
(n=987). Subjects with only history of stroke (
3 years), only APOE
4, and both factors had RRs of 2.3 (95% CI, 1.0 to 5.5), 1.6 (95%
CI, 1.1 to 2.3), and 4.8 (95% CI, 1.9 to 12.1), respectively. The RR
of interaction term was 1.3 (95% CI, 0.4 to 4.7; P=0.7).
Subjects with only incident stroke, only APOE 4, and both factors
had RRs of 2.6 (95% CI, 1.4 to 4.8), 1.6 (95% CI, 1.1 to 2.3), and
5.3 (95% CI, 2.3 to 12.4), respectively. The RR of interaction term
was 1.3 (95% CI, 0.4 to 3.8; P=0.6).
In this study stroke was considered a single entity. To avoid a misleading result, we reanalyzed the data when subjects with hemorrhagic stroke (10% of all stroke cases) were excluded. The results did not change substantially.
Finally, sensitivity analysis of missing values of APOE
genotypes was performed. When the relation among a history of
stroke, APOE, and dementia was analyzed with the method
reported in Table 3, the following results were obtained: (1)
For imputation 1 (all subjects with missing values of APOE
genotypes were assumed to have the 2 allele), the RRs in
relation to a history of stroke, only APOE 4, and both history of
stroke and the APOE 4 allele were 2.0, 1.4, and 4.7,
respectively. (2) For imputation 2 (all subjects with missing values of
APOE genotypes were assumed to have the 4 allele), the
RRs for subjects with only a history of stroke, only the APOE 4
allele, and both history of stroke and the APOE 4 allele
were 2.9, 1.6, and 3.4, respectively.
In the analysis concerning the subjects with incident stroke,
the following results were obtained. For imputation 1, the RRs in
relation to only incident stroke, only APOE 4, and both factors were
2.3, 1.4, and 4.0, respectively. For imputation 2, the corresponding
RRs were 2.4, 1.6, and 4.1, respectively. The interaction terms for all
the sensitivity analyses were not significant. The RRs listed
in Table 5 did not change substantially when the sensitivity
analysis was done.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The main findings from our study of Swedish elderly people may be summarized in the following points: (1) A relatively fresh stroke (stroke that occurred within 3 years before baseline or during follow-up) is a risk factor for dementia. (2) The APOE
4
allele increases the risk of dementia without stroke but not
dementia with stroke. APOE 4 does not increase the risk of stroke.
(3) There is an additive effect between stroke and APOE 4 on the
risk of dementia.
Some methodological aspects need to be addressed before these findings
are discussed. There are several strengths of our study. First, this is
a community-based prospective study, which is less likely to suffer
from selection and survival biases. Second, the procedures for
assessing dementia in this study are precise and comprehensive. All the
participants were examined clinically by physicians, and those who died
during follow-up were also traced through medical records and death
certificates. All final diagnoses were made by specialists and based on
double diagnostic procedure. Third, several factors
potentially associated with dementia and stroke were taken into account
in the analyses. Finally, there were very few dropouts from the
dementia-free cohort at follow-up (11.8%). However, there are also
some limitations that should be mentioned. The first limitation is the
relatively high dropout rate of APOE genotyping. To overcome possible
bias in the results due to the missing values, 2 extreme situations
have been simulated. In all of these additional analyses, the
results did not change substantially from the original. Second, we can
study only the association of clinically overt stroke with dementia but
not the role of silent brain infarction since neuroimaging data were
not available in our study. There is increasing evidence that silent
brain infarction is more common than clinically overt
stroke.51 For the same reason, we cannot specify the role
of the locations of stroke on the development of dementia. The third
limitation is the uncertainty of temporal relationship between stroke
and dementia, especially for incident stroke and incident dementia
cases. In our study, some incident stroke may have occurred after
dementia onset or just at the beginning of cognitive decline, acting as
a precipitating factor. At present, our data do not allow us any
differentiation of a subgroup that may be classified as poststroke
dementia in the incident stroke patients. Fourth, very mild cases may
be missed as false-negatives at the screening test. We estimated, on
the basis of our previous study,40 that there were 39
persons (22 men and 17 women) with false-negative results of MMSE. This
misclassification was present and impossible to correct. However,
very mild dementia cases may also have been present among those
with MMSE <24 but were not diagnosed as demented. Therefore, we
repeated the analyses in the subpopulation of subjects with
MMSE 24, and very similar results were obtained. Fifth, the incidence
of dementia among subjects who died before follow-up examination was
lower than that of those who survived. We may have missed some dementia
cases among the deceased because of the imprecision of the diagnosis in
the certificates and medical records (this also may have been due
to the short time). However, similar results were obtained when all the
analyses were repeated in the subpopulation of subjects who
underwent the clinical examination. Finally, the definition of dementia
of DSM-III-R, in which memory impairment is the main feature
of dementia, may exclude patients with specific cognitive deficits
rather than memory deficits, especially those with subcortical strokes,
from being diagnosed with dementia. Therefore, it is possible that the
number of subjects with dementia with stroke may have been
underestimated in this study.
Relatively Fresh Stroke Is a Risk Factor for Dementia
Strokes that occurred within 3 years before baseline or during the
follow-up doubled the risk of dementia. These RRs of dementia in
relation to stroke are lower than those reported in other studies. In
hospitalized patients, ischemic stroke increased the risk of
dementia by 5-1 to 9-fold.2 A
population-based study showed that the incidence of dementia in the
first year was nearly 9 times greater than would have been expected in
a population with the same age and sex distribution, and the risk of
dementia in the cohort each year thereafter was twice the risk in the
population.3 The reasons for the lower RR could be due to
the following facts: (1) We studied dementia as a whole rather than
vascular dementia or particularly stroke-related dementia. (2) Stroke
patients with prevalent dementia at baseline were already excluded from
the analyses. (3) A considerable proportion of subjects with a
history of stroke in the analyses had stroke occurrence >3
years before baseline. Indeed, stroke that occurred >3 years before
baseline interview did not increase the risk of dementia in this
population.
APOE 4 Increases the Risk of Dementia Without Stroke but Not
Dementia With Stroke
Some studies found an increased frequency of the 4 allele
in vascular dementia patients,17 20 21 22 although others
did not find the same result.23 24 25 26 27 28 In the present
longitudinal study, the APOE 4 allele did not significantly
increase the risk of dementia with stroke, in disagreement with a
previous case-control study.11 It has been shown that the
APOE 4 allele is related to early death,52
especially in those with good cognition.53 The survival
variation results in low frequency of the APOE 4 allele in those
with good cognition from whom the control group is selected in
case-control studies. Roses and Saunders54 argued that
coexistence of AD may be the reason for the association between 4
allele with vascular dementia.
APOE 4 Allele Is Not an Important Risk Factor for Stroke in
the Very Old
The association between the APOE 4 allele and stroke
supports the link between the APOE 4 allele and vascular
dementia since stroke is a risk factor for vascular dementia. We did
not find any association between the APOE 4 allele and incidence
of stroke, confirming a previous report from the Kungsholmen
Project38 and a population-based prospective study in
Finland.37 Both APOE 433 34 and
235 36 have been reported to be related to increased
risk for ischemic stroke. A recent study of 280 Austrians aged
50 to 75 years showed that APOE 2/3 was related to silent
microangiopathy-related cerebral damage, including white matter
abnormalities and lacunar infarctions, despite the favorable effects on
lipid levels.55 These findings underscore the complexity
of the association between APOE genotypes and vascular
lesions.
Relationship Between Stroke and APOE 4 Allele on Risk
of Dementia
In a population-based prospective study of 353 men aged 69 to 89,
Kalmijn and coworkers10 suggested that cerebrovascular
disease and the APOE 4 allele might have a synergistic effect on
cognitive decline. We found that there was no significant
multiplicative effect between stroke and the APOE 4 allele on
the incidence of dementia. Similar results were found in different
subpopulations after the missing values of the APOE genotype in
the sensitivity analysis were taken into account. However, we
found that stroke and the APOE 4 allele might have an additive
effect on dementia. Subjects with both stroke and APOE 4 had a
greater risk of dementia than did subjects with either of these 2
factors.
Possible Interpretations
We may speculate on the possible mechanism underlying the finding
that relatively fresh stroke increases the risk of dementia. In our
study, as well as other community-based studies,56 the
majority of strokes were ischemic. Similar results were
obtained when hemorrhagic strokes were excluded from the
analyses. We will therefore focus the discussion on
ischemic stroke.
Atherothromboembolism complicated by thrombosis or embolism is one of the most common causes of ischemic stroke. The pathophysiological process of atherothromboembolism may begin many years before the manifestation of a clinical stroke. The decline of the intellectual level of patients with overt or silent stroke varies, and only those patients with sufficient deterioration of cognitive function will meet the diagnostic criteria of dementia. Because of the adaptations of the neural network, most patients who survive an acute stroke have at least some lessening of their neurological impairments afterward. Moreover, cognitive functions show great adaptability.57 This may explain the phenomenon that an old stroke with already cooled pathophysiological processes or some degree of regression did not increase the risk of dementia. Arteries have the capacity to adapt and to recover from previous lesions in experimental models of atherosclerosis regression.58
Another finding in the present study is that APOE 4 increases
the risk of dementia without stroke and APOE 4 does not increase the
risk of stroke. There is evidence of individuals carrying the APOE 4
allele with a significantly higher level of senile plaques and
neurofibrillary tangles in the brain.59 This indicates
that the APOE 4 allele may increase the risk of degenerative
dementia by acting on the amyloid cascade. However, neuropathological
studies have not found any association of APOE genotype with
vascular lesions in the brain.54 The influence of the APOE
4 allele on cholesterol level decreases with
age.60 It would be expected that there is a weak
relationship between the APOE 4 allele and stroke, and therefore
vascular dementia, in the very old. We suggest that stroke and the APOE
4 allele increase the risk of dementia through different
pathogenic mechanisms. This view is supported by the finding that both
factors had an additive rather than a synergistic effect on the
development of dementia.
In summary, a relatively fresh stroke increases the risk of dementia.
The APOE 4 allele is a risk factor for dementia without stroke.
There might be an additive effect of stroke and the APOE 4
allele on dementia, although no evidence supporting a
multiplicative effect was found. We suggest that, in the very old,
stroke and the APOE genotype increase the risk for dementia
through different pathogenic mechanisms.
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Acknowledgments |
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This study was supported by the Swedish Medical Research Council, the Swedish Council for Social Research, the Swedish Municipal Pension Institute, the Torsten & Ragnar Söderbergs Foundation, the Gamla Tjänarinnor Foundation, the Groschinsky Foundation, the SHMF Foundation, and the Gun and Bertil Stohne Foundation. We thank Lena Lilius, Benita Engvall, and Inga Volkmann for their valuable technical assistance. We also thank all our colleagues of the Kungsholmen Project for data collection and management and Dr Margaret Maytan for revision of the manuscript.
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Footnotes |
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Reprint requests to Li Zhu, MD, Stockholm Gerontology Research Center, Olivecronas Väg 4, Box 6401, S-113 82 Stockholm, Sweden.
Received September 8, 1999; revision received October 11, 1999; accepted October 25, 1999.
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