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(Stroke. 2000;31:1263.)
© 2000 American Heart Association, Inc.
Original Contributions |
Effect of the Apolipoprotein E 
4 Allele on White Matter Hyperintensities in Dementia
From the Divisions of Clinical Neurosciences (N.H., S.T., E.M.), Basic Neurosciences (M.Y.), and Neuroimaging Research (H.K.), Hyogo Institute for Aging Brain and Cognitive Disorders, Himeji, Japan.
Correspondence to Dr Nobutsugu Hirono, Division of Clinical Neuroscience, Hyogo Institute for Aging Brain and Cognitive Disorders, 520 Saisho-ko, Himeji, 670-0981, Japan. E-mail hirono{at}hiabcd.go.jp
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Abstract |
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 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
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Background and Purpose—The clinical significance of the apoE
4 allele in white matter
changes in patients with dementia has been a subject of debate. We
studied the association between the apoE 4 allele and white
matter hyperintensities (WMHs) before and after control for (1)
potential vascular risk factors and (2) the presence of lacunar
infarcts in patients with dementia.
Methods—The subjects were 131 patients with dementia who had
either Alzheimer’s disease or vascular dementia, or a
combination of these 2 types of dementia, with or without WMHs, lacunar
infarcts, or both. The association of the 4 allele with WMHs was
examined before and after control for age, sex, duration of symptoms,
education level, severity of dementia, presence of lacunar infarcts,
and potential vascular risk factors, including hypertension, diabetes
mellitus, lipid disorders, smoking habit, drinking habit, and cardiac
diseases.
Results—WMHs were observed in 73 (55.7%) of the patients.
Neither the number of apoE 4 alleles nor their presence was
significantly associated with WMHs before or after control for the
potential confounding factors. Multiple logistic regression
analyses revealed that age, the presence of hypertension, and
the presence of lacunar infarcts were independently associated with
WMHs.
Conclusions—The apoE 4 allele was not associated with WMHs
in patients with dementia. The fact that WMHs were significantly
associated with hypertension and lacunar infarcts may indicate an
ischemic origin of WMHs.
Key Words: apolipoproteins • dementia • hypertension • lacunar infarction • white matter
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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White matter (WM) changes are common in vascular dementia (VaD), especially of small vessel/subcortical subtypes, including Binswanger’s disease and lacunar infarction, and are generally considered to be a consequence of chronic ischemia associated with microangiopathy.1 2 However, WM changes, which are characterized by attenuation on CT and by white matter hyperintensities (WMHs) on T2-weighted MRIs, have also been reported to be common in patients with Alzheimer’s disease (AD).3 4 5 6 7 8 9 Therefore, even though the impact of WM changes in dementia formation is ambiguous and highly controversial, WM changes cannot be considered to be an exclusive feature of VaD.
The apoE 4 allele, which is a genetic risk factor for AD, has
been reported to also be a risk factor for
atherosclerosis10 11 and coronary
heart disease.12 13 14 Moreover, evidence is accumulating
that the presence of the apoE 4 allele increases the risk of
cerebral amyloid angiopathy.15 16 17 These facts suggest an
association between the apoE 4 allele and cerebral
ischemic insults. A possible association between the apoE 4
allele and ischemic stroke with or without AD has been
reported in some studies,18 19 20 21 although this association
has not been supported in other studies.14 22 23 24 25 The
association between the apoE 4 allele and WM changes is still
controversial, with 1 report supporting an association of the apoE 4
allele with WM changes in demented subjects26 and
others refuting such an association in both demented and nondemented
subjects.22 27 28 29 In these studies, however, a possible
interaction of the vascular risk factors was not
simultaneously taken into consideration, or on the
contrary, a selection bias might have yielded a deviant result due to
the exclusion of those with vascular risk factors, thereby excluding
severe WM changes and ignoring the effects of ischemia. In the
present study, we examined the effect of the apoE 4 allele
on WMHs in patients with dementia with control of the effects of
vascular risk factors.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The present study was conducted at Hyogo Institute for Aging Brain and Cognitive Disorders (HI-ABCD), a research-oriented hospital for dementia. All procedures of this study strictly followed the 1993 Clinical Study Guidelines of the Ethics Committee of HI-ABCD and were approved by the Internal Review Board. After a complete description of all procedures of this study, written informed consent was obtained from patients or their relatives.
Patients
Based on the following inclusion/exclusion criteria, 131
patients were recruited from a consecutive series of 452 patients with
dementia who underwent a short-term admission for examination at the
HI-ABCD infirmary between April 1997 and June 1999. All patients were
examined by both neurologists and psychiatrists with the use of
standardized medical history inquiry, neurological examinations,
routine laboratory tests, electroencephalography, MRIs of the brain,
and MR angiography of the head and neck. All patients also were tested
with the Wechsler Adult Intelligence Scale-Revised,30 the
Wechsler Memory Scale-Revised,31 the Mini-Mental State
Examination (MMSE),32 the cognitive portion of the
Alzheimer’s Disease Assessment Scale,33 the
Neuropsychiatric Inventory,34 and the Clinical Dementia
Rating Scale35 ; the results were incorporated into the
diagnosis of dementia. The inclusion criteria were obtained from (1)
the Diagnostic and Statistical Manual of Mental
Disorders, Third Edition, Revised (DSM-III-R) for
dementia36 and National Institute of Neurological and
Communicable Disorders and Stroke/Alzheimer’s Disease and
Related Disorders Association (NINCDS/ADRDA) criteria for probable
AD37 when WM changes or lacunar infarcts demonstrated by
MRIs were disregarded. Other specific dementing illnesses, such as
frontotemporal lobar degeneration,38 dementia with Lewy
bodies,39 progressive supranuclear palsy, and normal
pressure hydrocephalus,40 were carefully considered and
differentiated on the basis of diagnostic criteria for
each disease.
Although 312 patients fulfilled the inclusion criteria in the
present study period, 181 of these patients were excluded on the
basis of the exclusion criteria: (1) the presence of a medical illness
that might cause cognitive impairment or WH lesions, including
demyelinating diseases, thyroid diseases, vitamin deficiencies, and
malignant diseases with or without antineoplastic agents (n=32), (2)
the presence of focal brain lesions, including large infarcts and
hematomas (n=83) (the presence of lacunar infarcts was not an excluding
condition regardless of a history of stroke), (3) the presence of a
complication of developmental abnormalities, mental diseases, substance
abuse, or significant neurological antecedents such as brain traumas,
brain tumors, epilepsies, and inflammatory diseases (n=25), (4) the
presence of evidence of severe intracranial or cervical
arterial occlusive lesions on MR angiography (n=2), (5) the
presence of the apoE 2 allele (which occurs at a low frequency
in the population, especially among patients with dementia) (n=4), and
(6) informed consent was not obtained (n=35).
Thus, 131 patients met the criteria for participation in the present study. The subjects consisted of 101 women and 30 men; the mean (SD) age at examination was 73.5 (8.4) years, and the mean educational attainment was 9.1 (2.5) years. The mean duration of symptoms, determined through an interview with the primary caregiver and defined as the time between the first appearance of symptoms of sufficient severity to interfere with social or occupational functioning and the admission,41 was 34.1 (23.0) months. The mean value on the MMSE was 18.4 (4.9).
Assessment of Vascular Risk Factors
Hypertension, diabetes mellitus, lipid disorders, smoking habit,
drinking habit, and cardiac diseases were evaluated as vascular risk
factors. Hypertension was judged as present when either
systolic pressure of >160 mm Hg or diastolic
pressure of >95 mm Hg was demonstrated on repeated examinations
or when a history of treatment for hypertension was present.
Diagnosis of diabetes mellitus was made when the fasting blood glucose
level was >7.770 mmol/L (140 mg/dL) or there was a history of
treatment for diabetes mellitus. Lipid disorder was judged as
present when laboratory examination of the serum at
presentation showed a total cholesterol level
of >5.698 mmol/L (220 mg/dL), a triglyceride level of
>1.695 mmol/L (150 mg/dL), or an HDL cholesterol
level of <1.036 mmol/L (40 mg/dL) or when a history of treatment
was present. Smoking habit was defined as 
1 cigarettes per day
for 1 years, and drinking habit was defined as 30 mL ethanol
equivalent per day for 1 years sometime in life. Cardiac diseases
were defined as a known history or clinical demonstration of any heart
disease, including myocardial infarction, angina pectoris, and
arrhythmia.
Reassignment of Subjects Into VaD
The differential diagnosis between AD and VaD reportedly depends
substantially on which criteria for VaD are adopted.42
Based on 2 diagnostic criteria systems for VaD (the
National Institute of Neurological Disorders and Stroke/Association
Internationale pour la Recherche et l’Enseignement en Neurosciences
[NINDS/AIREN]) International Workshop43 and the State of
California Alzheimer’s Disease Diagnostic and
Treatment Centers [ADDTC]44 ), we reassigned the
subjects.
MRI Acquisition
MRI was performed with a 1.5-T superconducting magnet (Signa
Advantage; General Electric Medical Systems). Axial double-echo fast
spin echo T2-weighted images (3000/105/2 [repetition time/effective
echo time/excitations]), spin-echo T1-weighted images (550/15/2), and
fast fluid attenuated inversion recovery (FLAIR) images
(9002/147/2200/1 [repetition time/effective echo time/inversion
time/excitations]) were obtained for 14 locations parallel to the
anteroposterior commissure plane with a section thickness of 5 mm
and an intersection gap of 2.5 mm covering the area from the base
of the cerebellum to the vertex. In all acquisitions, the field of view
was 200x200 mm and the matrix size was 256x256. WMHs were
defined as irregular periventricular, early confluent deep,
and confluent deep on T2-weighted and FLAIR images according to Fazekas
et al.45 46 Periventricular changes in the
forms of caps or smooth halos were not included because these changes
were reported to be of nonischemic origin.46 47
The test-retest reliability among 3 neuroradiologists for this
classification was examined with randomly selected 30 patients, and a
high 
coefficient was obtained (=0.82). Lacunar infarcts were
specified as lesions with diameters of 
15 mm with (1)
hyperintensity on T2-weighted images, (2) distinct hypointensity on
T1-weighted images, and (3) hyperintensity with central hypointensity
on FLAIR images. With the use of these criteria, lacunar infarcts can
be distinguished from the état criblé or punctuate
hyperintensity form of WMHs.48 MRIs were examined by 1
neuroradiologist without knowledge of the patients’ clinical data,
including apoE status.
Determination of apoE Genotype
The detailed method for apoE genotyping is described
elsewhere.49 In brief, genomic DNA was extracted from
whole blood samples through the phenol chloroform method and was
amplified with the polymerase chain reaction as described by Wenham et
al.50 The polymerase chain reaction products were
digested with 10 U HhaI for 5 hours at 37°C. The DNA
fragments were electrophoresed for 5 hours at 60 mA through a 15%
nondenaturing polyacrylamide gel. The gel was stained with
ethidium bromide and photographed under ultraviolet light. The
genotypes were determined on the basis of the size of the DNA
fragments.
Statistical Analysis
We used the 
2 test for nominal
variables and the 2-tailed t test or 1-way ANOVA for
continuous variables for unadjusted comparisons. Because a dose
effect of the apoE 4 alleles has been
shown,51 52 53 the effect of the number of apoE 4
alleles on WMHs was analyzed with multiple logistic
analysis. Each analysis was repeated with and without
control for the effects of potentially confounding variables by
incorporating age, sex, duration of symptoms, education level, MMSE as
a measure of the severity of dementia, the aforementioned vascular risk
factors, and the presence of lacunar infarcts into the model. The
presence/absence–based analysis of the 4 allele was
also tested as a secondary analysis. For all analyses,
the statistical 
level was set at 0.05.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The apoE genotyping was
3/3 in 62 patients, 3/4 in 59
patients, and 4/4 in 10 patients. Seventy-three (55.7%) of the
patients were positive for WMHs. Although there were 5 patients with a
history of stroke supposedly caused by lacunar infarcts, none of the
patients had an obvious relationship between stroke and dementia.
Therefore, on the basis of the NINDS/AIREN criteria for
VaD,43 none of the patients were classified as having
probable VaD. Thirteen-seven patients who had both dementia and focal
neurological signs, such as pseudobulbar palsy, extensor planter
response, and extrapyramidal signs, or who had both
dementia and a history of stroke without a relationship between each
other, were classified as having possible VaD. On the basis of the
ADDTC,44 11 of the patients who had both dementia and 2
lacunar infarcts were classified as having probable VaD, and 26
patients who had both dementia and a single lacunar infarct or had both
dementia and Binswanger’s syndrome defined as the presence of
early-onset urinary incontinence or gait disturbance, vascular
risk factors, and WMHs, were classified as having possible VaD. Only 13
patients were classified as having probable or possible VaD on the
basis of both criteria. Table 1
summarizes background characteristics, vascular risk factors, apoE
genotypes, lacunar infarcts, and WMHs for each subgroup. The
frequencies of apoE genotypes were comparable among the
subgroups reassigned according to either criterion. The patients who
fulfilled the ADDTC criteria for VaD more frequently had lacunar
infarcts, WMHs, hypertension, lipid disorder, and drinking habit and
were significantly older than those who did not fulfill the criteria.
Regarding the NINDS/AIREN criteria, a significant difference was noted
only for hypertension; those who fulfilled the VaD criteria more
frequently had hypertension than did those excluded on the basis of
this criterion.
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The frequencies of apoE genotypes, lacunar infarcts, background
characteristics, and vascular risk factors are summarized in Table 2 according to the presence or absence of
WMHs. The distribution of apoE genotypes was comparable between
the WMH-positive and WMH-negative groups (Table 2). The
frequency of the apoE 4 allele was 30.2% in the WMH-positive
group and 30.1% in the WMH-negative group. Sixteen WMH-positive
patients but only 3 WMH-negative patients had coexisting lacunar
infarcts. Moreover, WMH-positive patients were significantly more
hypertensive and older and were of lower education level than
WMH-negative patients. The number of apoE 4 alleles was not a
significant predictor for WMHs before (OR 1.00, 95% CI 0.58 to 1.73
for 1 increase in 4 allele) and after control for the
demographic factors, dementia severity, vascular risk factors, and the
presence of lacunar infarcts in a multiple logistic regression
analysis (OR 1.06, 95% CI 0.53 to 2.14 for 1 increase in 4
allele). The logistic regression analysis also demonstrated
that advanced age (OR 3.03, 95% CI 1.63 to 5.62 for 10-year increase),
hypertension (OR 3.83, 95% CI 1.35 to 10.90 for presence to absence),
and lacunar infarcts (OR 4.91, 95% CI 1.07 to 22.62 for presence to
absence), but not education level (OR 1.03, 95% CI 0.84 to 1.27 for
1-year increase), were independent significant predictors for WMHs. A
secondary multiple logistic regression analysis of apoE 4
allele presence/absence basis also revealed that the effect of apoE
4 allele on WMHs was not significant (OR 0.87, 95% CI 0.36 to
2.08 for the presence relative to the absence) and that the effects of
age (OR 3.07, 95% CI 1.64 to 5.71 for 10-year increase), hypertension
(OR 3.76, 95% CI 1.33 to 10.60 for presence to absence), and lacunar
infarcts (OR 4.82, 95% CI 1.05 to 22.18 for presence to absence) were
independently significant.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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In the present study, by using multivariate statistics, we investigated the possibility of an interaction of the potential vascular risk factors for WMHs in a large number of patients with dementia. Our results clearly demonstrated that the apoE
4
allele was not associated with WMHs and strongly support the view
that the apoE 4 allele has no effect on WM
changes.22 27 28 29 It is noteworthy that the apoE 4
allele frequency in the WMH-positive patients (30.1%) was as high
as it was in the WMH-negative patients (30.0%), who completely
fulfilled the criteria for probable AD. These figures were also quite
similar to those reported in patients with AD and higher than those
reported in the general population.54 The fact that the
apoE 4 allele frequency in the WMH-positive patients
corresponded to that of AD patients might indicate that the majority of
these patients had AD pathology regardless of the presence of WMHs,
because all of these patients actually fulfilled the NINCDS/ADRDA
criteria for probable AD when the changes in WM and lacunar infarcts
were disregarded.
Our finding that WMHs were significantly associated with hypertension
is compatible with previous reports8 55 56 and supports
the concept of an underlying hypertensive microangiopathy and chronic
cerebral ischemia.57 Lacunar infarcts in the basal
ganglia, thalamus, and WM were usually accompanied with WM changes in
Binswanger’s disease. Therefore, several authors have proposed the
term "microangiopathy-related cerebral damage" (MARCD), which
includes both WM changes and lacunar infarcts.58 59 Our
result that WMHs were significantly associated with lacunar infarcts is
consistent with this hypothesis. Schmidt et al59
examined 280 individuals without neuropsychiatric diseases through the
use of a multiple logistic regression analysis and demonstrated
that age and hypertension, but not the apoE 4 allele, were
independent significant predictors for MARCD (ie, for early confluent
or confluent WMHs or lacunar infarcts). Their result is
consistent with ours and may indicate that age and
hypertension, but not the apoE 4 allele, are independent risk
factors for MARCD in both patients with and patients without dementia.
Their study also demonstrated a significant effect of the apoE
2/3 allele. However, because the prevalence of the apoE
2/3 allele is very rare in the population with
dementia,60 61 it is quite difficult to examine the effect
of this allele in patients with dementia.
In conclusion, in patients with dementia, the apoE 4 allele was
not associated with WMHs, whereas advanced age, the presence of
hypertension, and the presence of lacunar infarcts were independently
associated with WMHs. The frequency of the apoE 4 allele in the
WMH-positive patients was quite similar to that in the WMH-negative
patients. These findings suggest that WMHs were of ischemic
origin and that WMHs were superimposed on the AD pathology in the
majority of our patients. The effect of the apoE 2 allele should
be assessed in patients with dementia. However, the very low prevalence
of this allele in the dementia population makes such studies
difficult.
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Acknowledgments |
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We thank Hiroaki Kazui, MD; Mamoru Hashimoto, MD; Tokiji Hanihara, MD; Toru Imamura, MD (Division of Clinical Neurosciences); Mieko Matsui, MD; Setsu Sakamoto, MD; and Kazunari Ishii, MD (Division of Neuroimaging Research); for their help in various portions of the study.
Received January 10, 2000; revision received February 18, 2000; accepted February 29, 2000.
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