(Stroke. 1996;27:216-218.)
© 1996 American Heart Association, Inc.
Articles |
Influence of Apolipoprotein E Genotype on Cerebral Amyloid Angiopathy in the Elderly
From the Departments of Internal Medicine (Y.I., E.O.) and Pathology (N.S.), Yokufukai Geriatric Hospital; the Department of Neurology, Tokyo Medical and Dental University (M.Y.); and the Department of Psychiatry, Faculty of Medicine, University of Tokyo (M.M.), Tokyo, Japan.
Correspondence to Yoshinori Itoh MD, Department of Internal Medicine, Yokufukai Geriatric Hospital, 1-12-1 Takaido-nishi, Suginami-ku, Tokyo 168, Japan.
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Abstract |
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 Top Abstract IntroductionSubjects and Methods Results Discussion References |
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Background and Purpose The inheritance of the
4
allele of the apolipoprotein E gene (APOE) is associated with
increased risk of developing dementia of the Alzheimer type
(DAT). We have investigated whether the APOE genotype
influences the severity of cerebral amyloid angiopathy (CAA) in elderly
individuals with or without DAT. Methods From a consecutive autopsy series, we studied 88 patients (85.2±8.1 years) without degenerative disorders other than DAT. The percentages of amyloid-laden vessels in the occipital lobes were calculated and compared between APOE genotypes.
Results For 3/3 and 3/4 genotypes, there was
a trend toward increased CAA in 3/4 individuals for non-DAT and
conversely in 3/3 individuals for DAT patients, but these did not
achieve significance.
Conclusions The present study suggests that the 4
allele is not a strong risk factor for CAA in elderly people.
Key Words: aging • Alzheimer's disease • amyloid • apolipoproteins
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Introduction |
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TopAbstractIntroductionSubjects and Methods Results Discussion References |
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In DAT patients and nondemented elderly individuals, CAA is a common pathological condition and an important etiologic factor of nonhypertensive intracerebral hemorrhages.1 2 3 4 Our previous study of Japanese elderly individuals indicated that CAA occurred in 57% of consecutive autopsied cases and 88% of DAT patients.2 The vascular amyloid in elderly and DAT brains is preferentially deposited on the vessel walls of the meninges and superficial portions of the cerebral cortex,2 and the major component of the amyloid is ß/A4 peptide.5
Recently, it has been reported that the inheritance of the APOE 4
allele is associated with increased risk of developing
DAT.6 7 Cerebrovascular amyloid, as well as senile
plaques
and neurofibrillary tangles, is positive for apoE
immunohistochemically.8 In the present study, we
investigated whether APOE genotype influences the severity of
CAA in elderly individuals with or without DAT.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and Methods Results Discussion References |
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From the consecutive autopsy series at Yokufukai Geriatric Hospital, we studied 88 patients (62 to 103 years; mean±SD, 85.2±8.1 years), all Japanese, without degenerative disorders other than DAT. Formalin-fixed, paraffin-embedded sections taken from representative areas of all the brains were stained with hematoxylin-eosin/luxol fast blue, Masson's trichrome, methenamine-Bodian,9 and Congo red for the routine neuropathological examination. For 15 cases with marked CAA, the sections were immunostained with the antibody to ß/A410 by the avidin-biotin-peroxidase complex method11 using Vectastain kits (Vector Labs).
The severity of CAA was assessed using the Congo red–stained preparations of the occipital lobes (about 4x4 cm in size), where CAA is most frequent and marked.2 One hundred vessels of the meninges and superficial portions of the cortex were randomly chosen, and the number of amyloid-laden vessels was counted in all patients. The amyloid deposits were identified by showing congophilia with green birefringence under polarized light. The quantification was performed without information on the result of genotypic analysis. The counts of affected vessels were compared among APOE genotypes in DAT, non-DAT, and total cases, respectively. Since the counts did not follow a normal distribution, the Mann-Whitney U (nonparametric) test was used for the comparison. Statistical significance was defined as P<.05. All DAT patients satisfied the criteria of the Consortium to Establish a Registry for Alzheimer's Disease (CERAD).12
The APOE genotypes were analyzed with a restriction fragment length polymorphism.13 Briefly, genomic DNA was isolated from the frozen brain tissue of all patients, and the APOE sequence (244 bp) containing two polymorphic sites (codons 112 and 158) was amplified by polymerase chain reaction. Then the products were digested with Hha I and electrophoresed on 8% polyacrylamide gels.
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Results |
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TopAbstractIntroductionSubjects and Methods Results Discussion References |
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Among the 88 patients examined,
2/3, 3/3, and 3/4
genotypes were found in 4, 64, and 20 individuals,
respectively. There was no patient with the 4/4 genotype.
Twenty individuals had the diagnosis of DAT. The frequency of the 4
allele was 20% for DAT and 8.8% for non-DAT patients
(P=.0502). The age at death did not differ significantly
between DAT (83.8±8.3 years) and non-DAT (85.6±8.0 years)
patients or
between 3/3 and 3/4 genotypes (Table 1
).
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The cerebrovascular amyloid was positive for ß/A4 in all the cases
examined immunohistochemically. The count of amyloid-laden vessels
is summarized in Table 2. There was a significant
increase of vascular amyloid deposition in DAT compared with non-DAT
patients (P<.0001). For DAT patients, CAA was observed in
11 of 12 individuals with the 3/3 genotype and 7 of 8
individuals with the 3/4 genotype. However, no significant
difference in the count of affected vessels was found between 3/3
and 3/4 genotypes in either DAT, non-DAT, or total cases.
This was the same even when the oldest 3/3 individuals were excluded
to equalize the mean age with 3/4 individuals. Eight subjects with
the 3/3 genotype had more than 50 (maximum 95)
amyloid-laden vessels; on the other hand, no vascular amyloid
deposition was observed in 8 subjects with the 3/4 genotype.
The statistical analysis was not performed for the 2/3
genotype because of the small number of samples.
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Discussion |
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TopAbstractIntroductionSubjects and Methods Results Discussion References |
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We could not find a significant difference in the severity of CAA between
3/3 and 3/4 genotypes. There was a trend toward
increased CAA in 3/4 individuals for non-DAT and conversely in
3/3 individuals for DAT patients, but these did not achieve
significance. It has been reported that patients with one or two 4
alleles have increased vascular and plaque amyloid deposits
compared with those without 4.14 15 In these
studies,
the individuals without the 4 allele typically showed slight or
no CAA, whereas we found a considerable number of 3/3 individuals
with severe CAA.
No patient had the 4/4 genotype in our series, probably due
to the rather low frequency of the 4 allele in the Japanese
population.16 17 In addition, 4 allele frequency
decreases with advancing age, both in DAT and cognitively normal
individuals.18 For most elderly persons in Japan, the
severity of CAA is unlikely to be influenced by the presence or absence
of one 4 allele. This is consistent with the observation
that the incidence of CAA in Japanese elderly persons is not
low2 despite the infrequency of the 4 allele.
Recent data have suggested that the association of DAT with the 4
allele is age dependent and that the 4 allele is not a risk
factor for DAT among the oldest elderly individuals.19 The
incidence of CAA increases with age,2 in contrast to 4
allele frequency. It would be useful to investigate whether
difference in age influences the association of CAA with the 4
allele.
In DAT patients, CAA was much more severe than in non-DAT individuals.
Almost all DAT patients with the 3/3 genotype showed CAA, as
did those with the 3/4 genotype. Therefore, CAA seems more
closely associated with DAT than any particular APOE
genotype.
Finally, the present study suggests that the 4 allele is not
a strong risk factor for CAA in elderly persons. Our results need to be
verified in larger autopsy series with wider age ranges, including
younger patients in whom the 4 allele is more clearly a risk
factor for DAT.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This work was supported in part by health science research grants (Molecular Biological Study for Mechanism of Abnormal Deposition in Dementia Brain) from the Ministry of Health and Welfare of Japan. We are grateful to Dr H. Mori for the kind gift of anti-ß/A4 antibody and to I. Isahai, M. Takeda, H. Konuma, and Y. Miura for expert technical assistance. The APOE genotype was analyzed with the cooperation of U. Ogasa and R. Kawaguchi (Special Reference Laboratory, Tokyo, Japan).
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References |
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TopAbstractIntroductionSubjects and Methods Results Discussion References |
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