(Stroke. 1997;28:2219-2221.)
© 1997 American Heart Association, Inc.
Articles |
Association of Presenilin-1 Polymorphism With Cerebral Amyloid Angiopathy in the Elderly
From the Department of Neurology, Tokyo Medical and Dental University (M.Y., N. Sodeyama, H.M.); Departments of Internal Medicine (Y.I., E.O.) and Pathology (N. Suematsu), Yokufukai Geriatric Hospital; and Department of Psychiatry, University of Tokyo (M.M.), Tokyo, Japan.
Correspondence to Dr Masahito Yamada, Department of Neurology, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo 113, Japan. E-mail m-yamada.nuro{at}med.tmd.ac.jp
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Abstract |
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 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
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Background and Purpose An intronic polymorphism of presenilin-1 (PS-1), a gene responsible for early-onset familial Alzheimer's disease, has been reported to be associated with late-onset sporadic Alzheimer's disease. In a search for a genetic risk factor of sporadic cerebral amyloid angiopathy (CAA), we investigated the association of the polymorphism of PS-1 with CAA.
Methods The association between the severity of CAA and genotypes of a polymorphism in intron 8 of PS-1 was investigated in 137 autopsy cases of the elderly.
Results A significant decrease of PS-1 2/2 genotype frequency was associated with severe or moderate CAA.
Conclusions Our results suggest that PS-1 intronic polymorphism may be associated with the severity of CAA in the elderly.
Key Words: Alzheimer's disease • amyloid • elderly • polymorphism (genetics)
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Cerebral amyloid angiopathy is commonly found in elderly individuals and patients with AD and is an important etiologic factor in intracerebral hemorrhage and other cerebrovascular disorders.1 2 3 In some hereditary cases, CAA is caused by mutations in amyloid protein precursor genes, ie, the amyloid ß-protein (Aß) precursor and cystatin C genes; however, most cases of CAA are sporadic. Recently, the
4 allele of the
APOE gene, a genetic risk factor for AD, has been suggested to
influence development of CAA,4 5 although this has not
been observed in some populations.6 7 8 Missense mutations in the PS-1 gene cause the most common form of early-onset familial AD.9 The PS-1 mutations are linked with increased extracellular and brain concentrations of Aß ending at residue 42 (Aß42), which would lead to severe Aß deposition in the brain.10 11 12 In the PS-1 mutation–related familial AD, prominent CAA showing increased deposition of Aß42 is found with severe cerebellar pathology.11 Wragg et al13 described the genetic association between a polymorphism in intron 8 of PS-1 and late-onset sporadic AD.13 This relationship has been a matter of controversy.14 15 16 17 18 19 20
In the present study we investigated whether PS-1 intronic polymorphism is associated with the severity of CAA in elderly individuals.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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We studied 137 patients (age range, 62 to 103 years; mean±SD age, 85.0±7.9 years), all Japanese, from the autopsy series at Yokufukai Geriatric Hospital, Tokyo. The 137 patients consisted of two groups: the AD group (n=36), in which the neuropathological findings satisfied the criteria of the Consortium to Establish a Registry for Alzheimer's Disease,21 and the non-AD group (n=101), in which patients had no AD or other neurodegenerative disorders. The age at death did not differ significantly between AD (84.5±7.7 years) and non-AD groups (85.1±8.0 years). No familial case of AD or CAA was included in this series.
For the neuropathological examinations, formalin-fixed, paraffin-embedded sections taken from representative areas of all the brains were stained with hematoxylin-eosin/Luxol fast blue, Masson trichrome, methenamine-Bodian, and Congo red. The congophilic deposits with green birefringence under polarized light were identified as amyloid. For 15 patients with severe CAA, the sections were immunostained with a mouse monoclonal antibody to Aß peptide (1-42)22 with the use of the avidin-biotin-peroxidase complex method.23
The severity of CAA was assessed as previously described.6
Briefly, the number of amyloid-bearing vessels was counted for 100
randomly chosen meningeal and cortical vessels of the occipital lobe
(
4x4 cm) in each case (CAA count=the percentage of the
amyloid-laden vessels). The occipital lobe was most commonly affected
with CAA in elderly individuals, as shown in our previous
study.2 The quantification was performed without knowledge
of the polymorphisms of the PS-1 or APOE.
The PS-1 intronic polymorphism was analyzed as described by Wragg et al.13 Briefly, genomic DNA was isolated from the frozen brain tissue of all patients, and the sequence containing a polymorphic site in intron 8 of the PS-1 gene was amplified by polymerase chain reaction with a mismatched primer. This primer produces a BamHI cut site for allele 2 but not for allele 1 at the polymorphic site. Then the products were digested with BamHI and electrophoresed on a 3% agarose gel.
APOE genotype was also analyzed to examine the
association of the PS-1 polymorphism with CAA in subgroups divided
by APOE status (with/without 4 allele) when APOE 4 affects
risk for CAA. APOE genotyping was performed as described by Hixson and
Vernier.24 The results for APOE genotype in the
smaller number of samples included in this study were reported
previously.6
For statistical analyses, the CAA counts (ie, the numbers of amyloid-bearing vessels per 100 vessels) were compared between the PS-1 genotypes in AD, non-AD, and total cases. Since the counts did not follow a normal distribution in any group, the Mann-Whitney U test or Kruskal-Wallis test was used for the comparison.
In our previous studies of elderly subjects,2 3
intracerebral hemorrhage, a major complication
of CAA, was found to be associated with moderate or severe CAA
(affected vessels 
40%) but not with CAA of lower degree. Therefore,
we decided in advance to compare frequencies of the PS-1
genotypes between patients with severe or moderate CAA
(affected vessels 40%) and those with slight or no CAA (affected
vessels <40%). The 
2 test or Fisher's exact
probability test was used for the comparison.
Statistical significance was defined as P<.05. The statistical analyses were performed with the use of the computer software StatView J-7.5 (Abacus Concepts).
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Among the 137 patients examined, the PS-1 1/1, 1/2, and 2/2 genotypes were found in 51 (0.37 in frequency), 65 (0.47), and 21 individuals (0.15), respectively. The age at death did not differ significantly between genotypes in AD, non-AD, or total cases (data not shown). PS-1 genotype or allele frequencies were not significantly different between AD (genotypes 1/1, 0.36; 1/2, 0.50; 2/2, 0.14) and non-AD patients (genotypes 1/1, 0.38; 1/2, 0.47; 2/2, 0.16). The distribution of PS-1 genotypes was similar to that reported in Japanese nondemented individuals.15 In addition, when the cases were divided by their APOE
4 status, there was also no significant difference in
PS-1 genotype or allele frequencies between AD and non-AD
cases (data not shown). As reported in many studies, the frequency of
the APOE 4 allele was significantly higher in AD (0.22) than in
non-AD cases (0.079) (P=.0021). No significant relationship
was found between PS-1 genotype and APOE 4 status (data not
shown).
The cerebrovascular amyloid was positive for Aß in all the cases
examined. The average values (mean±SE) of the CAA counts are shown in
Table 1
. Compared with the PS-1 1/1 or
1/2 genotype, the patients with the 2/2 genotype showed
lower average counts of CAA in AD and non-AD cases. However, the
differences were not significant. The count of amyloid-bearing vessels
was significantly increased in AD compared with non-AD patients
(P<.0001) (Table 1), consistent with previous
reports.1 2 There was no significant difference in the CAA
count between subjects with APOE 4 and those without (data not
shown), despite higher 4 frequency and CAA severity in AD
patients.
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The PS-1 genotype and allele frequencies in cases of severe
or moderate CAA were compared with those in cases of slight or no CAA
(Table 2). The 2/2 genotype was
not found in cases of severe or moderate CAA. The frequency of the 2/2
genotype in cases of severe or moderate CAA (0%) was
significantly lower than that in cases of slight or no CAA (18.9%)
(P=.013).
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Our results suggest that the PS-1 intronic polymorphism may be associated with the severity of CAA in the elderly. The PS-1 2/2 genotype may be associated with lower clinical risk of CAA.
It has been well known that aging and AD are strong risk factors for CAA.1 2 There was no significant difference in age between the PS-1 genotypes in this study. The PS-1 1/1 genotype has been reported to be associated with late-onset AD in some populations.13 14 15 18 However, in our study of autopsy-confirmed cases, no relationship was found between PS-1 polymorphism and AD. These findings indicate that the association of PS-1 polymorphism with CAA found in this study may not be attributable to the association between PS-1 and such risk factors for CAA.
The APOE 4 allele has been also reported as a risk factor for
CAA in some populations.4 5 In our study with the Japanese
elderly, however, the association between APOE 4 and severity of CAA
was not significant statistically, which was consistent with
our previous report with the smaller number of samples.6
Furthermore, there was no significant relation between the PS-1 and
APOE genotypes.
The strength of the association between the PS-1 2/2 genotype and lower risk of CAA that we found needs to be tested further because it is possible that our findings are due to chance or population stratification. When our observation is significant, two possible explanations for the mechanism underlying this association are as follows: (1) the polymorphism is in linkage disequilibrium with the actual risk-causing genetic variability elsewhere in the PS-1 gene or another adjacent gene, and (2) the intronic polymorphism is biologically relevant through the altered expression of the gene, through modulation of alternative splicing. Since allelic dose effects of PS-1 polymorphism on CAA were not evident, the direct biological role of the polymorphism in the pathogenesis of cerebrovascular Aß deposition, the latter explanation, seems unlikely. For Aß deposits in the brain parenchyma, Mann et al19 recently reported that PS-1 polymorphism did not influence the amount or molecular form of Aß deposited in AD patients.19 The association of this polymorphism with the expression of PS-1 and Aß precursor genes in the cerebral vessels should be further studied.
In conclusion, we suggest that PS-1 intronic polymorphism may be associated with the severity of CAA in the elderly. As suggested in the first report on the association of this polymorphism with AD,13 the association of this polymorphism may be different between different ethnic groups. Our results with elderly Japanese subjects warrant further study with samples from populations with different ethnic backgrounds.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This study was supported in part by a health science research grant (Mechanism of Abnormal Deposition in Dementia Brain) (to Dr Yamada) from the Ministry of Health and Welfare, Japan, and a grant-in-aid for scientific research (to Dr Yamada) from the Ministry of Education, Science, Sports, and Culture, Japan. The authors are grateful to Dr H. Mori for the kind gift of anti-Aß antibody and to I. Isahai, M. Takeda, H. Konuma, and Y. Miura for expert technical assistance.
Received May 22, 1997; revision received July 8, 1997; accepted August 7, 1997.
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References |
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