(Stroke. 1996;27:1310-1315.)
© 1996 American Heart Association, Inc.
Articles |
Apolipoprotein E Polymorphism and Stroke in a Population Sample Aged 75 Years or More
the Karolinska Institute, Department of Clinical Neuroscience and Family Medicine, Huddinge University Hospital, Huddinge (H.B., E.H.C., Z.G., L.L., B.W., M.V.); the Stockholm Gerontology Research Center, Stockholm (H.B., E.H.C., Z.G., M.V., B.W.), Sweden; and the Center for Demographic Studies, Duke University, Durham, NC (E.H.C., L.S.C., K.G.M.).
Correspondence to Hans Basun, MD, PhD, Karolinska Institute, Department of Clinical Neuroscience and Family Medicine, Division of Geriatric Medicine B56, Huddinge University Hospital, S-141 86 Huddinge, Sweden.
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Abstract |
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Background and Purpose We investigated apolipoprotein E polymorphism stroke risk in a population sample of 1810 persons aged 75 years or more in Stockholm (the Kungsholmen Project). Information on cognition at cohort inception (from 1987 to 1989) and on stroke occurrence (from 1969 to 1994) is available for the cohort. In the cohort, cognitive impairment is associated with the
4 allele, and longer survival in subjects aged 
85 years with good cognition is associated with the 2 allele and the absence of 4.
Methods We compared stroke incidence in the 1077 of 1124 genotyped subjects who carried 2/3, 3/3, or 3/4 and estimated the proportion of cognitive impairment attributable to stroke.
Results Risk of stroke did not vary with apolipoprotein E polymorphism (P=.82): 24% of 87 incident stroke patients during follow-up compared with 25% of 827 subjects with normal cognition and no stroke diagnosis at baseline carried the 3/4 genotype. An estimated 9% of cognitive impairment was attributable to stroke. Notably, a reduced 3/4 frequency of 20% was found in subjects who survived a prior stroke and were included in the cohort, and risk of hemorrhagic stroke tended to be associated with the presence of the 3/4 genotype and the absence of 2/3.
Conclusions This population-based study indicates that apolipoprotein E polymorphism is not a risk factor for ischemic stroke in subjects aged 75 years (although it might possibly influence survival after stroke occurrence and be a risk factor for infrequent hemorrhagic stroke) and that approximately 10% of cognitive impairment in this age group is attributable to stroke.
Key Words: aged • amyloid • apolipoproteins • cerebral hemorrhage • dementia
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Risk of atherosclerosis1 2 3 4 and coronary heart disease in middle age4 5 6 7 8 appears to be higher in the presence of the apoE
4 allele, possibly because of altered lipid metabolism. Not all studies, especially those of elderly subjects or survivors of heart attack, however, find an association between 4 and coronary heart disease.9 10 11 12 13 The studies finding an association of 4 and coronary heart disease suggest that the 4 allele may increase the risk for ischemic stroke, possibly by altering lipid metabolism.14 However, other studies,13 15 16 17 18 including a population-based prospective study in persons aged 64 to 74 years,13 dispute this claim.
Whether 4 is a common risk factor for both ischemic stroke and AD19 20 21 —and more generally, cognitive impairment22 —in very old adults aged 75 years who are at high risk for both disorders has not been investigated in a defined population. Evaluation of 4 as a risk factor for stroke is complicated at late ages by the overlap of AD and vascular dementia. Both positive23 and negative (ie, no increased prevalence of 4)24 associations have been reported for 4 and vascular dementia. Strittmatter et al19 used stroke patients as control subjects when measuring the association of apoE 4 with AD. They suggested that patients with AD pathology are misdiagnosed as having vascular dementia often enough, using current exclusionary criteria, to generate a spurious association of 4 with stroke.16
In contrast to the findings on ischemic stroke, evidence is accumulating that apoE 4 increases the risk for hemorrhagic stroke via CAA. This mechanism may be independent of the risk for AD conferred by 4. Greenberg and coworkers25 found that 4 tripled the risk for moderate/severe CAA (ie, 13-fold in 4/4 subjects). Furthermore, 4 had a higher than expected frequency in 13 hemorrhagic stroke patients compared with control subjects (40% versus 14%). The association of 4 with CAA remained after adjustment for plaque count (also associated with 4). This suggests that CAA and AD may share 4 as a common risk factor (rather than CAA being a prelude to AD). Alberts et al26 found a similar elevation of 4 frequency in 44 hemorrhagic stroke patients. Interestingly, in this series, hemorrhagic stroke was more often fatal in those subjects who carried 3/4 (11 of 16) versus 3/3 (5 of 18). Kalaria and Premkumar27 found that 4 was associated with more severe CAA and a higher risk of hemorrhagic stroke in 206 AD patients: 12 of 13 instances of hemorrhagic stroke were in subjects carrying 4. Those who carried 2 had little CAA and no instances of hemorrhagic stroke. This is consistent with AD and hemorrhagic stroke having 4 as a common risk factor. Finally, Jordan et al28 found an unusual prominence of Aß-associated pathology in a boxer who carried 4 and died of cerebral hemorrhage.
In this study, we compared the risks of stroke, ischemic and hemorrhagic, for the common apoE genotypes in a population sample of adults in Stockholm, Sweden, aged 75 years in 1987 through 1989 who were followed up for an average of 7 years. We also estimated the proportion of prevalent cognitive impairment found at baseline attributable to prior stroke occurrence in the cohort.
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Subjects and Methods |
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Sample
In 1987 through 1989, 1810 persons aged 75 years and over were evaluated as part of the Kungsholmen Project, of 2368 eligible subjects living in the Kungsholmen parish district of Stockholm.29 30 The study was organized to describe aging and dementia. Informed consent was obtained for each subject in accordance with protocols approved by the ethics committee at the Karolinska Institute.
Assessment
MMSE score at the initial assessment was used to divide subjects into cognitively impaired (MMSE <24) and "normal" (MMSE >23) groups. All cognitively impaired subjects and a sample of normal subjects received complete neurological examinations. Demented subjects were assigned diagnoses and clinically staged. Follow-up of the cohort continues for mortality by both monthly polling of Stockholm vital records and regular contact with subjects or their relatives.
Stroke Occurrence
Information on the occurrence of stroke was obtained for each subject from computerized hospital discharge records and death certificates for 1969 through 1994 for Stockholm. ICD-8 codes, as adapted for Sweden,31 denoting cerebrovascular disease are as follows: hemorrhagic events, 430 to 431 and 432 (1987 through 1994); infarcts, 432 (1969 through 1986) and 433 to 435; and less well-defined ischemic stroke, 436 to 438. The group with less well-defined cerebrovascular disease included subjects with clinical manifestations of stroke but without evident changes of infarcts or hemorrhages on acute-stage CT scan. Information on the occurrence of stroke in the sample population is available for 18 to 20 years before and 6 to 8 years after cohort inception. Registry records on stroke agreed 92% of the time with interview information obtained from the subject or a proxy (ie, 572 of 624 subjects). Six additional cases in which stroke was listed only as a cause of death were not included in the analysis.
Laboratory Methods
Genotyping for apoE was undertaken for 1124 Kungsholmen Project subjects. DNA was extracted from peripheral white blood cells by use of standard methods. ApoE genotype was determined using a microsequencing method on microtiter plates (AffiGen APOE Sangtec Medical). ApoE genotyping is performed with nonradioactive solid-phase minisequencing on microtiter plates. The principle of the reaction is to amplify a part of the apoE gene by polymerase chain reaction with one of the primers biotinylated. The amplified product is divided onto two streptavidin-coated microtiter plates, one for each variable nucleotide at positions 112 and 158. The nonbiotinylated strand is removed by a brief alkali treatment. In a minisequencing reaction, two detection primers are annealed to the immobilized single-strand target DNA, proximal to the variable nucleotides 112 and 158. Dinitrophenyl-modified dTTP or dCTP is incorporated where there is a complementary nucleotide in separate DNA polymerase extension reactions. The modified dinitrophenyl nucleotide is recognized by an antibody in the detection step. The reaction is measured colorimetrically at 405 nm. The ratio of label in respective reaction is measured, and the numerical values correspond to the different genotypes. For 25% of the subjects, blood was obtained in subsequent studies of the Kungsholmen Project in surviving subjects.
Statistical Analysis
Tests were two sided with significance set at the 
=.05 level. A 
2 test was used to compare genotypic frequencies in incident stroke and unaffected subjects, excluding those who were cognitively impaired and those with a diagnosis of stroke before the baseline evaluation. This simple comparison of allelic frequencies might be biased to the null by the shorter survival times of 3/4 subjects. This survival differential has previously been observed in the cohort.32 Hence, the overall comparison involving stroke incidence was supplemented by the construction of Kaplan-Meier plots for subjects with each genotype, censoring each subject at death or January 1, 1995 (not shown). Log-rank tests were used to compare the plots.33 Separate plots were made for subjects aged 75 to 84 years and those aged 85 at study inception to allow for possible age heterogeneity. To determine whether survival rate after the occurrence of stroke may be lower in subjects with the 3/4 genotype, the frequency of 3/4 was compared in subjects with and without stroke diagnosis before the baseline evaluation, using a 2 test. This comparison was also limited to subjects with good cognition at baseline to avoid admixture with AD patients.
With data from all 1810 subjects, the proportion of cognitive impairment attributable to stroke in the cohort was estimated as (PCogImp-PCogImp, no prior stroke)/PCogImp, where PCogImp is the prevalence of cognitive impairment in the cohort and PCogImp, no prior stroke is the prevalence of cognitive impairment in subjects without a prior occurrence of stroke.34
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Results |
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Stroke Incidence During Follow-up
We did not investigate the risk of stroke for subjects with the
2/2, 2/4, and 4/4 genotypes because of the small number of stroke diagnoses recorded for these subjects (eight diagnoses in seven subjects) from 1969 through 1995. Comparisons were limited to the three common genotypes: 2/3, 3/3, and 3/4. Considering these genotypes, there were 87 first occurrences of stroke during follow-up in the 914 subjects not cognitively impaired at baseline and who had apoE information. A similar proportion (10%) was found when those without apoE information were included (Table 1
, top).
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The stroke incidence did not vary significantly with apoE polymorphism: 8% of those with 2/3, 10% with 3/3, and 10% of those with 3/4 were diagnosed with stroke (2=0.39 with 2 df, P=.82). Expressed differently, genotypic frequencies were similar in subjects with and without incident stroke: 11% versus 14% for 2/3, 60% versus 57% for 3/3, and 24% versus 25% for 3/4.
The shorter survival of persons with the 3/4 genotype (found in a previous study of the same cohort), and consequent shorter interval of risk of stroke, could mask a real association between stroke and 3/4. This possibility is raised by survival differentials observed during follow-up in the cohort that were dependent on apoE genotype.32 In addition, the pattern of risk might depend on age, given the wide age range (from 75 to 98 years) in the sample. Thus, Kaplan-Meier plots were constructed that described the pattern of stroke incidence during follow-up for subjects with each genotype, separately for ages 75 to 84 and 85+ years, censoring subjects at age of death or the end of follow-up (not shown). Genotype-specific incidence distribution results were compared with those of log-rank tests. With this approach, there was no statistically significant evidence that the pattern of incidence varied with apoE genotype in subjects initially aged 75 to 84 years (2=0.45 with 2 df, P=.80) or for those aged 85+ (2=2.78 with 2 df, P=.25). However, there was a tendency toward variation (still statistically insignificant) in the incident proportions among the 127 subjects aged 85+: 10.7% for 2/3, 15.5% for 3/3, and 23.1% for 3/4. There was a total of 20 events after age 85 years. Hence, the power to detect variation in incidence related to polymorphism was limited in this age group.
ApoE Polymorphism in Subjects With Prior Stroke
The frequency of the 3/4 genotype was 20% in 50 subjects with prior stroke and 25% in 914 subjects not diagnosed with stroke at baseline, among those with "normal" cognition, raising the possibility of poorer survival in subjects with 4 compared with those with 2/3 or 3/3. This difference was not statistically significant (2=0.70 with 1 df, P=.40).
Risk of Hemorrhagic Stroke
Table 2 indicates the frequencies of hemorrhagic stroke, stroke involving infarcts (which predominated), and other less well-defined diagnostic entities (which were more common in cognitively impaired compared with normal subjects).
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The evidence suggested that the risk of hemorrhagic stroke might depend on apoE polymorphism, although the numbers involved were very small. Of reported occurrences, 25 of 26 were in subjects with normal cognition. ApoE information was available for 14 of the 26 subjects. All 14 subjects had an occurrence of hemorrhagic stroke during follow-up and normal cognition at baseline. The expected frequency distribution for the 14 subjects was 14% for 2/3, 59% for 3/3, and 27% for 3/4. There were no occurrences in subjects who carried 2/3 (2.0 expected), 8 events in those with 3/3 (8.3 expected), and 6 events in those with 3/4 (3.8 expected).
The observed and expected numbers of stroke occurrences, respectively, were very close for the other two categories—infarct (during follow-up in normal subjects): 11 (10.9 expected) for 2/3, 47 (46.0 expected) for 3/3, and 20 (21.1 expected) for 3/4; and less well-defined events (all events): 3 (5.2 expected) for 2/3, 23 (21.8 expected) for 3/3, and 11 (10.0 expected) for 3/4, although the slight deviations from expected values for the less well-defined events were in the same direction as for subjects with hemorrhagic stroke.
Stroke and Cognitive Impairment
Of cognitively impaired subjects, 17.1% (66 of 385) were diagnosed with stroke before baseline evaluation compared with 6.1% (87 of 1425) of those with normal cognition. Thus, prevalence of cognitive impairment in those with a prior stroke was nearly three times higher than in those not diagnosed with stroke before baseline.
Despite this threefold elevation in risk, an estimated 9% of cognitive impairment at baseline was attributable to stroke because cognitive impairment was common in this age group: 21.3% (385 of 1810) of all subjects were cognitively impaired compared with 19% (319 of 1657) of those without a prior stroke. Hence, the majority of cognitive impairment in the study sample was related to other factors. In those with apoE information, 8% of cognitive impairment was attributable to prior stroke. The attributable proportion of cognitive impairment due to stroke was 9% for 3/3 and 3/4 (although the prevalence of cognitive impairment was higher for 3/4 than 3/3) compared with 2% for 2/3. The total number of subjects with prior stroke and 2/3 was 8. Hence, the low estimate of attributable proportion for 2/3 might be due to chance.
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Discussion |
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The incidence of a first occurrence of stroke, primarily ischemic stroke, did not vary with apoE polymorphism (
2/3, 3/3, or 3/4) in this population sample of persons aged 75 years who were followed up for 7 years, consistent with the majority of previous reports in younger samples.13 15 16 17 18 19 This prospective comparison involved subjects who were not cognitively impaired at baseline and who did not have a previous diagnosis of stroke. The good agreement between computerized inpatient records and interview reports for stroke history suggests that most cerebrovascular events in study subjects were included in the analysis. Thus, underreporting of stroke in 4 subjects, for example, is not likely to explain the observed lack of association between 4 and stroke.
There was no difference in stroke incidence distributions that were constructed to avoid masking a real association of 3/4 with stroke due to reduced survival in 3/4 subjects. This was important because survival differentials have been observed in the cohort, depending on apoE polymorphism (longer with 2/3 and shorter with 3/4).32 The robustness of the finding of lack of association of 4 with stroke is supported by similar results using age at cognitive assessment and age when blood was obtained (not shown). However, the increase in the proportion of stroke occurring during follow-up from 11% for 2/3 to 23% for 3/4 raises the possibility that larger samples might allow detection of differences in the risk of stroke in the oldest elderly (85 years) depending on apoE polymorphism.
In contrast to the lack of association between apoE 4 and stroke found in the present study, previous reports have found that the risks of cognitive impairment, dementia, and AD have each been associated with 4 in the study population.32 35 36 The association of 4 and cognitive impairment appears to weaken with age: the odds ratio between 3/4 and 3/3 declined from 4.8 at ages 75 to 79 years to 1.7 at ages 80 to 84 and to 1.0 (ie, no association) at age 85+.32 After an average of 3 years of follow-up, the prevalence of dementia was higher for 3/4 (26%), and lower for 2/3 (8%), than for 3/3 (16%).35 AD patients more often carried 4 than non-AD subjects: 12 (60%) of 20 patients with familial AD and 10 (37%) of 27 with sporadic AD carried 4 compared with 20 (20%) of 101 control subjects in a subset clinically evaluated for AD shortly after baseline.36
The low estimated (9%) attributable proportion of cognitive impairment due to prior stroke indicates that other factors (eg, AD pathology, frequent diabetes, and low educational level) are often responsible for cognitive impairment in this age group. A larger proportion, 26%, of dementia was attributable to ischemic stroke survivors aged 60 years37 compared with the present sample. The attributable proportions of cognitive impairment due to stroke were similar for the three common genotypes, rather than higher for 3/4 and lower for 3/3 as would be expected if apoE polymorphism determined the risk of cognitive impairment via the risk of stroke.
This study adds evidence from a defined population to previous studies25 26 27 28 that unanimously suggest that the risk of hemorrhagic stroke, in contrast to the more frequent ischemic stroke, is higher with the occurrence of 4 and lower with the occurrence of 2. This is consistent with the pattern of cerebral amyloid deposition.27 38 In a clinic series, more frequent death in hemorrhagic stroke victims who carried 426 suggests that the association between 4 and hemorrhagic stroke may be stronger than observed in the cohort, since subjects with 4 may have been less likely to survive prior events to become part of the cohort or to donate blood as part of the study. On the assumption that amyloid angiopathy accumulates with age, risk related to 4 and protection related to 2 might increase rather than decrease with age in contrast to risk of cognitive impairment and, possibly, AD. These findings suggest that preventive interventions based on apoE metabolism, to be devised in the future, may delay the onset of AD and prevent hemorrhagic stroke but probably will not prevent ischemic stroke.
Given that stroke incidence did not vary with apoE polymorphism, the survival differentials observed in the cohort32 are not likely to derive from differentials in ischemic stroke risk. However, the lower 4 frequency in those with prior stroke and the higher frequency of stroke in those initially aged 85 years with 4 suggests that the observed survival differentials may partially result from variation in the risk of stroke via poor survival in stroke victims carrying the 4 allele. If differential rates of amyloid deposition continue into late age, survival differentials might be accounted for by variation in the risk of hemorrhagic stroke or be otherwise consequent to CAA.
In summary, in this population sample aged 75 years, the incidence of first ischemic stroke in subjects with normal cognition did not vary with apoE polymorphism. This implies that variation in the prevalence of cognitive impairment and the survival differentials observed in the cohort (longer with 2/3 and shorter with 3/4 compared with 3/3) during follow-up are not likely to derive from differences in ischemic stroke risk. An estimated 9% of cognitive impairment in this age group was attributable to prior stroke, indicating the importance of other factors (eg, AD pathology, diabetes, and low educational attainment) in this age group.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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The following individuals, foundations, and agencies are acknowledged for supporting this study: Einar Belven, Claes Groschinsky, Gamla Tjanarinnor, National Institute on Aging grants AG07198-09 and P20-AG12852-02, SHMF-90, Swedish Council for Social Research, Swedish Medical Research Council, and Tornspiran. Lena Lilius and Benita Engvall are acknowledged for valuable technical assistance. Thanks to all the members of the Kungsholmen Project Study Group, especially to Laura Fratiglioni, and to two anonymous outside reviewers.
Received February 8, 1996; revision received April 26, 1996; accepted April 30, 1996.
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C. Qiu, E. von Strauss, B. Winblad, and L. Fratiglioni Decline in Blood Pressure Over Time and Risk of Dementia: A Longitudinal Study From the Kungsholmen Project Stroke, August 1, 2004; 35(8): 1810 - 1815. [Abstract] [Full Text] [PDF]
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 C Qiu, M Kivipelto, H Aguero-Torres, B Winblad, and L Fratiglioni Risk and protective effects of the APOE gene towards Alzheimer's disease in the Kungsholmen project: variation by age and sex J. Neurol. Neurosurg. Psychiatry, June 1, 2004; 75(6): 828 - 833. [Abstract] [Full Text] [PDF]
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 M. Santos, M. do Carmo Costa, M. E. Rio, M. J. Sa, M. Monteiro, A. Valenca, A. Sa, J. Dinis, J. Figueiredo, L. B. de Almeida, et al. Genotypes at the APOE and SCA2 loci do not predict the course of multiple sclerosis in patients of Portuguese origin Multiple Sclerosis, April 1, 2004; 10(2): 153 - 157. [Abstract] [PDF]
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A. Pezzini, M. Grassi, E. Del Zotto, E. Bazzoli, S. Archetti, D. Assanelli, N. M. Akkawi, A. Albertini, and A. Padovani Synergistic Effect of Apolipoprotein E Polymorphisms and Cigarette Smoking on Risk of Ischemic Stroke in Young Adults Stroke, February 1, 2004; 35(2): 438 - 442. [Abstract] [Full Text] [PDF]
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L. S. Honig, M.-X. Tang, S. Albert, R. Costa, J. Luchsinger, J. Manly, Y. Stern, and R. Mayeux Stroke and the Risk of Alzheimer Disease Arch Neurol, December 1, 2003; 60(12): 1707 - 1712. [Abstract] [Full Text] [PDF]
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C. Qiu, B. Winblad, J. Fastbom, and L. Fratiglioni Combined effects of APOE genotype, blood pressure, and antihypertensive drug use on incident AD Neurology, September 9, 2003; 61(5): 655 - 660. [Abstract] [Full Text] [PDF]
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 L. Backman, S. Jones, B. J. Small, H. Aguero-Torres, and L. Fratiglioni Rate of Cognitive Decline in Preclinical Alzheimer's Disease: The Role of Comorbidity J. Gerontol. B. Psychol. Sci. Soc. Sci., July 1, 2003; 58(4): P228 - 236. [Abstract] [Full Text] [PDF]
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C. Qiu, B. Winblad, M. Viitanen, and L. Fratiglioni Pulse Pressure and Risk of Alzheimer Disease in Persons Aged 75 Years and Older: A Community-Based, Longitudinal Study Stroke, March 1, 2003; 34(3): 594 - 599. [Abstract] [Full Text] [PDF]
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J. Chapman, A. D. Korczyn, D. M. Karussis, and D. M. Michaelson The effects of APOE genotype on age at onset and progression of neurodegenerative diseases Neurology, October 23, 2001; 57(8): 1482 - 1485. [Abstract] [Full Text] [PDF]
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A.J.C. Slooter, M. L. Bots, L. M. Havekes, A. I. del Sol, M. Cruts, D. E. Grobbee, A. Hofman, C. Van Broeckhoven, J.C.M. Witteman, and C. M. van Duijn Apolipoprotein E and Carotid Artery Atherosclerosis: The Rotterdam Study Stroke, September 1, 2001; 32(9): 1947 - 1952. [Abstract] [Full Text] [PDF]
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 L. Steed, R. Kong, J. Stygall, J. Acharya, M. Bolla, M. J.G. Harrison, S. E. Humphries, and S. P. Newman The role of apolipoprotein E in cognitive decline after cardiac operation Ann. Thorac. Surg., March 1, 2001; 71(3): 823 - 826. [Abstract] [Full Text] [PDF]
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 G. B. Frisoni, J. Louhija, C. Geroldi, and M. Trabucchi Longevity and the {{varepsilon}}2 Allele of Apolipoprotein E: The Finnish Centenarians Study J. Gerontol. A Biol. Sci. Med. Sci., February 1, 2001; 56(2): 75M - 78. [Abstract] [Full Text]
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 Z. Guo, L. Fratiglioni, M. Viitanen, L. Lannfelt, H. Basun, J. Fastbom, and B. Winblad Apolipoprotein E Genotypes and the Incidence of Alzheimer's Disease among Persons Aged 75 Years and Older: Variation by Use of Antihypertensive Medication? Am. J. Epidemiol., February 1, 2001; 153(3): 225 - 231. [Abstract] [Full Text] [PDF]
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M. G. Dik, D. J. H. Deeg, L. M. Bouter, E. H. Corder, A. Kok, and C. Jonker Stroke and Apolipoprotein E {epsilon}4 Are Independent Risk Factors for Cognitive Decline : A Population-Based Study Stroke, October 1, 2000; 31(10): 2431 - 2436. [Abstract] [Full Text] [PDF]
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 A. Hassan and H. S. Markus Genetics and ischaemic stroke Brain, September 1, 2000; 123(9): 1784 - 1812. [Abstract] [Full Text] [PDF]
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J. M. Olichney, L. A. Hansen, C. R. Hofstetter, J.-H. Lee, R. Katzman, and L. J. Thal Association Between Severe Cerebral Amyloid Angiopathy and Cerebrovascular Lesions in Alzheimer Disease Is Not a Spurious One Attributable to Apolipoprotein E4 Arch Neurol, June 1, 2000; 57(6): 869 - 874. [Abstract] [Full Text] [PDF]
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N. Hirono, M. Yasuda, S. Tanimukai, H. Kitagaki, and E. Mori Effect of the Apolipoprotein E {epsilon}4 Allele on White Matter Hyperintensities in Dementia Stroke, June 1, 2000; 31(6): 1263 - 1268. [Abstract] [Full Text] [PDF]
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Y. Kokubo, A. H. Chowdhury, C. Date, T. Yokoyama, H. Sobue, and H. Tanaka Age-Dependent Association of Apolipoprotein E Genotypes With Stroke Subtypes in a Japanese Rural Population Stroke, June 1, 2000; 31(6): 1299 - 1306. [Abstract] [Full Text] [PDF]
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H. Sawada, F. Udaka, Y. Izumi, K. Nishinaka, H. Kawakami, S. Nakamura, and M. Kameyama Cerebral white matter lesions are not associated with apoE genotype but with age and female sex in Alzheimer's disease J. Neurol. Neurosurg. Psychiatry, May 1, 2000; 68(5): 653 - 656. [Abstract] [Full Text]
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L. Zhu, L. Fratiglioni, Z. Guo, H. Basun, E. H. Corder, B. Winblad, and M. Viitanen Incidence of Dementia in Relation to Stroke and the Apolipoprotein E {epsilon}4 Allele in the Very Old : Findings From a Population-Based Longitudinal Study Stroke, January 1, 2000; 31(1): 53 - 60. [Abstract] [Full Text] [PDF]
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M. O. McCarron, D. Delong, and M. J. Alberts APOE genotype as a risk factor for ischemic cerebrovascular disease: A meta-analysis Neurology, October 1, 1999; 53(6): 1308 - 1308. [Abstract] [Full Text]
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C. DeCarli, T. Reed, B. L. Miller, P. A. Wolf, G. E. Swan, and D. Carmelli Impact of Apolipoprotein E {epsilon}4 and Vascular Disease on Brain Morphology in Men From the NHLBI Twin Study Stroke, August 1, 1999; 30(8): 1548 - 1553. [Abstract] [Full Text] [PDF]
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L. Zhu, L. Fratiglioni, Z. Guo, H. Aguero-Torres, B. Winblad, and M. Viitanen Association of Stroke With Dementia, Cognitive Impairment, and Functional Disability in the Very Old : A Population-Based Study Stroke, October 1, 1998; 29(10): 2094 - 2099. [Abstract] [Full Text] [PDF]
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M. O. McCarron, K. W. Muir, C. J. Weir, A. G. Dyker, I. Bone, J.A.R. Nicoll, and K.R. Lees The Apolipoprotein E {epsilon}4 Allele and Outcome in Cerebrovascular Disease Stroke, September 1, 1998; 29(9): 1882 - 1887. [Abstract] [Full Text] [PDF]
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K. Axelman, H. Basun, and L. Lannfelt Wide Range of Disease Onset in a Family With Alzheimer Disease and a His163Tyr Mutation in the Presenilin-1 Gene Arch Neurol, May 1, 1998; 55(5): 698 - 702. [Abstract] [Full Text] [PDF]
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M. Margaglione, D. Seripa, C. Gravina, E. Grandone, G. Vecchione, G. Cappucci, G. Merla, S. Papa, A. Postiglione, G. Di Minno, et al. Prevalence of Apolipoprotein E Alleles in Healthy Subjects and Survivors of Ischemic Stroke : An Italian Case-Control Study Stroke, February 1, 1998; 29(2): 399 - 403. [Abstract] [Full Text] [PDF]
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I. Skoog, C. Hesse, O. Aevarsson, S. Landahl, J. Wahlström, P. Fredman, and K. Blennow A population study of apoE genotype at the age of 85: relation to dementia, cerebrovascular disease, and mortality J. Neurol. Neurosurg. Psychiatry, January 1, 1998; 64(1): 37 - 43. [Abstract] [Full Text]
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L. Ferrucci, J. M. Guralnik, M. Pahor, T. Harris, M.-C. Corti, M.-C. MHS, B. T. Hyman, R. B. Wallace, and R. J. Havlik Apolipoprotein E {epsilon}2 Allele and Risk of Stroke in the Older Population Stroke, December 1, 1997; 28(12): 2410 - 2416. [Abstract] [Full Text]
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M. Hiramoto, H. Yoshida, T. Imaizumi, N. Yoshimizu, and K. Satoh A Mutation in Plasma Platelet-Activating Factor Acetylhydrolase (Val279->Phe) is a Genetic Risk Factor for Stroke Stroke, December 1, 1997; 28(12): 2417 - 2420. [Abstract] [Full Text]
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