(Stroke. 1996;27:2230-2235.)
© 1996 American Heart Association, Inc.
Articles |
Cerebrovascular Disease, the Apolipoprotein e4 Allele, and Cognitive Decline in a Community-Based Study of Elderly Men
the Department of Chronic Diseases and Environmental Epidemiology, National Institute of Public Health and the Environment, Bilthoven (S.K., E.J.M.F., L.J.L., D.K.); Department of Epidemiology and Biostatistics, Erasmus University Medical School, Rotterdam (S.K., L.J.L.); and Netherlands Institute for Health Sciences, Rotterdam (S.K.), Netherlands.
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Abstract |
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Background and Purpose Cerebrovascular disease and the apolipoprotein e4 (APOE*4) allele are both important risk factors for cognitive decline. We investigated the combined effect of APOE*4 and cerebrovascular disease on cognitive decline.
Methods Data are from a cohort of 353 men, aged 69 to 89 years at baseline, living in Zutphen, Netherlands. The 30-point Mini-Mental State Examination (MMSE) was used to measure cognitive decline (drop of >2 points) from 1990 to 1993 (14% of the sample). Odds ratios (OR [95% confidence interval]) for cognitive decline were adjusted for age, education, and baseline MMSE score.
Results Compared with those without APOE*4 and without a history of cerebrovascular disease, the adjusted OR was 4.7 (1.7 to 12.7) for subjects without APOE*4 but with cerebrovascular disease, 3.3 (1.6 to 6.8) for those with APOE*4 and no cerebrovascular disease, and 17.2 (2.7 to 110.0) for those with both risk factors. The risk for cerebrovascular disease and APOE*4 combined was more than expected from the separate effects. The combined risk of coronary heart disease and APOE*4 was 6.1 (1.7 to 22.3). The analysis of cardiovascular risk factors showed that the risk of cognitive decline was highest in subjects with both APOE*4 and a high cholesterol level, high fibrinogen level, normal blood pressure, or diabetes mellitus.
Conclusions Cerebrovascular disease and APOE*4 may have a synergistic effect on cognitive decline.
Key Words: apolipoproteins • cerebrovascular disorders • cognition • dementia
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Introduction |
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Cerebrovascular diseases have been associated with an increased risk of cognitive impairment and vascular dementia.1 2 Other cardiovascular diseases, such as coronary heart disease and peripheral arterial disease, have also been related to cognitive impairment2 or vascular dementia.3 Furthermore, several studies observed an association of cognitive impairment to cardiovascular risk factors, such as hypertension, diabetes mellitus, total cholesterol level, and fibrinogen level.4 5 6 7 8
In addition, several studies have shown that APOE*4 allele on chromosome 19 is an important risk factor for Alzheimer's disease.9 10 11 This was also demonstrated for cognitive impairment, which is a major component of dementia.12 13 14 Feskens et al12 estimated that 22% of the incident cases of cognitive impairment in a community-based sample of elderly men were attributable to the APOE*4 allele and that subjects with APOE*4 were at a twofold increased risk of developing impaired cognitive function. Furthermore, APOE*4 has been related to cardiovascular diseases and their risk factors. Apolipoprotein E is a constituent of plasma chylomicrons, lipoproteins, and their remnants. It serves as a ligand for their receptor-mediated uptake. Total and LDL cholesterol concentrations are higher in subjects carrying the APOE*4 allele.15 Carriers of APOE*4 may also have an increased risk of coronary heart disease15 16 17 and cerebrovascular disease.18
In this study we examined whether the combined effect of cardiovascular diseases and the APOE*4 allele may lead to a higher risk of cognitive decline than would be expected from the separate effects. The existence of subgroups with an especially high risk may throw light on the etiology of cognitive impairment and could have important implications for preventive intervention. These relations were examined in the context of a community-based longitudinal study of elderly men.
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Subjects and Methods |
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Study Population
The Zutphen Elderly Study is a longitudinal study of risk factors for chronic diseases in men living in Zutphen, a town in the eastern part of the Netherlands.19 It is the continuation of the Zutphen Study, which was initiated in 1960 as the Dutch contribution to the Seven Countries Study.20 In 1985, 1266 men were asked to participate, 555 from the original cohort and 711 from a randomly selected sample from all other men living in Zutphen in the same age range. In 1985, 939 agreed to participate, and in 1990, 560 of 718 surviving men (78%) were reexamined. The examinations were repeated in 1993 on 390 of 553 surviving men (71%). Complete information on all risk factors was available for 353 men participating in both 1990 and 1993. The study has been approved by the medical ethics committee of the University of Leiden, the Netherlands, and informed consent was obtained from all participants.
MMSE
Global cognitive function was tested with the Dutch version of the 30-point MMSE.21 The MMSE includes questions on orientation to time and place, registration, attention and calculation, recall, language, and visual construction. This screening test was originally created for a clinical setting21 and is extensively used in epidemiological studies.22 Although it tests a limited set of cognitive functions, these are important to daily functioning and severely affected in dementia. In 1990 it was administered in a controlled hospital setting, and in 1993 it was administered at the subject's homes. If fewer than four individual items (of a total of 20 items) were not answered by the subject, these were rated as errors,23 unless items could not be performed because of severe physical disability, in which case a weighted total score was given. If a subject did not answer four or more individual items, the total MMSE score was considered missing. Before we performed the analyses, we defined the cutoff point for cognitive decline as a drop in the MMSE of >2 points (>1 SD) from 1990 to 1993, which corresponded to the 14th percentile of change. In test-retest studies it was found that the maximum difference between two mean measurements was 2.1 points, with a standard error varying between 0.4 and 0.7.24
Apolipoprotein E Phenotype
During the examination in 1990, serum samples were obtained and frozen at -20°C until determination of phenotype in 1993. For 19 subjects, samples stored at the same temperature from 1985 were used. The apolipoprotein E phenotype was determined by isoelectric focusing of delipidated plasma samples followed by immunoblotting.25 The use of stored serum for this purpose has been judged to be valid.25 Because of a relatively small sample size, homozygotes (2.5%) and heterozygotes (20.7%) for the APOE*4 allele were considered together.
Cardiovascular Disease
In the spring of 1990, interviews and physical examinations by trained physicians were performed at home and in a study center. History of myocardial infarction, angina pectoris, and intermittent claudication was obtained from the Dutch translation of a questionnaire developed at the London School of Hygiene and Tropical Medicine.26 A history of stroke, transient ischemic attack, and diabetes was assessed with a standardized questionnaire. Medical records, including electrocardiograms, hospital discharge data, and written information from general practitioners, were collected to verify diagnoses. All information was uniformly coded by two trained medical staff members. Cerebrovascular disease was considered present when either stroke or transient ischemic attack was diagnosed, and coronary heart disease was considered present when either myocardial infarction or angina pectoris was diagnosed. Diabetes mellitus was defined as known or newly diagnosed diabetes, as defined by a fasting glucose concentration >7.8 mmol/L or a 2-hour postload glucose concentration >11.1 mmol/L.27
Cardiovascular Risk Factors
Systolic and diastolic (fifth Korotkoff phase) blood pressures were measured with a random zero sphygmomanometer in duplicate on the right arm with the subject in supine position at the end of the physical examination. The mean of the two blood pressure values was used in the analyses. Hypertension was defined as a systolic blood pressure 
160 mm Hg or a diastolic blood pressure 95 mm Hg or the use of antihypertensive medication, regardless of blood pressure level.28 Blood was taken to determine the concentrations of lipids and hemostatic factors. Total and HDL cholesterol were analyzed in nonfasting blood samples by the standardized Lipid Laboratory at the Department of Human Nutrition, Wageningen Agricultural University, Netherlands. Serum cholesterol was determined enzymatically with the CHOD-PAP mono-test kit from Boehringer Mannheim.29 It was dichotomized, and a concentration of 
6.5 mmol/L was taken as the reference category. Serum HDL cholesterol was determined enzymatically after precipitation of apolipoprotein B–containing particles by dextran sulfate–Mg2+.30 HDL cholesterol was dichotomized, and a concentration of 0.9 mmol/L was used as the reference category. Fibrinogen concentration was determined in citrate plasma by the method of Clauss.31 Analyses were performed at the Laboratory of the Department of Human Biology, University of Limburg, Maastricht, Netherlands. We used the upper tertile of fibrinogen (3.8 g/L) as cutoff point because there is no consensus on this matter. Age (continuous) and education (6 years, 7 to 12 years, and >12 years of education) were considered confounding variables.
Statistical Analysis
Differences in baseline characteristics were evaluated between carriers, defined as either homozygote or heterozygote for the APOE*4 allele, and noncarriers. We used the nonparametric Mann-Whitney test for continuous variables and the 
2 test for categorical variables. The proportion of men with cognitive decline according to the presence or absence of cardiovascular factors was calculated for the total group and for the two APOE*4 strata separately. These percentages were adjusted for age and education by multiple linear regression analysis.
Next, we investigated whether the combined effect of the APOE*4 allele and cardiovascular factors on cognitive decline was different from the separate effects.32 We categorized subjects into four groups: subjects without the APOE*4 allele and the risk factor (reference group); subjects without APOE*4 and with the risk factor; subjects with APOE*4 and without the risk factor; and subjects in whom both APOE*4 and the risk factor were present. These groups were entered into a multiple logistic regression model as dummy variables. We adjusted for age, education, and baseline MMSE score. We additionally adjusted for the score on the self-rating depression scale that was available for a subgroup. Since the results did not essentially change, we decided not to present the results with adjustment for depression.
We examined whether subjects who did and did not participate in 1993 differed at baseline (1990). In addition, we investigated whether the relation between cardiovascular diseases, APOE*4, and cognitive impairment at baseline was different for those who dropped out of our study population compared with those who did not. All tests were two-sided, and a value of P<.05 was considered statistically significant. The SAS program, version 6.10, was used.
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Results |
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The mean age of the participants at baseline (1990) was 74.6 (SD=4.2) years. The median MMSE score was 27 (10th centile, 23; 90th centile, 29). Fourteen percent (n=51) showed a drop in the MMSE of >2 points. Carriers of the APOE*4 allele more often showed cognitive decline and had a higher serum cholesterol concentration (Table 1
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In the total group, a history of cerebrovascular disease was significantly associated with cognitive decline, after adjustment for age, education, and baseline MMSE score (OR, 4.3; 95% CI, 1.8 to 9.9). A history of coronary heart disease slightly increased the risk of cognitive decline (OR, 1.7; 95% CI, 0.8 to 3.5). Intermittent claudication and cardiovascular risk factors were not significantly associated with cognitive decline in the total group.
After adjustment for age and education, the proportion of subjects with cognitive decline in those without APOE*4 and without a history of cerebrovascular disease was 9% and in those without APOE*4 and with cerebrovascular disease was 32% (Table 2). Therefore, among noncarriers, the difference in the percentage of men with cognitive decline in those with cerebrovascular disease and those without was 23%. In the stratum of APOE*4 carriers, the proportion of subjects with cognitive decline in those without cerebrovascular disease was 22% and in those with cerebrovascular disease it was 66%. Thus, among APOE*4 carriers, the difference in the percentage of men with a decline in those with cerebrovascular disease and those without was 44%. This percentage (44%) was approximately twice as high as in the noncarriers (23%). The difference in percentage of men with cognitive decline in those with and without coronary heart disease was also two times higher in carriers of APOE*4 compared with the noncarriers (13% versus 6%). Intermittent claudication was not associated with cognitive decline among noncarriers, but 11% more subjects experienced cognitive decline among APOE*4 carriers, which was not significant.
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The results of the logistic regression analysis, in which subjects without cardiovascular disease and without the APOE*4 allele were taken as the reference group, are shown in the Figure. The presence of both the APOE*4 allele and cerebrovascular disease increased the risk of cognitive decline substantially to 17.2 (95% CI, 2.7 to 110.0) (Figure, left panel). This OR was more than would be expected from the sum of the separate ORs (4.7 and 3.3), suggesting that the effect of the two factors together on cognitive decline was synergistic.33 The same synergy, although not as strong, may be present for coronary heart disease and the APOE*4 allele (Figure, right panel). The OR for subjects with APOE*4 and coronary heart disease was 6.1 (95% CI, 1.7 to 22.3). Intermittent claudication did not seem to be related to cognitive decline, whether APOE*4 was present or not (results not shown).
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The analysis of cardiovascular risk factors showed that in the APOE*4 stratum, there were proportionally more men with cognitive decline in the high than in the low category of total cholesterol, HDL cholesterol, and fibrinogen, although these differences were not significant (Table 3). None of the ORs of the cardiovascular risk factors were significantly increased in the absence of APOE*4 (Table 4). The risk of cognitive decline was highest in subjects with both APOE*4 and a high cholesterol or high fibrinogen level or diabetes mellitus. On the other hand, the risk of cognitive decline appeared to be lower in subjects with APOE*4 and hypertension than in those with APOE*4 and without hypertension.
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Cognitive impairment in 1990 (MMSE score <26) and a history of major cardiovascular diseases (stroke or myocardial infarction) were more frequent in those who did not participate in 1993 than in those who did (results not shown). The APOE*4 frequency was not significantly different between these groups. In both nonparticipants and participants, the percentage of men with cognitive impairment at baseline tended to be higher in those with an APOE*4 allele than in those without (42% versus 36% and 38% versus 27%, respectively). In both nonparticipants and participants, the percentage of men with cognitive impairment did not differ significantly between those with a history of cardiovascular disease and those without (45% versus 39% and 26% versus 30%, respectively). There was no significant interaction between participation status and one of these risk factors (P>.1).
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Discussion |
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Our study was a community-based prospective study in which the change in cognitive function was measured. To our knowledge, this is one of the first studies that investigated the combined effect of cardiovascular diseases and APOE*4 on cognitive decline. We found that APOE*4 carriers who suffered a stroke or transient ischemic attack had a particularly increased risk of cognitive decline, which was more than could be expected from the separate effects of these risk factors combined. This suggests synergism.33 The same synergy may be present between coronary heart disease and APOE*4, although this was less clear. These results were independent of age, education, baseline MMSE score, and depression. However, there is still a possibility that our results are due to residual confounding.
The MMSE is a reliable and valid indicator of cognitive impairment.34 We used the MMSE to assess change in cognitive function, for which it was not originally created. One study examined the reliability of change in the MMSE in patients with dementia. They found that for a time interval between the MMSEs of 1 year, the reliability was approximately 0.74, which is reasonable.35 We chose a cutoff point of a drop in the MMSE of >2 points, which may not be pathologically significant on an individual level but can be of major importance on a population level.
The synergism we observed may suggest that APOE*4 potentiates the effect of cerebrovascular disease on cognitive decline. Frisoni et al36 hypothesized that different insults, either degenerative or vascular, might result in greater damage when a particular apolipoprotein E isoform allele is present. The possibility that cerebrovascular disease is more harmful in carriers of APOE*4 is suggested in a study showing that after hemorrhagic stroke, the functional neurological outcome in subjects with an APOE*4 allele was worse and survival reduced compared with subjects with no APOE*4 allele.37 This may result from reduced neuronal repair in APOE*4 carriers.38 Alternatively, cerebrovascular disease may potentiate the effect of APOE*4 on cognitive decline by increasing the susceptibility of the brain to the effects of APOE*4. Coronary heart disease and peripheral arterial disease are associated with an increased risk of cerebral damage. Thus, the same mechanisms may account for the association between these diseases, APOE*4, and cognitive decline. However, in this study there was no obvious synergism between coronary heart disease and APOE*4. In addition, intermittent claudication was not clearly associated with cognitive decline, irrespective of APOE*4. This may be due to the relatively small number of subjects with intermittent claudication in our study and to the fact that our diagnosis was based on typical symptoms and information on peripheral atherosclerosis was lacking.
Total cholesterol, fibrinogen, hypertension, and diabetes mellitus were not independently associated with cognitive decline. However, the data suggest that the risk of cognitive decline was increased in subjects with APOE*4 and one of these cardiovascular risk factors, except for hypertension. Perhaps these risk factors have an effect on cognition only when the brain tissue is altered by the effects of APOE*4. Our results on total cholesterol correspond to a recent case-control study, which suggested that the association between apolipoprotein E genotype and Alzheimer's disease was stronger when cholesterol levels were higher.39 We found that high HDL cholesterol was insignificantly associated with an increased risk of cognitive decline, irrespective of APOE*4. Additional adjustment for cigarette smoking and alcohol consumption did not essentially alter this association, while additional adjustment for cholesterol reduced it only slightly. Several other studies have not found an association between cognitive function and HDL cholesterol.14 40 We cannot exclude the possibility that this is a chance finding.
We investigated the possibility of selection bias due to nonparticipation. The association between APOE*4 and cognitive impairment in 1990 was not different for those who participated in 1993 compared with those who did not, nor was the association between a history of cardiovascular disease and cognitive impairment. This suggests that our results were probably not biased by selective nonparticipation.
From this study we conclude that cerebrovascular disease and the APOE*4 allele may have a synergistic effect on cognitive decline. In addition, coronary heart disease and cardiovascular risk factors may interact with APOE*4 to increase the risk of cognitive decline above and beyond the effect of APOE*4 alone. This study suggests that genetic risk factors are important to consider when studying the association between cardiovascular diseases and cognitive function. Additional studies will be needed to determine whether synergism is also suggested when the risk of dementing disorders such as Alzheimer's disease and vascular dementia is examined.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This study was supported by grants from the Praeventie Fonds, the Hague, the Netherlands, and the National Institute on Aging, Bethesda, Md. We thank the fieldwork team in Zutphen, especially Dr E.B. Bosschieter and Dr B.P.M. Bloemberg; C. de Lezenne Coulander for data management; and Dr L.M. Havekes for the determination of the apolipoprotein E polymorphism and for reviewing the manuscript.
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Footnotes |
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Reprint requests to Dr S. Kalmijn, Department of Epidemiology and Biostatistics, Erasmus University Medical School, Dr Molewaterplein 50, 3015 GE Rotterdam, PO Box 1738, 3000 DR Rotterdam, Netherlands. E-mail kalmijn@epib.fgg.eur.nl.
Received June 3, 1996; revision received August 23, 1996; accepted August 25, 1996.
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 M. A Beydoun, J. S Kaufman, J. A Satia, W. Rosamond, and A. R Folsom Plasma n-3 fatty acids and the risk of cognitive decline in older adults: the Atherosclerosis Risk in Communities Study Am. J. Clinical Nutrition, April 1, 2007; 85(4): 1103 - 1111. [Abstract] [Full Text] [PDF]
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 C. M. de Frias, D. Bunce, A. Wahlin, R. Adolfsson, K. Sleegers, M. Cruts, C. Van Broeckhoven, and L.-G. Nilsson Cholesterol and Triglycerides Moderate the Effect of Apolipoprotein E on Memory Functioning in Older Adults J. Gerontol. B. Psychol. Sci. Soc. Sci., March 1, 2007; 62(2): P112 - P118. [Abstract] [Full Text] [PDF]
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D. J. Vinkers, M. L. Stek, R. C. van der Mast, A.J.M. de Craen, S. Le Cessie, J. Jolles, R. G.J. Westendorp, and J. Gussekloo Generalized atherosclerosis, cognitive decline, and depressive symptoms in old age Neurology, July 12, 2005; 65(1): 107 - 112. [Abstract] [Full Text] [PDF]
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 R. M. Lane and M. R. Farlow Lipid homeostasis and apolipoprotein E in the development and progression of Alzheimer's disease J. Lipid Res., May 1, 2005; 46(5): 949 - 968. [Abstract] [Full Text] [PDF]
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C. Reitz, J. Luchsinger, M. -X. Tang, J. Manly, and R. Mayeux Impact of plasma lipids and time on memory performance in healthy elderly without dementia Neurology, April 26, 2005; 64(8): 1378 - 1383. [Abstract] [Full Text] [PDF]
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 A. M. Kanaya, E. Barrett-Connor, G. Gildengorin, and K. Yaffe Change in Cognitive Function by Glucose Tolerance Status in Older Adults: A 4-Year Prospective Study of the Rancho Bernardo Study Cohort Arch Intern Med, June 28, 2004; 164(12): 1327 - 1333. [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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 S. C. Ferguson, I. J. Deary, J. C. Evans, S. Ellard, A. T. Hattersley, and B. M. Frier Apolipoprotein-E Influences Aspects of Intellectual Ability in Type 1 Diabetes Diabetes, January 1, 2003; 52(1): 145 - 148. [Abstract] [Full Text] [PDF]
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K. Yaffe, E. Barrett-Connor, F. Lin, and D. Grady Serum Lipoprotein Levels, Statin Use, and Cognitive Function in Older Women Arch Neurol, March 1, 2002; 59(3): 378 - 384. [Abstract] [Full Text] [PDF]
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R. Peila, L.R. White, H. Petrovich, K. Masaki, G.W. Ross, R.J. Havlik, L.J. Launer, and J. Poirier Joint Effect of the APOE Gene and Midlife Systolic Blood Pressure on Late-Life Cognitive Impairment: The Honolulu-Asia Aging Study Editorial Comment: The Honolulu-Asia Aging Study Stroke, December 1, 2001; 32(12): 2882 - 2889. [Abstract] [Full Text] [PDF]
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E. L. Mortensen and P. Hogh A gender difference in the association between APOE genotype and age-related cognitive decline Neurology, July 10, 2001; 57(1): 89 - 95. [Abstract] [Full Text] [PDF]
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N. Helbecque, C. Berr, D. Cottel, I. Fromentin-David, V. Sazdovitch, F. Ricolfi, P. Ducimetiere, C. Di Menza, and P. Amouyel VLDL receptor polymorphism, cognitive impairment, and dementia Neurology, May 8, 2001; 56(9): 1183 - 1188. [Abstract] [Full Text] [PDF]
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S. A. Small Age-Related Memory Decline: Current Concepts and Future Directions Arch Neurol, March 1, 2001; 58(3): 360 - 364. [Abstract] [Full Text] [PDF]
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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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K. Juva, A. Verkkoniemi, P. Viramo, T. Polvikoski, K. Kainulainen, K. Kontula, and R. Sulkava APOE {epsilon}4 does not predict mortality, cognitive decline, or dementia in the oldest old Neurology, January 25, 2000; 54(2): 412 - 412. [Abstract] [Full Text] [PDF]
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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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 J. T. Moroney, M.-X. Tang, L. Berglund, S. Small, C. Merchant, K. Bell, Y. Stern, and R. Mayeux Low-Density Lipoprotein Cholesterol and the Risk of Dementia With Stroke JAMA, July 21, 1999; 282(3): 254 - 260. [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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D. Carmelli, C. DeCarli, G. E. Swan, L. M. Jack, T. Reed, P. A. Wolf, and B. L. Miller Evidence For Genetic Variance in White Matter Hyperintensity Volume in Normal Elderly Male Twins Stroke, June 1, 1998; 29(6): 1177 - 1181. [Abstract] [Full Text] [PDF]
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L. H. Kuller, L. Shemanski, T. Manolio, M. Haan, L. Fried, N. Bryan, G. L. Burke, R. Tracy, and R. Bhadelia Relationship Between ApoE, MRI Findings, and Cognitive Function in the Cardiovascular Health Study Stroke, February 1, 1998; 29(2): 388 - 398. [Abstract] [Full Text] [PDF]
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