Donate Help Contact The AHA Sign In Home
American Heart Association
Stroke
Search: search_blue_button Advanced Search
« Previous Article | Table of Contents | Next Article »
Stroke. 1997;28:2410-2416

This Article
Right arrow Abstract Freely available
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Ferrucci, L.
Right arrow Articles by Havlik, R. J.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Ferrucci, L.
Right arrow Articles by Havlik, R. J.

(Stroke. 1997;28:2410-2416.)
© 1997 American Heart Association, Inc.

Articles

Apolipoprotein E {epsilon}2 Allele and Risk of Stroke in the Older Population

Luigi Ferrucci, MD, PhD; Jack M. Guralnik, MD, PhD; Marco Pahor, MD; Tamara Harris, MD, MS; Maria-Chiara Corti, MD, MHS; Brad T. Hyman, MD, PhD; Robert B. Wallace, MD; Richard J. Havlik, MD, MPH

From the Geriatric Department, "I Fraticini," National Research Institute (INRCA), Florence, Italy (L.F.); Epidemiology, Demography, and Biometry Program, National Institute on Aging, National Institutes of Health, Bethesda, Md (L.F., J.M.G., T.H., M.-C.C., R.J.H.); Department of Preventive Medicine, University of Tennessee, Memphis (M.P.); Neurology Service, Massachusetts General Hospital, Boston (B.T.H.); and Department of Preventive Medicine and Environmental Health, University of Iowa, Iowa City (R.B.W.).


*    Abstract
up arrowTop
 *Abstract
down arrowIntroduction
 down arrowSubjects and Methods
 down arrowResults
 down arrowDiscussion
 down arrowReferences
 
Background and Purpose There is evidence for a role of apolipoprotein E (apoE) in atherosclerosis. Coronary heart disease morbidity is higher in persons carrying an {epsilon}4 allele and lower in those carrying an {epsilon}2 allele, but the effect on cerebrovascular disease is controversial. We estimated the risk of stroke associated with different apoE genotypes in older persons.

Methods At the sixth annual follow-up of the Iowa cohort of the Established Populations for Epidemiologic Studies of the Elderly, 1664 persons aged >=71 years and free of stroke were genotyped for apo E. Occurrence of ischemic strokes was prospectively assessed from subsequent hospital discharge records and death certificates.

Results One hundred fifty persons had an ischemic stroke over the subsequent 5 years (21.2 per 1000 person-years). The presence of {epsilon}3 and {epsilon}4 did not influence stroke risk. Among persons aged <80 years at the time of genotyping, {epsilon}2 carriers had lower risk of incident stroke, while no effect was detected in the older group. Compared with {epsilon}2 carriers aged 70 to 79 years (reference group), those in the same age group and not carrying an {epsilon}2 had 2.6-fold higher risk of incident stroke, and those aged >=80 years had even higher risks of stroke but without any difference according to presence/absence of {epsilon}2 (relative risks 3.6 and 3.3). Results remained substantially unchanged when adjusted for potential confounders and in models estimating the effect of apoE polymorphism on the risk of developing a stroke at ages between 70 and 79 years (56 events) and separately at ages >=80 years (94 events).

Conclusions The conditioning influence of age on the protection conferred by the apoE {epsilon}2 allele on stroke risk may account for previous controversies. This hypothesis should be verified in a population with a wider age range.


Key Words: aging • apolipoproteins • risk factors • stroke


*    Introduction
up arrowTop
 up arrowAbstract
 *Introduction
down arrowSubjects and Methods
 down arrowResults
 down arrowDiscussion
 down arrowReferences
 
Apolipoprotein E is a plasma protein involved in the metabolism of lipids.1 2 Six main isoforms of the apoE genotype exist, each consisting of a pair of the three major codominant alleles {epsilon}2, {epsilon}3, and {epsilon}4, encoding, respectively, the three protein isoforms E2, E3, and E4.1 3

Most current research on apoE focuses on {epsilon}4 and {epsilon}2 being associated with, respectively, increased and decreased risk of both sporadic and late-onset familial Alzheimer's disease,4 5 6 7 8 although after 80 years of age the association becomes less consistent.9 10 Many experimental and clinical observations also suggest that apoE is implicated in the atherosclerotic process through multiple local and general mechanisms.2 11 12 13 14 15 16 17 18 19 20 Epidemiological studies performed mainly in young and middle-aged persons have shown that severity of atherosclerosis in the thoracic aorta,21 risk22 and severity23 of CHD, chance of restenosis after angioplasty and endoarteriectomy,24 25 26 family history of CHD,27 and CHD mortality28 are higher in persons carrying an {epsilon}4 allele and lower in those carrying an {epsilon}2 allele. These associations are explained only in part by differences in serum lipid concentrations.29 Analogous with findings for Alzheimer's disease, the association between apoE polymorphism and CHD is less evident in older populations.30

A logical extension of the findings on CHD is to hypothesize that apoE polymorphism is also implicated in cerebrovascular atherosclerosis. Pedro-Botet et al31 found that patients with ischemic strokes were more likely to carry an {epsilon}4 allele than age-matched control subjects. However, in a case-control study by Courdec et al,32 patients affected by ischemic stroke had an {epsilon}2/{epsilon}3 genotype more often than nonstroke control subjects but less often than younger healthy blood donors. Two studies found a higher prevalence of {epsilon}4 in patients with multi-infarct dementia compared with older control subjects.33 34 35 There is evidence of a synergistic interaction of {epsilon}4 and severity of atherosclerosis for the risk of dementia.36

In contrast, two prospective studies in older persons performed in Finland30 and in Sweden37 failed to show a significant relationship between apoE polymorphism and risk of stroke. In the Finnish study the apoE polymorphism also had no effect on CHD.30 In the Swedish study37 the rates of stroke showed a rising, but not significant, trend across the {epsilon}2/{epsilon}3, {epsilon}3/{epsilon}3, and {epsilon}4/{epsilon}3 genotypes, and the fraction of cognitive impairment attributable to stroke was lowest (2%) in the {epsilon}2/{epsilon}3 group compared with the {epsilon}3/{epsilon}3 and the {epsilon}3/{epsilon}4 groups (9%).

We tested the hypothesis that apoE polymorphism is related to the risk of stroke, but analogous to what has been suggested for Alzheimer's disease and CHD, the strength of this association is age dependent. This may explain some of the inconsistencies in the findings of previous studies.


*    Subjects and Methods
up arrowTop
 up arrowAbstract
 up arrowIntroduction
 *Subjects and Methods
down arrowResults
 down arrowDiscussion
 down arrowReferences
 
Sources of Data
This study uses data from the Iowa site of the EPESE. The general design of the study is described elsewhere.38 Briefly, between 1981 and 1983, a survey was conducted on the entire population aged >=65 years living in two Iowa counties, and follow-up data were collected yearly for 7 years. Blood specimens were obtained from 1940 (76.1%) of the 2548 subjects who were found alive and were reinterviewed for the sixth annual follow-up in 1988. Of these, 1898 had apoE genotyping.

Detection of Strokes
Occurrence of stroke was assessed by examining hospital discharge records and death certificates. The MEDPAR files, which include data on hospitalizations for persons covered by Medicare program part A (97% of the US population aged >=65 years),39 supplied information on hospital admissions, including discharge diagnoses coded according to the ICD-9-CM.40 Uniform data from these files were available from 1985 through 1992. Nine persons who could not be matched with the MEDPAR files were excluded from the analysis.

Vital status was established from a subsequent follow-up, contact with proxies, and the National Death Index. ICD-9-CM codes for underlying causes of death were obtained from death certificates.

Codes for ischemic/thrombotic or generic strokes (ICD-9-CM codes 434 to 434.9, 436.0) listed as the principal discharge diagnosis or reported as the underlying cause of death were considered stroke events.

ApoE Genotype and Other Potential Risk Factors
Determination of apoE genotype was performed by restriction enzyme digestion of an apoE polymerase chain reaction product derived from blood samples.41 Several potential risk factors for stroke were examined. Smoking status was classified as current/past smoker and never smoked, based on self-report. At each follow-up participants were asked if they had ever been told by a doctor that they had diabetes, heart attack, or stroke. Blood pressure was measured at the sixth follow-up of the EPESE, the zero time for this analysis, by trained interviewers. The average of two readings was used in the analysis. Hypertension was considered present if the subject reported a physician's diagnosis and was taking any antihypertensive drug or if blood pressure values exceeded 90 mm Hg diastolic or 160 mm Hg systolic.

Blood samples were collected in a nonfasting state at participants' homes and processed by a commercial laboratory (Nichols Institute, San Juan Capistrano, Calif). Total cholesterol and triglyceride concentrations were measured with the use of standard enzymatic methods. For the multivariate analysis, participants were classified into four total cholesterol categories: <=160, 161 to 199, 200 to 239, and >=240 mg/dL; three HDL-cholesterol categories: <35, 35 to 59, and >=60 mg/dL; and three triglyceride categories: <200, 200 to 300, and >=300 mg/dL. The choice of the cut points follows the National Cholesterol Education Program criteria,42 with an additional category for low cholesterol, which is an important risk factor in older persons.43 The number of hospital admissions before stroke or before censoring was also calculated.

Population at Risk
A total of 225 persons had a history of stroke or had been hospitalized for CVD (ICD-9-CM codes 431 to 436) at or before the sixth annual follow-up. The prospective analysis presented in this report uses data from the 1664 participants without history of stroke at baseline. In agreement with previous cross-sectional findings from the same data set,41 we found similar distributions of apoE genotypes in those with and without a history of CVD.

Data Analysis
Tests for association between apoE alleles, potential confounders, and risk of incident stroke were fitted by using single gene models that gave equal weight to heterozygotes and homozygotes for a given allele.44 The association between apoE polymorphism and potential risk factors for stroke was explored by dividing the study population into three partially overlapping groups, according to presence of the alleles {epsilon}2, {epsilon}3, or {epsilon}4 in the apoE genotype. The effects of presence versus absence of specific alleles in the apoE genotype on the distribution of potential confounders were simultaneously estimated in linear (continuous variables) and logistic (dichotomous variables) regression models.

The first occurrence of stroke was utilized in the analyses. Stroke incidence rates are reported as events per 1000 person-years. RRs and their 95% CIs of incident stroke, comparing persons carrying and not carrying a specific allele, were estimated by Cox proportional hazards regression models. Participants with no stroke events were censored at the end of 1992 or at death, whichever came first. The interaction between age and carrying an {epsilon}2 on the risk of stroke was tested both by creating indicator variables for the cross-combination of age (<80 versus >=80 years) and {epsilon}2 ({epsilon}2+ versus {epsilon}2-) and by introducing an interaction "age*{epsilon}2" term in the model. The proportionality of the hazards, which is the main assumption of this regression technique, was verified by plotting the log (-log) survival function and the baseline hazard functions against time for the four groups (70 to 79 {epsilon}2+; 70 to 79 {epsilon}2-; >=80 {epsilon}2+; >=80 {epsilon}2-). Both the log (-log) survival function and the hazard functions were roughly parallel for these four groups, suggesting proportionality of the hazards over the entire follow-up. The six most influential observations were identified by calculating for each of the participant the likelihood displacement statistic,45 which indicates how much the 2-log likelihood of the model will change if the individual is removed. After any of these subjects were excluded from the analysis, the findings of the analysis were very similar and their interpretation did not change.

Further models were created to estimate the risk of developing a stroke at a specific age and how apoE polymorphism affects this risk. Two models were fitted to examine separately the age ranges 70 to 79 and >=80. These two models, rather than setting the zero time at the date of the baseline interview, considered age 70 and age 80 as time 0 for the time-to-event analyses. Participants were sequentially entered into the population at risk at the time of their baseline age and were considered at risk up to the time when they developed an event, died, or were censored, whichever came first. The first model included only participants who were aged <80 years at baseline. Of these, those who survived free of stroke beyond 80 years were censored at that age. The second model included participants who were aged >=80 years at baseline and participants who had survived free of stroke beyond 80 years of age. This last group was entered in the population at risk at age 80.


*    Results
up arrowTop
 up arrowAbstract
 up arrowIntroduction
 up arrowSubjects and Methods
 *Results
down arrowDiscussion
 down arrowReferences
 
ApoE Genotype
The population at risk for incident strokes consisted of 1664 subjects (mean±SD age, 78.9±5.8 years; range, 71 to 102 years; 65.4% women). Isoform prevalences were 0.6% for {epsilon}2/{epsilon}2, 15.2% for {epsilon}3/{epsilon}2, 57.9% for {epsilon}3/{epsilon}3, 22.5% for {epsilon}3/{epsilon}4, 2.0% for {epsilon}4/{epsilon}2, and 1.8% for {epsilon}4/{epsilon}4, with small, nonsignificant differences according to age and sex.

ApoE Polymorphism and Risk of Stroke
Over the follow-up (median follow-up time, 4.2 years), 150 stroke events were recorded (21.2 per 1000 person-years; 56 events at age <80 years and 94 events at age >=80 years). Of these, 28 were the cause of in-hospital death and 24 were the underlying cause of death for persons not hospitalized. Stroke incidence rates were higher in persons who were older at baseline (age <80 versus >=80 years: 18.6 versus 26.7 per 1000 person-years; P<.001) and in men compared with women (25.9 versus 19.0 per 1000 person-years, respectively; P<.001).

Table 1Down compares annual incidence rates of stroke between persons carrying and not carrying specific apoE alleles, for the total population and according to baseline age and sex. Compared with persons without an {epsilon}2 allele ({epsilon}2-), carriers of an {epsilon}2 allele ({epsilon}2+) had lower risk of incident stroke. The protective effect of {epsilon}2+ resulted from the very low incidence rates of stroke in {epsilon}2 carriers aged 71 to 79 years (Table 1Down), with no effect detected in the older age group (Fig 1Down). Risk of stroke was not related to carrying an {epsilon}4 allele.


View this table:
[in this window]
[in a new window]
  		Table 1. Incidence Rates of Stroke in Persons Carrying and Not Carrying an {epsilon}2 and an {epsilon}4 Allele in Their Apo-E Genotype, for the Total Population and According to Age and Sex



View larger version (14K):
[in this window]
[in a new window]
  		Figure 1. Kaplan-Meier survival curves describing the risk of stroke over the follow-up according to age (71 to 79 versus >=80 years) and presence ({epsilon}2+) versus absence ({epsilon}2 -) of an {epsilon}2 allele in the apoE genotype.

When we restricted the analysis to persons aged 71 to 79 years at baseline and after adjustment for age and sex, persons with {epsilon}3/{epsilon}3, {epsilon}4/{epsilon}4, and {epsilon}3/{epsilon}4 isoforms were, respectively, 2.9 (95% CI, 1.2 to 6.6), 3.3 (95% CI, 1.4 to 8.0), and 3.2 (95% CI, 0.6 to 15.7) times more likely to develop a stroke over the follow-up compared with the reference group of {epsilon}2 carriers. No such effect was found when the same analysis was performed in those aged >=80 years.

Potential Confounders
Potential risk factors for stroke were compared among three partially overlapping groups of participants, defined according to presence of an {epsilon}2, {epsilon}3, and {epsilon}4 allele (Table 2Down). Total cholesterol levels were lower in individuals carrying an {epsilon}2 allele, while HDL cholesterol and triglycerides were higher. Differences were statistically significant only for total cholesterol and triglycerides. Participants with an {epsilon}4 showed, on average, higher total cholesterol and lower HDL cholesterol, although none of these effects was statistically significant. Cross-sectionally, apoE polymorphism was not associated with age, sex, blood pressure, prevalence of smoking, hypertension, CHD, and diabetes mellitus.


View this table:
[in this window]
[in a new window]
  		Table 2. Potential Risk Factors for Stroke in Three Groups of Participants Selected According to Presence/Absence of at Least One Allele ({epsilon}2, {epsilon}3, and {epsilon}4) in the Apo-E Genotype

Multivariate Analysis
When we considered persons aged <80 years at baseline and carrying an {epsilon}2 as the reference group, those in the same age group but not carrying an {epsilon}2 had a threefold higher risk of developing a stroke, and those aged >=80 years were 3.8 times more likely to develop a stroke, regardless of their {epsilon}2 status (Table 3Down, model 1). These results remained substantially unchanged after adjustment for multiple potential confounders and serum lipids (Table 3Down, models 2 and 3). In the fully adjusted model, presence of hypertension and total cholesterol <160 mg/dL were still significant predictors of stroke.


View this table:
[in this window]
[in a new window]
  		Table 3. Association Between Presence ({epsilon}2+)/Absence ({epsilon}2-) of an {epsilon}2 Allele in the Apo-E Genotype and Risk of Incident Stroke According to Age Group

We fitted two further models aimed at estimating the effect of apoE on the risk of developing a stroke between 70 and 79 years of age and after 80 years of age. In these models, age 70 and age 80, respectively, were considered the starting points for the time-to-event analyses, and participants were sequentially entered into the population at risk at the time of their baseline age. After adjustment for potential confounders, carrying an {epsilon}2 allele was associated with low risk of developing a stroke at ages between 70 and 79 years (RR, 0.2; 95% CI, 0.0 to 0.7) but not after 80 years (RR, 1.2; 95% CI, 0.7 to 2.2).

Fig 2Down illustrates the interaction between age and {epsilon}2 status on the risk of stroke. Findings are from a model similar to model 3 in Table 3Up, except that age is a continuous variable and an interaction term of age with {epsilon}2 status (age*{epsilon}2) is also included. The protective effect of {epsilon}2 decreased progressively with age and after 80 years was no longer statistically significant.



View larger version (12K):
[in this window]
[in a new window]
  		Figure 2. Change of the RR of incident stroke associated with presence versus absence of an {epsilon}2 allele in the apoE genotype according to age. RRs were estimated from a proportional hazard model including age as a continuous variable, an "age*{epsilon}2 " interaction term, and the same potential confounders as in model 3 of Table 3Up. The dashed lines are 95% CIs estimated from the same model.


*    Discussion
up arrowTop
 up arrowAbstract
 up arrowIntroduction
 up arrowSubjects and Methods
 up arrowResults
 *Discussion
down arrowReferences
 
Using data from a large prospective study of persons aged >=70 years, we found that, independent of other traditional risk factors, carrying an {epsilon}2 allele was associated with lower risk of ischemic stroke. This protective effect was limited to persons who developed a stroke within the age range 70 to 79 years, while no effect was detected in persons who developed a stroke when they were aged >=80 years. These findings are consistent with a protective effect of apoE {epsilon}2 for CHD, which has been found in young and middle-aged persons21 22 23 27 but not always confirmed in older populations.30 This is the first time this association has been reported for CVD.

Our results are in conflict with the case-control study by Courdec et al,32 in which the {epsilon}3/{epsilon}2 genotype was more frequent in stroke patients than in control subjects, but are compatible with data suggesting that apoE {epsilon}2 is underrepresented in patients with vascular dementia compared with control subjects.33 34 Two previous longitudinal studies did not demonstrate a significant relationship between apoE genetic polymorphism and risk of stroke.30 37 Both negative studies were performed in North European populations, which show distinct differences from other populations in dietary intake and distribution of apoE genotypes.46 However, the reason why the findings of those studies differ from ours remains unclear.

Despite the strong evidence that {epsilon}4 is a strong risk factor for atherosclerosis and that cross-sectional data have shown a relationship between {epsilon}4 and stroke,31 47 we found no relationship between {epsilon}4 and stroke. The detection of an effect for {epsilon}2 but not for {epsilon}4 suggests that the two alleles may play a role in atherosclerosis through different mechanisms and possibly with different "time tables" over the life span. This hypothesis is also suggested by studies on the relationship between apoE polymorphism and survival, showing a decreasing survival across {epsilon}4, {epsilon}3, and {epsilon}2 carriers that has been ascribed to the effect of apoE isoforms on atherosclerosis and perhaps dementia.48 In fact, {epsilon}4 and {epsilon}2 allelic frequencies tend to decline and to increase with age, respectively,48 but a reduction of {epsilon}4 is already present in octogenarians,2 while the increment in {epsilon}2 allelic frequency has been detected only in centenarians.48

Our data suggest that risk of stroke is affected by a complex interaction between the aging process and genetic and environmental risk factors, similar to that currently proposed for dementia7 8 9 and CHD.30 Several hypotheses may be proposed to explain the interaction between age and apoE genotype. If a specific risk factor is potentiated in the presence of a specific genotype, and if this risk factor is related to selective mortality at younger ages, the genotype may appear to have less of an impact at older ages. Indeed, a mechanism of selective mortality has been also suggested to explain why some risk factors for stroke, such as hypertension,49 become less important in old age. Furthermore, since the incidence rate of stroke increases with age, other (possibly not already identified) risk factors may play a critical role in the causation of strokes in older individuals. An alternative hypothesis is based on the fact that {epsilon}2 has been associated with both antiatherogenic2 14 and atherogenic50 changes, and the balance between these two effects may be different in different periods of life.

The lack of a cross-sectional relationship between apoE polymorphism and history of CVD is of concern. We hypothesized that the discrepancy between the findings of the cross-sectional and of the prospective analyses was due to the different methods used for the detection of prevalent and incident cases of stroke. In fact, since hospital discharge records were available only for the 3 years before genotyping, detection of CVD events before this period was based on self-report. Indeed, considering only hospitalizations over the 3 years before baseline, we found that participants who were admitted to the hospital for a stroke between 70 and 79 years of age (n=65; {epsilon}2+, 10.7%) were less likely to carry an {epsilon}2 allele compared with aged-matched control subjects (n=1335; {epsilon}2+, 17.7%). Analogously, participants who were hospitalized for a stroke at age >=80 years (n=37; {epsilon}2+, 13.5%) were less likely to carry an {epsilon}2+ compared with aged-matched control subjects (n=731; {epsilon}2+, 18.1%), although the difference was somewhat smaller than for those developing stroke at younger age. In similar analyses, the presence of the alleles {epsilon}3 and {epsilon}4 was not associated with different rates of past hospitalization for stroke over the 3 years before baseline.

A potential shortcoming of this study is the fact that the outcome, incident stroke, was detected from hospital discharge records and death certificates. Lower detection of stroke in {epsilon}2 carriers may result from persons being hospitalized less often for nonstroke-related conditions, such as CHD. However, our findings were substantially unchanged after we adjusted for number of hospital admissions over the follow-up. Furthermore, strokes that were not hospitalized remained undetected. There is, however, no reason why apoE polymorphism should influence the probability of being hospitalized after a stroke.

In conclusion, in this study we found an age-dependent protective effect of apoE {epsilon}2 on the risk of ischemic stroke. Our results should be interpreted with caution because they are based on subjects aged >70 years, and they need to be verified in populations with a wider age range. Recent findings emphasize that CVDs may play a role in age-related cognitive decline that is more important than previously expected36 51 52 and in fact promotes the clinical manifestations of Alzheimer's disease.53 Research addressing the interaction between apoE polymorphism and other risk factors for stroke may shed new light on our understanding of the pathophysiology of CVD in old age and its relationship to cognitive decline.


*    Selected Abbreviations and Acronyms
 
apoE = apolipoprotein E
CHD = coronary heart disease
CI = confidence interval
CVD = cerebrovascular disease
EPESE = Established Populations for Epidemiologic Studies of the Elderly
ICD-9-CM = International Classification of Diseases, 9th Revision, Clinical Modification
MEDPAR = Medicare Provider Analysis and Review
RR = relative risk


*    Acknowledgments
 
Data collection was supported by contract N01-AG-0 to 2105 from the National Institute on Aging, National Institutes of Health, Bethesda, Md. This study was completed when Dr Ferrucci was a Visiting Scientist at the National Institute on Aging.


*    Footnotes
 
Reprint requests to Luigi Ferrucci, MD, PhD, Epidemiology, Demography, and Biometry Program, National Institute on Aging, 7201 Wisconsin Ave, Gateway Building, Suite 3C-309, Bethesda, MD 20892.

Received March 27, 1997; revision received September 12, 1997; accepted September 12, 1997.


*    References
up arrowTop
 up arrowAbstract
 up arrowIntroduction
 up arrowSubjects and Methods
 up arrowResults
 up arrowDiscussion
 *References
 

  1. Mahley RW. Apolipoprotein E: cholesterol transport protein with expanding role in cell biology. Science. 1988;240:622–630.[Abstract/Free Full Text]
  2. Davignon J, Gregg RE, Sing CF. Apolipoprotein E polymorphism and atherosclerosis. Arteriosclerosis. 1988;8:1–21.[Abstract/Free Full Text]
  3. Utermann G. Apolipoprotein E polymorphism in health and disease. Am Heart J. 1987;113:433–440.[Medline] [Order article via Infotrieve]
  4. Corder EH, Saunders AM, Strittmatter WJ, Schmechel DE, Gaskell PC, Small GW. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families. Science. 1993;261:921–923.[Abstract/Free Full Text]
  5. Brousseau T, Le Grain S, Barr C, Gourley V, Vidal O, Amble P. Confirmation of the epsilon four allele of the apolipoprotein E gene as a risk factor for late-onset Alzheimer's disease. Neurology. 1994;44:342–344.[Abstract/Free Full Text]
  6. Strittmatter WJ, Roses AD. Apolipoprotein E and Alzheimer disease. Proc Natl Acad Sci.. 1995;92:4725–4727.[Abstract/Free Full Text]
  7. Corder EH, Saunders AM, Risch NJ, Strittmatter WJ, Schmechel DE, Gaskell PCJ, Rimmler JB, Locke PA, Conneally PM, Schmader KE, Small GW, Roses AD, Haines JL, Pericak-Vance MA. Protective effect of apolipoprotein E type 2 allele for late onset Alzheimer disease. Nat Genet. 1994;7:180–184.[Medline] [Order article via Infotrieve]
  8. Saunders AM, Strittmatter WJ, Schmechel DE, George-Hyslop PH, Pericak-Vance MA, Joo SH. Association of apolipoprotein E allele epsilon 4 with late-onset familial and sporadic Alzheimer's disease. Neurology. 1993;43:1467–1472.[Abstract/Free Full Text]
  9. Sobel E, Louhija J, Sulkava R, Davanipour Z, Kontula K, Miettinen H, Tikkanen M, Kainulainen K, Tilvis R. Lack of association of apolipoprotein E allele epsilon 4 with late-onset Alzheimer's disease among Finnish centenarians. Neurology. 1995;45:903–907.[Abstract]
  10. Corder EH, Basun H, Lannfelt L, Viitanen M, Winblad B. Attenuation of apolipoprotein E epsilon4 allele gene dose in late age. Lancet. 1996;347:542. Letter.
  11. O'Brien KD, Deeb SS, Ferguson M, McDonald TO, Allen MD, Alpers CE, Chait A. Apolipoprotein E localization in human coronary atherosclerotic plaques by in situ hybridization and immunohistochemistry and comparison with lipoprotein lipase. Am J Pathol. 1994;144:538–548.[Abstract]
  12. Basu SK, Goldstein JL, Brown MS. Independent pathways for secretion of cholesterol and apolipoprotein E by macrophages. Science. 1983;219:871–873.[Abstract/Free Full Text]
  13. Zhang SH, Reddick RL, Piedrahita JA, Maeda N. Spontaneous hypercholesterolemia and arterial lesions in mice lacking apolipoprotein E. Science. 1992;258:468–471.[Abstract/Free Full Text]
  14. Sing CF, Davignon J. Role of the apolipoprotein E polymorphism in determining normal plasma lipid and lipoprotein variation. Am J Hum Genet. 1985;37:268–285.[Medline] [Order article via Infotrieve]
  15. Eto M, Watanabe K, Ishii K. Reciprocal effects of apolipoprotein E alleles (epsilon 2 and epsilon 4) on plasma lipid levels in normolipidemic subjects. Clin Genet. 1986;29:477–484.[Medline] [Order article via Infotrieve]
  16. Kao JT, Tsai KS, Chang CJ, Huang PC. The effects of apolipoprotein E polymorphism of the distribution of lipids and lipoproteins in Chinese population. Atherosclerosis. 1995;114:55–59.[Medline] [Order article via Infotrieve]
  17. Avila EM, Holdsworth G, Sasaki N, Jackson RL, Harmony JA. Apoprotein E suppresses phytohemagglutinin-activated phospholipid turnover in peripheral blood mononucleate cells. J Biol Chem. 1982;257:5900–5909.[Abstract/Free Full Text]
  18. Vogel T, Guo NH, Guy R, Drezlich N, Krutzsch HC, Blake DA. Apolipoprotein E: a potent inhibitor of endothelial and tumor cell proliferation. J Cell Biochem. 1994;54:299–308.[Medline] [Order article via Infotrieve]
  19. Saxena U, Ferguson E, Bisgaier CL. Apolipoprotein E modulates low density lipoprotein retention by lipoprotein lipase anchored to the sub-endothelial matrix. J Biol Chem. 1993;268:14812–14819.[Abstract/Free Full Text]
  20. Greenberg SM, Rebeck GW, Vonsattel JPG, Gomez-Isla T, Hyman BT. Apolipoprotein E epsilon4 and cerebral hemorrhage associated with amyloid angiopathy. Ann Neurol. 1995;38:254–259.[Medline] [Order article via Infotrieve]
  21. Hixson JE. Apolipoprotein E polymorphisms affect atherosclerosis in young males: pathobiological determinants of atherosclerosis in Youth (PDAY) Research Group. Arterioscler Thromb. 1991;11:1237–1244.[Abstract/Free Full Text]
  22. Katzel LI, Fleg JL, Paidi M, Ragoobarsingh N, Godberg AP. ApoE4 polymorphism increases the risk for exercise-induced silent myocardial ischemia in older men. Arterioscler Thromb. 1993;13:1495–1500.[Abstract/Free Full Text]
  23. Lehtinen S, Lehtimaki T, Sisto T, Salenius JP, Nikkila M, Jokela H. Apolipoprotein E polymorphism, serum lipids, myocardial infarction and severity of angiographically verified coronary artery disease in men and women. Atherosclerosis. 1995;114:83–91.[Medline] [Order article via Infotrieve]
  24. van Bockxmeer FM, Mamotte CDS, Gibbons FA, Burke V, Taylor RR. Angiotensin-converting enzyme and apolipoprotein E genotypes and restenosis after coronary angioplasty. Circulation. 1995;92:2066–2071.[Abstract/Free Full Text]
  25. van Bockxmeer FM, Mamotte CDS, Gibbons FR, Taylor RR. Apolipoprotein epsilon4 homozygosity: a determinant of restenosis after coronary angioplasty. Atherosclerosis. 1994;110:195–202.[Medline] [Order article via Infotrieve]
  26. Colyvas N, Rapp JH, Phillips NR, Stoney R, Perez S, Kane JP. Relation of plasma lipid and apoprotein levels to progressive intimal hyperplasia after arterial endarterectomy. Circulation. 1992;85:1286–1292.[Abstract/Free Full Text]
  27. Tiret L, de Knijff P, Menzel H-J, Ehnholm C, Nicaud V, Havekes LM. ApoE polymorphism and predisposition to coronary heart disease in youths of different European populations: the EARS Study. Arterioscler Thromb. 1994;14:1617–1624.[Abstract/Free Full Text]
  28. Stengard JH, Zerba KE, Pekkanen J, Ehnholm C, Nissinen A, Sing CF. Apolipoprotein E polymorphism predicts death from coronary heart disease in a longitudinal study of elderly Finnish men. Circulation. 1995;91:265–269.[Abstract/Free Full Text]
  29. Wang XL, McCredie RM, Wilcken DEL. Polymorphism of the apolipoprotein E gene and severity of coronary artery disease defined by angiography. Arterioscler Thromb Vasc Biol. 1995;15:1030–1034.[Abstract/Free Full Text]
  30. Kuusisto J, Mykkanen L, Kervinen K, Kesaniemi YA, Laakso M. Apolipoprotein E4 phenotype is not an important risk factor for coronary heart disease or stroke in elderly subjects. Arterioscler Thromb Vasc Biol. 1995;15:1280–1286.[Abstract/Free Full Text]
  31. Pedro-Botet J, Sentì M, Rubiés-Prat J. Apolipoprotein-E polymorphism and ischemic cerebrovascular disease. Stroke. 1994;25:521. Letter.[Medline] [Order article via Infotrieve]
  32. Courdec R, Mahieux F, Bailleul S, Fenelon G, Mary R, Fermanian J. Prevalence of apoliprotein E phenotypes in ischemic cerebrovascular disease: a case-control study. Stroke. 1993;24:661–664.[Abstract/Free Full Text]
  33. Frisoni GB, Calabresi L, Geroldi C, Bianchetti A, D'Acquarica AL, Govoni S, Sirtori CR, Trabucchi M, Franceschini G. Apolipoprotein E epsilon4 allele in Alzheimer's disease and vascular dementia. Dementia. 1994;5:240–242.
  34. Frisoni GB, Geroldi C, Bianchetti A, Trabucchi M, Govoni S, Franceschini G, Calabresi L. Apolipoprotein E epsilon4 allele frequency in vascular dementia and Alzheimer's disease. Stroke. 1994;25:1703–1704.[Medline] [Order article via Infotrieve]
  35. Shimano H, Ishibashi S, Murase T, Gotohda T, Yamada N, Takafu F. Plasma apolipoproteins in patients with multi-infarct dementia. Arteriosclerosis. 1996;79:257–260.
  36. Hofman A, Breteler MMB, Bots ML, Slooter AJ, van Harskamp F, van Duijn C, Van Broeckhoven C, Grobbee DE. Atherosclerosis, apolipoprotein E, and prevalence of dementia and Alzheimer's disease in the Rotterdam Study. Lancet. 1997;349:151–154.[Medline] [Order article via Infotrieve]
  37. Basun H, Corder EH, Guo Z, Lannfelt L, Corder LS, Manton KG. Apolipoprotein E polymorphism and stroke in a population sample aged 75 years or more. Stroke. 1996;27:1310–1315.[Abstract/Free Full Text]
  38. Cornoni-Huntley J, Ostfeld AM, Taylor JO, Wallace RB, Blazer D, Berkman LF, Evans DA, Kohout FJ, Lemke JH, Scherr PA, Korper SP. Established Populations for Epidemiologic Studies of the Elderly: study design and methodology. Aging. 1993;5:27–37.[Medline] [Order article via Infotrieve]
  39. Vladeck BC, King KM. Medicare at 30: preparing for the future. JAMA. 1995;274:259–270.[Medline] [Order article via Infotrieve]
  40. Public Health Service. International Classification of Diseases, 9th Revision, Clinical Modification. Washington, DC: Public Health Service; 1988.
  41. Hyman BT, Gomez-Isla T, Briggs M, Chung H, Nichols S, Kohour F, Wallace R. Apoliprotein E cognitive change in an elderly population. Ann Neurol. 1996;40:55–66.[Medline] [Order article via Infotrieve]
  42. National Cholesterol Education Program Expert Panel. Second report of the National Cholesterol Education Program Expert Panel on detection, evaluation, and treatment of high blood cholesterol in adults. Circulation. 1994;89:1329–1445.
  43. Corti MC, Guralnik JM, Salive ME, Harris T, Ferrucci L, Glynn RJ, Havlik RJ. Clarifying the direct relation between total cholesterol levels and death from coronary heart disease in older persons. Ann Intern Med. 1997;126:753–759.[Abstract/Free Full Text]
  44. Boerwinkle E, Utermann G. Simultaneous effects of the apolipoprotein E polymorphism on apolipoprotein E, apolipoprotein B, and cholesterol metabolism. Am J Hum Genet. 1988;42:104–112.[Medline] [Order article via Infotrieve]
  45. Allison PD. Survival Analysis Using the SAS System: A Practical Guide. Cary, NC: SAS Institute Inc; 1995.
  46. Corbo RM, Scacchi R, Mureddu L, Mulas G, Alfano G. Apolipoprotein E polymorphism in Italy investigated in native plasma by a simple polyacrylamide gel isoelectric focusing technique: comparison with frequency data of the European populations. Ann Hum Genet. 1995;59:197–209.[Medline] [Order article via Infotrieve]
  47. Pedro-Botet J, Sentì M, Nogues X, Rubies-Prat J, Roquer J, D'Olhaberriague L, Olive J. Lipoprotein and apolipoprotein profile in men with ischemic stroke: role of lipoprotein(a), triglyceride-rich lipoproteins, and apolipoprotein E polymorphism. Stroke. 1992;23:1556–1563.[Abstract/Free Full Text]
  48. Schachter F, Faure-Delanef L, Guénot F, Rouger H, Froguel P, Lesueur-Ginot L, Cohen D. Genetic associations with human longevity at the APOE and ACE loci. Nat Genet. 1994;6:29–32.[Medline] [Order article via Infotrieve]
  49. Curb JD, Abbott RD, MacLean CL, Rodriguez BL, Burchfiel CM, Sharp DS. Age-related changes in stroke risk in men with hypertension and normal blood pressure. Stroke. 1996;27:819–824.[Abstract/Free Full Text]
  50. Utermann G, Hees M, Steinmetz A. Polymorphism of apolipoprotein E and occurrence of dysbetalipoproteinaemia in man. Nature. 1977;269:604–607.[Medline] [Order article via Infotrieve]
  51. Ferrucci L, Guralnik JM, Salive ME, Pahor M, Corti MC, Baroni A, Havlik RJ. Cognitive impairment and risk of stroke in the older population. J Am Geriatr Soc. 1996;44:237–241.[Medline] [Order article via Infotrieve]
  52. Skoog I, Nilsson L, Palmertz B, Andreasson LA, Svanborg A. A population-based study of dementia in 85-year-olds. N Engl J Med. 1993;328:153–158.[Abstract/Free Full Text]
  53. Snowdon DA, Greiner LH, Mortimer JA, Riley KP, Greiner PA, Markesbery WR. Brain infarction and the clinical expression of Alzheimer's disease: the Nun Study. JAMA. 1997;277:813–817.[Abstract]



This article has been cited by other articles:


Home page
 J. Gerontol. A Biol. Sci. Med. Sci.Home page
D. C. Ewbank
Differences in the Association Between Apolipoprotein E Genotype and Mortality Across Populations
J. Gerontol. A Biol. Sci. Med. Sci., August 1, 2007; 62(8): 899 - 907.
[Abstract] [Full Text] [PDF]

Home page
 J. Gerontol. A Biol. Sci. Med. Sci.Home page
N. Stakias, P. Liakos, E. Tsiapali, M. Goutou, and G. N. Koukoulis
Lower Prevalence of Epsilon 4 Allele of Apolipoprotein E Gene in Healthy, Longer-Lived Individuals of Hellenic Origin
J. Gerontol. A Biol. Sci. Med. Sci., December 1, 2006; 61(12): 1228 - 1231.
[Abstract] [Full Text] [PDF]

Home page
 Journal of Applied GerontologyHome page
J. C. Hays, B. M. Burchett, G. G. Fillenbaum, and D. G. Blazer
Is the APOE {epsilon}4 Allele a Risk to Person-Environment Fit?
Journal of Applied Gerontology, September 1, 2004; 23(3): 247 - 265.
[Abstract] [PDF]

Home page
 StrokeHome page
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]

Home page
 J Aging HealthHome page
D. G. Blazer, G. G. Fillenbaum, D. T. Gold, B. M. Burchett, and J. C. Hays
Apoe {epsilon}4 as a Predictor of Subjective Quality of Life in a Biracial Older Person Community Sample
J Aging Health, November 1, 2003; 15(4): 645 - 660.
[Abstract] [PDF]

Home page
 ANGIOLOGYHome page
G. D. Kolovou, D. Ch. Daskalova, M. Hatzivassiliou, N. Yiannakouris, N. D. Pilatis, M. Elisaf, D. P. Mikhailidis, M. A. Cariolou, and D. V. Cokkinos
The Epsilon 2 and 4 Alleles of Apolipoprotein E and Ischemic Vascular Events in the Greek Population -- Implications for the Interpretation of Similar Studies
Angiology, January 1, 2003; 54(1): 51 - 58.
[Abstract] [PDF]

Home page
 ANGIOLOGYHome page
G. Kolovou, D. Daskalova, and D. P. Mikhailidis
Apolipoprotein E Polymorphism and Atherosclerosis
Angiology, January 1, 2003; 54(1): 59 - 71.
[Abstract] [PDF]

Home page
 AJGPHome page
D. G. Blazer, B. B. Burchett, and G. G. Fillenbaum
APOE {epsilon}4 and Low Cholesterol as Risks for Depression in a Biracial Elderly Community Sample
Am J Geriatr Psychiatry, October 1, 2002; 10(5): 515 - 520.
[Abstract] [Full Text] [PDF]

Home page
 J. Gerontol. A Biol. Sci. Med. Sci.Home page
D. G. Blazer, G. Fillenbaum, and B. Burchett
The APOE-E4 Allele and the Risk of Functional Decline in a Community Sample of African American and White Older Adults
J. Gerontol. A Biol. Sci. Med. Sci., December 1, 2001; 56(12): M785 - 789.
[Abstract] [Full Text] [PDF]

Home page
 StrokeHome page
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]

Home page
 ANGIOLOGYHome page
T. J. Tegos, E. Kalodiki, S.-S. Daskalopoulou, and A. N. Nicolaides
Stroke: Epidemiology, Clinical Picture, and Risk Factors: Part I of III
Angiology, October 1, 2000; 51(10): 793 - 808.
[Abstract] [PDF]

Home page
 Arch NeurolHome page
M. O. McCarron, K. W. Muir, J. A. R. Nicoll, J. Stewart, Y. Currie, K. Brown, and I. Bone
Prospective Study of Apolipoprotein E Genotype and Functional Outcome Following Ischemic Stroke
Arch Neurol, October 1, 2000; 57(10): 1480 - 1484.
[Abstract] [Full Text] [PDF]

Home page
 BrainHome page
A. Hassan and H. S. Markus
Genetics and ischaemic stroke
Brain, September 1, 2000; 123(9): 1784 - 1812.
[Abstract] [Full Text] [PDF]

Home page
 StrokeHome page
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]

Home page
 StrokeHome page
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]

Home page
 NeurologyHome page
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]

Home page
 StrokeHome page
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]