Apolipoprotein E Genotypes and the Incidence of Alzheimer's Disease among Persons Aged 75 Years and Older: Variation by Use of Antihypertensive Medication?
Zhenchao Guo,
Laura Fratiglioni,
Matti Viitanen,
Lars Lannfelt,
Hans Basun,
Johan Fastbom and
Bengt Winblad
From the Stockholm Gerontology Research Center and Department of Geriatric Medicine, Karolinska Institute, Stockholm, Sweden.
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ABSTRACT
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The authors examined the impact of the apolipoprotein E (APOE)*
4 allele on Alzheimer's disease incidence in relation to use of antihypertensive medication. A population-based (Kungsholmen Project) cohort of 985 nondemented Swedish subjects aged
75 years was followed for an average of 3 years (19901992); 164 dementia (122 Alzheimer's disease) cases were identified. Compared with *
3/*
3, the APOE*
4 allele increased the risk of developing dementia (relative risk (RR) = 1.5, 95% confidence interval (CI): 1.1, 2.1) and Alzheimer's disease (RR = 1.7, 95% CI: 1.2, 2.5). Subjects using antihypertensive medication at baseline (n = 432, 80% used diuretics) had a decreased risk of dementia (RR = 0.6, 95% CI: 0.5, 0.9) and Alzheimer's disease (RR = 0.5, 95% CI: 0.3, 0.8) after adjustment for several variables, including APOE. The effect of antihypertensive medication use was more pronounced among *
4 carriers. For those not using antihypertensive medication, the relative risks of dementia and Alzheimer's disease for carriers were 2.2 (95% CI: 1.4, 3.4) and 2.3 (95% CI: 1.4, 3.7), respectively. The corresponding relative risks for those using antihypertensive medication were 0.9 (95% CI: 0.5, 1.6) and 1.1 (95% CI: 0.6, 2.2). The APOE*
4 allele is an important predictor of dementia and Alzheimer's disease incidence. Further studies are needed to clarify whether use of antihypertensive medication, especially diuretics, modifies the effect of the allele.
Alzheimer disease; apolipoproteins E; dementia; diuretics; genotype; incidence
Abbreviations:
APOE, apolipoprotein E genotype; ATC, Anatomical Therapeutic Chemical; CI, confidence interval; MMSE, Mini-Mental State Examination; RR, relative risk.
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INTRODUCTION
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Increasing evidence indicates that the apolipoprotein E (APOE)*
4 allele is a major genetic risk factor for late-onset Alzheimer's disease (1
, 2
). An increased frequency of the *
4 allele has consistently been found in both familial and sporadic Alzheimer's disease cases in different ethnic samples (3


17
). APOE*
4 is related to global cognitive decline in the general elderly population (18

21
), and it also increases the risk of developing Alzheimer's disease for memory-impaired persons (22
, 23
). A community-based prospective study has provided strong evidence supporting the APOE*
4 allele as a risk factor for Alzheimer's disease, but it also suggested that previous family and case-control studies may have overestimated the contribution (24
). Indeed, *
4 alone is neither necessary nor sufficient for development of the disease (11
); a considerable proportion of *
4 carriers do escape the disease (9
). Several studies have also noted a lack of significant association between *
4 and Alzheimer's disease (25
, 26
). A recent study (27
) found evidence supporting a previous view that the APOE*
4 allele is not a significant risk factor for Alzheimer's disease among African Americans and Hispanics. It has been argued that the effect of APOE*
4 may be mediated by other genetic factors or may be modified by some environmental exposures (28
, 29
).
The Kungsholmen Project is a community-based longitudinal study of aging and dementia in people aged 75 years and older (30
). In our previous analysis, we found that use of antihypertensive medication (80 percent diuretics) was related to a lower prevalence of dementia, a decreased risk of developing dementia, and a slower cognitive decline among patients with dementia (31
). We therefore examined the effect of the APOE*
4 allele on the incidence of dementia and Alzheimer's disease by considering use of these drugs.
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MATERIALS AND METHODS
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Study population
The study population consisted of 1,310 subjects who were free of dementia at baseline and who participated in the first follow-up of the Kungsholmen Project. Of these subjects, 985 with APOE genotyping were included in this analysis. The Kungsholmen Project is a longitudinal study of aging and dementia that targeted all inhabitants of the Kungsholmen district of Stockholm, Sweden, who were aged 75 years and older on October 1, 1987 (30
). To detect prevalent cases of dementia at baseline, the Mini-Mental State Examination (MMSE) was administered to 1,810 participants (32
). Those with an MMSE score of <24 (n = 314) and a random sample of subjects with an MMSE score of
24 (n = 354) were then examined clinically (33
). Of 1,475 baseline participants who were free of dementia as diagnosed by means of the two-phase design, 174 were excluded from further follow-up because they refused to participate or moved away from Stockholm. Thus, 1,301 subjects remained for the follow-up assessment of incident dementia cases; of these 1,301 subjects, 985 agreed to provide a blood sample for APOE genotyping.
Identification of dementia
Of the 985 subjects who provided a blood sample, 840 were administered a comprehensive clinical examination between November 1990 and April 1992. A total of 145 subjects died before the follow-up examination; the medical records and death certificates of these subjects were reviewed by physicians. Diagnostic and Statistical Manual of Mental Disorders, third edition, revised, diagnostic criteria (34
) were used to define dementia. A diagnosis of Alzheimer's disease requires gradual onset, progressive deterioration, and lack of specific causes of dementia. Our criteria for identifying Alzheimer's disease were similar to those used by the National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA) (35
) for probable Alzheimer's disease. Three steps were used for diagnosis. First, the examining physician made a preliminary diagnosis. Second, all cases were reviewed independently by a neurologist, and a second preliminary diagnosis was made. In the event of agreement between the first and second diagnoses, this second diagnosis was considered final; in the event of disagreement, a third opinion was requested and the concordant diagnosis was accepted. Details of the clinical examination, diagnostic procedure, and primary results of data on the age- and sex-specific incidence of dementia have been presented elsewhere (36
).
Data collection
The baseline examination was conducted from October 1987 to December 1989. Arterial blood pressure was measured by using a mercury sphygmomanometer, with the subject in a seated position after a 5-minute rest (37
). A standard polymerase chain reaction procedure was used for APOE genotyping (38
, 39
), and the DNA was prepared from peripheral blood samples. Information regarding the medical history of each participant was derived from the computerized inpatient register, which covers all hospitals in the Stockholm area. Heart disease (myocardial infarction, cardiac dysrhythmia, and heart failure) and stroke were treated as two potential confounders.
Information on drug use, both prescription and nonprescription, was collected for the 2 weeks preceding the baseline interview (40
, 41
), and drug containers and prescription forms were inspected to verify the information. Antihypertensive drugs included all medicines potentially used to lower blood pressure (Anatomical Therapeutic Chemical (ATC) classification system (42
) codes C02, C03, and C07). For analysis, we first divided the whole sample into two groups according to use of antihypertensive medication. We then divided the whole sample into two groups by use of diuretics (ATC code C03), regardless of other antihypertensive medication. Finally, the sample was divided into three groups: the group receiving diuretic monotherapy, the group using other antihypertensive medications (ATC codes C02 and C07), and the group not using antihypertensive medications. Among those who participated in the first follow-up of the Kungsholmen Project (n = 1,310), the drugs used by more than 20 subjects at baseline included diuretics (bendroflumethiazide, hydrochlorothiazide, furosemide, spironolactone, amiloride hydrochloride), calcium channel antagonists (verapamil, nifedipine, diltiazem), and ß-blockers (metoprolol tartrate, propranolol hydrochloride, alprenolol hydrochloride, atenolol). Among them, bendroflumethiazide, furosemide, amiloride hydrochloride, and verapamil were used by more than 100 subjects.
Statistical analysis
Frequencies of variables between groups were examined by using the chi-square method. Incidence rates were calculated by dividing the number of events by the number of person-years of follow-up. The follow-up time for nondemented subjects was determined from the date of baseline interview to the date of follow-up examination or death. For demented subjects, half of this time was assumed. We used the Cox proportional hazards regression model to calculate the relative risks of developing dementia in relation to APOE genotypes, according to use of antihypertensive medication. Because of limited numbers, we treated *
2/*
4, *
3/*
4, and *
4/*
4 as a group that we labeled *
4, which was compared with *
3/*
3. We considered age (in years), sex (female vs. male), education (<8 vs.
8 years), systolic blood pressure (two dummy variables, <130 and >160 compared with 130160 mmHg), heart disease (yes vs. no), and stroke (yes vs. no) as covariates in the models. When age at dementia onset was used as the time scale in the Cox proportional hazards regression model, as suggested by Korn et al. (43
), very similar results were obtained. Therefore, this paper presents results from the models in which the follow-up time was used.
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RESULTS
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Among the 1,301 subjects who participated in the follow-up evaluation, 224 were diagnosed as demented (164 Alzheimer's disease, 41 vascular dementia, 19 other dementias). The mean follow-up interval for the cohort was 36.7 months, and the maximum was 63.1 months. Use of antihypertensive medication was related to a significantly reduced risk of all dementias (relative risk (RR) = 0.7, 95 percent confidence interval (CI): 0.5, 0.9) and Alzheimer's disease (RR = 0.6, 95 percent CI: 0.4, 0.8). APOE genotyping was available for 75.7 percent (n = 985) of the 1,301 subjects. Among those without APOE genotyping, compared with those with APOE genotyping, slightly more (not significant) subjects became demented during the follow-up period (all dementias, 19.6 vs. 16.4 percent; Alzheimer's disease, 13.3 vs. 12.4 percent).
Among the 985 subjects for whom APOE genotyping was available, 162 dementia cases (122 Alzheimer's disease, 40 vascular or other dementias) were identified after the 3-year follow-up. Compared with those who did not develop dementia, subjects who developed Alzheimer's disease were older (aged 83.2 (standard deviation, 4.9) years vs. aged 80.6 (standard deviation, 4.6) years; p <0.001), had less education (<8 years, 69.7 vs. 46.1 percent; p <0.001), were more likely to be female (88.5 vs. 73.0 percent; p <0.001), were more likely to have had a stroke (18.0 vs. 10.0 percent; p <0.001), and were less likely to use antihypertensive medication (34.4 vs. 44.7 percent; p = 0.03). More Alzheimer's disease patients than those without dementia carried at least one APOE*
4 allele (36.9 vs. 27.5 percent; p = 0.03). All of these differences between patients with and without dementia remained significant when we adjusted for age by using logistic regression.
Subjects who used antihypertensive medication at baseline (n = 432) were more likely to be female (p = 0.002) and to have a history of heart disease (p <0.001) or stroke (p <0.001) than those not using antihypertensive medication (table 1). There were no significant differences in age, education, systolic blood pressure, or APOE genotypes between the two groups. The incidence of all dementias and of Alzheimer's disease was lower among subjects using versus not using antihypertensive medication. The adjusted relative risks of all dementias and Alzheimer's disease associated with use of antihypertensive medication were 0.6 (95 percent CI: 0.5, 0.9) and 0.5 (95 percent CI: 0.3, 0.8), respectively.
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TABLE 1. Characteristics of subjects, according to use of antihypertensive medication, in a community-based population aged 75 years and older, first follow-up of the Kungsholmen Project, Stockholm, Sweden, 19901992
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The APOE*
4 allele, compared with *
3/*
3, significantly increased the risk of dementia (RR = 1.5, 95 percent CI: 1.1, 2.1) and Alzheimer's disease (RR = 1.7, 95 percent CI: 1.2, 2.5). The population attributable risks (44
) of APOE*
4 were 12.9 percent for all dementias and 16.4 percent for Alzheimer's disease. Among those not using antihypertensive medication, *
4 carriers had a twofold higher risk of dementia and Alzheimer's disease compared with *
3/*
3 carriers (table 2). Carriers of the *
2 allele were at a lower risk of dementia, but this finding was not significant. Among those who used antihypertensive medication, no significant difference was found in the incidence of dementia and Alzheimer's disease between *
4 carriers and *
3/*
3 carriers (table 2).
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Table 2. Incidence, * number of cases, relative risks (RR), and 95% confidence intervals (CI) of dementias, according to apolipoprotein E genotypes and use of antihypertensive medication, first follow-up of the Kungsholmen Project, Stockholm, Sweden, 19901992
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The simultaneous effect of APOE*
4 and antihypertensive medication was examined further by considering, as a reference group, all persons who did not carry the *
4 allele and did not use antihypertensive medication (table 3). The risk of dementia and Alzheimer's disease associated with the APOE*
4 allele differed according to use of antihypertensive medication. We then divided the entire sample into three groups according to APOE genotypes. A significantly reduced risk of dementia associated with use of antihypertensive medication was found for APOE*
4 carriers only: the relative risks were 0.4 (95 percent CI: 0.2, 0.7) for all dementias and 0.3 (95 percent CI: 0.2, 0.7) for Alzheimer's disease.
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TABLE 3. Relative risks (RR)* and 95% confidence intervals (CI) of dementia, according to apolipoprotein E * 4 allele and use of antihypertensive medication, first follow-up of the Kungsholmen Project, Stockholm, Sweden, 19901992
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The same analyses were performed for subjects who had a baseline MMSE score of
23 (n = 938) and for those who participated in the follow-up clinical examination (n = 840). All of these analyses produced very similar results concerning the relation between APOE*
4 and dementia. There were no significant differences in baseline use of estrogens, nonsteroidal anti-inflammatory drugs, and salicylic acid agents between those who used and did not use antihypertensive medication. Inclusion of the variables for these drugs in analyses did not change our results significantly.
Among those subjects using antihypertensive medication, 80 percent used diuretics (55 percent with diuretic monotherapy). Among those using other antihypertensive drugs, about 50 percent used calcium channel antagonists and 45 percent used ß-blockers. Table 4 shows the results when the population was divided into two groups by use of diuretics, regardless of other antihypertensive medications. The population was then divided into three groups, the group receiving diuretic monotherapy, the group using other antihypertensive medications, and the group not using any antihypertensive medication. APOE*
4 carriers on diuretic monotherapy (n = 242) had relative risks of 0.9 (95 percent CI: 0.4, 2.0) for all dementias and 0.7 (95 percent CI: 0.3, 1.9) for Alzheimer's disease; those carriers using other antihypertensive medications (n = 190) had relative risks of 1.0 (95 percent CI: 0.5, 2.4) for all dementias and 1.7 (95 percent CI: 0.6, 5.3) for Alzheimer's disease.
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TABLE 4. Relative risks (RR)* and 95% confidence intervals (CI) of dementia, according to apolipoprotein E genotypes and use of diuretics, first follow-up of the Kungsholmen Project, Stockholm, Sweden, 19901992
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DISCUSSION
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In this large community-based cohort of persons aged 75 years and older, a significantly increased incidence of dementia and Alzheimer's disease was associated with the APOE*
4 allele among those not using antihypertensive medication at baseline; this increased incidence was not found among those who used antihypertensive medication. The latter group had a significantly decreased risk of dementia and Alzheimer's disease. These results were derived from the analyses in which age, sex, education, systolic blood pressure, heart disease, and stroke were considered.
Our study may shed new light on the relation between APOE*
4 and Alzheimer's disease. First, the large-scale, prospective data from a general population confirm the link between APOE*
4 and Alzheimer's disease. However, we estimated that only 12.9 percent of incident dementia cases and 16.4 percent of Alzheimer's disease cases could be accounted for by the *
4 allele. This result is very similar to that of a recent study concluding that 13.5 percent of incident Alzheimer's disease may be explained by *
4 (24
). The lower population attributable risk could be due to the decreased relative risk of Alzheimer's disease associated with the APOE*
4 allele after age 70 years (45
, 46
) and to the lower frequency of the APOE*
4 allele in the very old. In a meta-analysis, the risk of Alzheimer's disease associated with the APOE*
4 allele increased until age 60 years in *
3/*
4 and *
4/*
4 carriers and until age 70 years in *
2/*
4 carriers, and it diminished thereafter (14
). Second, our finding of the lack of a significant association between *
4 and Alzheimer's disease among those using antihypertensive medication supports a previous view that the effect of the APOE*
4 allele is not uniform or is modifiable, as suggested in several studies (25
27
). Third, antihypertensive medication use significantly decreased the incidence of dementia; the effect was more pronounced in those subjects with the APOE*
4 allele. The probable explanation for these results is that antihypertensive medication can significantly reduce the number of cerebrovascular events or lesions now believed to be important in the pathogenesis of both Alzheimer's disease and vascular dementia, and that there may be an interaction between cerebrovascular disease and APOE*
4 on dementia (47
, 48
). A recent clinical trial showed that antihypertensive treatment reduced the incidence of dementia by 50 percent (49
).
It is unlikely that the lower risk associated with use of antihypertensive medication was due to the potential protective effect of the *
2 allele (50
), as we found no differences in the frequencies of APOE genotypes between the two groups. If we assume that *
4 carriers using antihypertensive medication have the same risk of Alzheimer's disease as *
4 carriers not using antihypertensive medication, there would be no difference in the incidence of Alzheimer's disease between the two groups.
Subjects who use antihypertensive medication may differ in many aspects, including genetic factors, from those who do not use these drugs. Use of these drugs may just be a marker of an unknown factor or factors that can modify the effect of APOE*
4 and thereby reduce the incidence of Alzheimer's disease. However, there were no significant differences in baseline use of estrogens, nonsteroidal anti-inflammatory drugs, and salicylic acid agents between those who did and did not use antihypertensive medication. We also examined several other drugs, including other cardiovascular agents, and did not find that these drugs could account for the results.
In this study, the diagnosis of dementia was based on clinical data. No neuroimaging and/or pathologic data were available for the diagnosis of dementia and Alzheimer's disease. We could not distinguish definite Alzheimer's disease from probable Alzheimer's disease. Misclassification of dementia and dementia types may have occurred, leading to decreased power in detecting small effects. However, it is unlikely that differential misclassification occurred. In fact, had we classified more Alzheimer's disease patients as non-Alzheimer's disease patients in the group that used antihypertensive medication, because they were more likely to have had heart disease and stroke, we would have expected an excess of non-Alzheimer's disease cases to be associated with *
4 in the group. However, this was not the case. Importantly, the results were consistent for all dementias and for Alzheimer's disease.
The first limitation of this study is that about 24 percent of eligible subjects did not undergo APOE genotyping. Although the dropout rate was lower in this study than in previous studies, caution is necessary in interpreting the results. However, there was no significant difference in the cumulative incidence of dementia and Alzheimer's disease between those with and without APOE genotyping. Also, among those subjects without APOE genotyping, use of antihypertensive medication was associated with a lower incidence of dementia and Alzheimer's disease, although this finding was not significant. The second limitation is use of a two-phase design in the initial survey of prevalent cases. We estimated that 26 patients might have been missing from the screening test (51
) and were thereby possibly included in the cohort of 1,301 participants in the follow-up assessment. This problem may have led to an overestimation of the total incidence of dementia. However, there is no reason to think that it may have significantly biased our results of the relation between APOE*
4 and Alzheimer's disease.
The third limitation is that the groups using antihypertensive medication were relatively small. This problem might have reduced power to detect the difference in risk between *
3/*
3 and *
4 and resulted in the wide range of confidence intervals that occurred. Some confidence intervals overlapped between *
4 carriers who did and did not use antihypertensive medication if different references were used (table 2). However, there was little overlap if the same reference was used (tables 3 and 4). Furthermore, among those using antihypertensive medication, 80 percent used diuretics. Although all results associated with use of antihypertensive medication were mostly due to use of diuretics, a similar trend for all dementias was also found with use of other antihypertensive medications. However, it seemed that use of other antihypertensive medications mainly affected the relation between APOE*
4 and vascular or other dementias. Alternatively, this finding could have been due to misclassification between types of dementia in the group using other antihypertensive drugs. The fourth limitation is the lack of information on duration of drug use. Generally, this limitation may have decreased the power to detect a given association or led to an underestimation of the association. We performed Cox regression analyses by using age at onset as the time scale, which produced similar results. Finally, unlike a clinical trial, our study was not designed to specifically assess the effects of antihypertensive medication. In our cohort, the group using antihypertensive medication may have differed in many ways from the group not using antihypertensive medication. Although we adjusted for a number of variables, including drugs that have been reported to protect against Alzheimer's disease, we cannot rule out the possibility that our results were biased by factors that we did not examine.
In conclusion, our large-scale prospective data support the view that the APOE*
4 allele is an important risk factor for late-onset dementia and Alzheimer's disease. However, this allele may account for only less than 20 percent of incident cases in people aged 75 years and older. Furthermore, a significant association between the APOE*
4 allele and dementia or Alzheimer's disease was found only among those not using antihypertensive medication (80 percent used diuretics). Use of these drugs was related to a significantly reduced incidence of dementia and Alzheimer's disease, which was more pronounced among APOE*
4 carriers. Further studies are needed to clarify whether these drugs, especially diuretics, can modify the effect of the APOE*
4 allele. At this time, antihypertensive drugs should not be prescribed to treat or prevent dementia.
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ACKNOWLEDGMENTS
|
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This study was supported by grants from the Swedish Medical Research Council, the Swedish Council for Social Research, the Swedish Municipal Pension Institute, the National Corporation of Swedish Pharmacies' Fund for Research and Studies in Health Economics and Social Pharmaceutics, the Torsten and Ragnar Söderbergs Foundation, and the Foundation for Medical Research (Stiftelsen Hjälp till Medicin Forskning).
The authors thank all Kungsholmen Project workers for collecting and managing the data. They also thank Lena Lilius, Benita Engvall, and Inga Volkmann for their invaluable technical assistance.
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NOTES
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Reprint requests to Dr. Zhenchao Guo, Stockholm Gerontology Research Center, Box 6401, S-113 82 Stockholm, Sweden (e-mail: Li.Zhu{at}cnsf.ki.se).
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Received for publication July 8, 1999.
Accepted for publication March 31, 2000.