Context Laboratory findings have suggested that oxidative stress may contribute
to the pathogenesis of Alzheimer disease. Therefore, the risk of Alzheimer
disease might be reduced by intake of antioxidants that counteract the detrimental
effects of oxidative stress.
Objective To determine whether dietary intake of antioxidants is related to risk
of Alzheimer disease.
Design and Setting The Rotterdam Study, a population-based, prospective cohort study conducted
in the Netherlands.
Participants A total of 5395 participants who, at baseline (1990-1993), were aged
at least 55 years, free of dementia, and noninstitutionalized and had reliable
dietary assessment. Participants were reexamined in 1993-1994 and 1997-1999
and were continuously monitored for incident dementia.
Main Outcome Measures Incidence of Alzheimer disease, based on Diagnostic
and Statistical Manual of Mental Disorders, Revised Third Edition (DSM-III-R) criteria and National Institute of Neurological
and Communicative Disorders and Stroke and Alzheimer Disease and Related Disorders
Association (NINCDS-ADRDA) criteria, associated with dietary intake of beta
carotene, flavonoids, vitamin C, and vitamin E.
Results After a mean follow-up of 6 years, 197 participants developed dementia,
of whom 146 had Alzheimer disease. When adjustments were made for age, sex,
baseline Mini-Mental State Examination score, alcohol intake, education, smoking
habits, pack-years of smoking, body mass index, total energy intake, presence
of carotid plaques, and use of antioxidative supplements, high intake of vitamin
C and vitamin E was associated with lower risk of Alzheimer disease (rate
ratios [RRs] per 1-SD increase in intake were 0.82 [95% confidence interval
{CI}, 0.68-0.99] and 0.82 [95% CI, 0.66-1.00], respectively). Among current
smokers, this relationship was most pronounced (RRs, 0.65 [95% CI, 0.37-1.14]
and 0.58 [95% CI, 0.30-1.12], respectively) and also was present for intake
of beta carotene (RR, 0.49 [95% CI, 0.27-0.92]) and flavonoids (RR, 0.54 [95%
CI, 0.31-0.96]). The associations did not vary by education or apolipoprotein
E genotype.
Conclusion High dietary intake of vitamin C and vitamin E may lower the risk of
Alzheimer disease.
Several findings suggest that oxidative stress may play an important
role in the pathogenesis of Alzheimer disease. First, the brains of patients
with Alzheimer disease contain lesions that are typically associated with
exposure to free radicals.1,2
In addition, oxidative stress in brains of Alzheimer patients is indicated
by elevated cerebral levels of endogenous antioxidants that scavenge free
radicals.3 Moreover, in vitro studies suggest
that exogenous antioxidants reduce the toxicity of β-amyloid in brains
of Alzheimer patients.1,2 Based
on these findings, it has been hypothesized that antioxidants from food may
reduce the risk of Alzheimer disease.
A previous randomized controlled trial4
found that patients taking vitamin E supplement had a slower progression of
Alzheimer disease than patients taking placebo. It is thus possible that high
intake of antioxidants may also prevent the onset of dementia, because antioxidants
may reduce neuronal loss due to oxidative damage.1,2
Two studies examined the longitudinal relationship between antioxidants
from supplements and risk of Alzheimer disease.5,6
These studies found conflicting results: vitamin C supplement use was related
to lower risk of Alzheimer disease in one study,5
whereas the other found no association for combined use of vitamin C and vitamin
E supplements.6 However, studies on supplement
use are prone to bias, because people who use supplements may also have more
health problems7 and more health-seeking behavior.8 In addition, use of supplements is generally of short
duration.
To date, only 1 study has prospectively examined the association between
dietary antioxidants and risk of dementia,9
and found a reduced risk of dementia associated with increased intake of flavonoids.
We investigated whether intake of a range of antioxidants from food, namely
beta carotene, flavonoids, vitamin C, and vitamin E, was associated with the
risk of Alzheimer disease, using data from a population-based cohort study.
The Rotterdam Study is a population-based, prospective cohort study
of the frequency and determinants of neurological, cardiovascular, locomotor,
and ophthalmologic diseases in elderly persons. The medical ethics committee
of the Erasmus University Rotterdam approved the study. The eligible population
comprised all inhabitants of a suburb in Rotterdam, the Netherlands, who were
aged at least 55 years (n = 10 275). Of these, 7983 subjects (response
rate, 78%) gave their written informed consent and participated in the study.10
During the baseline examination (1990-1993), a research assistant interviewed
participants in their homes and obtained information on current and past health,
medication, lifestyle, and risk factors for chronic diseases. In addition,
participants visited the research center twice for baseline clinical examinations.
Follow-up examinations took place in 1993-1994 and 1997-1999. The total cohort
was continuously monitored for mortality and major morbidity.
Diagnosis of Dementia and Alzheimer Disease
Case-finding and diagnostic procedures for dementia and Alzheimer disease
have been described in detail.11 At baseline
visit and both follow-up examinations, a 3-stage protocol was used. Participants
were cognitively screened with the Mini-Mental State Examination (MMSE)12 and the Geriatric Mental State schedule (GMS) organic
level.13 If subjects scored lower than 26 on
the MMSE or higher than 0 on the GMS organic level, the Cambridge Examination
of Mental Disorders in the Elderly (CAMDEX)14
was administered. The CAMDEX also included an informant interview. Finally,
participants in whom dementia was suspected were examined by a neurologist
and neuropsychologist and, if possible, had magnetic resonance imaging of
the brain. In addition, the total cohort was continuously monitored for incident
dementia cases through computerized linkage between the study database and
computerized medical records from general practitioners and the Regional Institute
for Outpatient Mental Health Care.11 The diagnoses
of dementia and Alzheimer disease were based on Diagnostic
and Statistical Manual of Mental Disorders, Revised Third Edition (DSM-III-R)15 criteria and
the National Institute of Neurological and Communicative Disorders and Stroke
and Alzheimer Disease and Related Disorders Association (NINCDS-ADRDA) criteria,16 respectively, and were made by a panel of a neurologist
(J.C.V.S.), neuropsychologist, and research physicians (M.J.E. and A.R.) who
reviewed all existing information.11 Follow-up
with respect to dementia was virtually complete (99.9%).
Dietary intake was assessed at baseline by means of a 2-stage protocol.
Participants first indicated on a checklist all foods and drinks they had
consumed at least twice a month during the preceding year. The checklist also
contained questions on dietary habits, use of supplements, and prescribed
diets. At the second baseline visit to the research center, the participants
were interviewed on the basis of the completed checklist. This interview was
performed by a dietitian, who used an extensive, validated semiquantitative
food-frequency questionnaire (SFFQ).17,18
The SFFQ data were converted to energy intake and nutrient intake using the
computerized Dutch Food Composition Table.19,20
We used data on intake of the antioxidants beta carotene, flavonoids, vitamin
C, and vitamin E. Important sources of beta carotene are kale, carrots, broccoli,
and spinach. Flavonoids are found in cranberries, green and black tea, and
pulses. Vitamin C is mainly found in citrus fruits, kiwi, sprouts, broccoli,
and cabbage. Important sources of vitamin E are grain, nuts, milk, and egg
yolk. Daily dietary intake of the antioxidants from food was calculated in
milligrams.
During the baseline home interview, participants were asked about their
highest attained level of education and their smoking habits. At the visits
to the research center, which were part of the baseline clinical examination,
the MMSE was performed, height and weight were measured, and intake of alcohol,
total energy, antioxidative supplements, total fat, and saturated fat were
indicated on the SFFQ. Furthermore, ultrasonography of the carotid arteries
was performed21 and blood samples were drawn.
Level of education was categorized in 3 groups: low (primary education
only); intermediate (lower vocational or general education); and high (intermediate
or higher vocational or general education, college, or university). Smoking
habits were categorized as never, former, and current smoking. For former
and current smokers, the number of pack-years was defined as the number of
years of smoking times the number of cigarettes smoked daily divided by 20.
Alcohol intake was categorized in 5 groups: no alcohol intake, less than 1
drink per week, between 1 drink per week and 1 drink per day, between 1 and
4 drinks per day, and 4 drinks per day or more. Subjects who used beta carotene
supplement, flavonoid supplement, vitamin C supplement, vitamin E supplement,
or multivitamin supplement were classified as users of antioxidative supplements;
all others were classified as nonusers. Intake of total and saturated fat
was expressed in grams per day. Atherosclerotic plaques in the carotid arteries
were defined as a focal widening relative to adjacent segments, with the protrusion
into the lumen composed of either only calcified deposits or a combination
of calcification and noncalcified material.21
The presence of carotid plaques was assessed at 6 different locations: the
common carotid artery, carotid bifurcation, and internal carotid artery at
both left and right side.21 Subsequently, according
to the number of locations with plaques, 4 categories were made: plaques at
0, 1 to 2, 3 to 4, and 5 to 6 locations. Apolipoprotein E (APOE) genotype was assessed on coded DNA samples using polymerase chain
reaction without knowledge of the dementia diagnosis.22
We dichotomized APOE genotype into presence or absence
of the apolipoprotein E*4 (APOE*4) allele.
At the baseline clinical examination, 7525 participants of the Rotterdam
Study were screened for dementia. Dementia was diagnosed in 482 participants,
resulting in 7043 participants who were free of dementia at baseline. Of these,
we excluded 602 participants from dietary assessment for 2 reasons. First,
dietary intake was not assessed in 125 participants who had questionable cognitive
status (<80 CAMDEX score), because the participants might provide unreliable
answers regarding their food patterns. Second, we excluded nursing home residents
(n = 477), because their current diet may not reflect dietary habits in the
past. Thus, 6441 participants were eligible for dietary assessment. Of these,
reliable dietary data were missing in 1046 participants (16%) for several
reasons. First, due to logical inconsistencies in dietary interviews, 212
participants were excluded. Second, because the SFFQ was administered at the
second baseline visit to the research center, participants who did not complete
the second visit did not have dietary assessment (n = 192). Finally, 642 participants
did not have dietary data due to logistic reasons. Thus, the sample comprised
5395 participants who had normal cognition, lived independently, and had reliable
dietary assessment at baseline.
Eligible participants without dietary data were somewhat older (2.6
years) compared with participants with dietary data, a somewhat lower percentage
(4%) were women and a higher percentage had only primary education (7%). Smoking
habits and body mass index were similar across the 2 groups.
To assess the relationship between intake of antioxidants from food
and cognitive function at baseline, we performed linear regression analysis
with antioxidant intake as the dependent variable and baseline MMSE score
as independent variable. We adjusted for age, sex, alcohol intake, education,
smoking habits, pack-years of smoking, body mass index, total energy intake,
presence of carotid plaques, and use of antioxidative supplements.
To determine whether the incidences of Alzheimer disease differed between
the sample and the eligible population with missing dietary data, we performed
a Cox proportional hazards regression analysis with adjustment for age, sex,
and education.
We evaluated the associations of daily dietary intake of antioxidants
with risk of Alzheimer disease using Cox proportional hazards regression analysis.
Intake of antioxidant was represented in the model either by a linear term
or by 2 dummy variables representing the 2 highest tertiles. In the first
case, the regression coefficient was expressed per SD increase. Standard deviations
and tertiles of the respective intake of antioxidants were based on the distribution
of the complete sample (N = 5395). All analyses were initially adjusted for
age and sex. Subsequently, additional adjustments were made for baseline MMSE
score and alcohol intake, respectively. In another model, adjustments were
simultaneously made for the following confounders: age, sex, baseline MMSE
score, alcohol intake, education, smoking habits, pack-years of smoking, body
mass index, total energy intake, presence of carotid plaques, and use of antioxidative
supplements. Missing values were indicated by a missing indicator for categorical
variables. For continuous variables, we replaced missing values by the mean
or median of the study population, depending on the distribution. Age was
used as the timescale in the model. Entry time was defined as age at study
entry. Participants were followed up until onset of Alzheimer disease, onset
of other types of dementia, death, or end of study, whichever came first.
Age at onset of Alzheimer disease and other types of dementia was determined
as the midpoint between the age of participant last known to be at risk of
dementia and age at diagnosis of dementia.
To avoid confounding by supplement use, we also performed the analyses
excluding users of antioxidative supplements (n = 639). We investigated the
combined effect of antioxidant intake from food and from supplements in an
analysis in which users of an antioxidative supplement were added to the highest
tertile of the corresponding antioxidant intake from food. For instance, users
of beta carotene supplements were added to the highest tertile of beta carotene
intake from food. Users of multivitamins were added to the highest tertile
of each of the 4 antioxidant intakes from food, because multivitamins can
contain more than 1 antioxidant and because multivitamins generally contain
higher amounts of antioxidants than antioxidant intake from food.
All rate ratios (RRs) in the subsequent analyses were calculated in
1-SD increases in intake of antioxidants after adjustment for age, sex, baseline
MMSE score, alcohol intake, education, smoking habits, pack-years of smoking,
body mass index, total energy intake, presence of carotid plaques, and use
of antioxidative supplements. Because low intake of total fat and saturated
fat is related to both high intake of antioxidants23
and risk of dementia,24 the analyses were repeated
with additional adjustments for total fat intake and saturated fat intake.
To examine possible effect modification by education, we performed stratified
analysis by educational level. Furthermore, because smoking increases the
load of free radicals and thus the extent of oxidative stress,25
we also performed the analyses within strata of smoking habits. Because the APOE*4 allele is an important risk factor for Alzheimer
disease26 and is related to oxidative stress,2 we also performed the analyses within strata of APOE*4 allele. In this latter analysis, 226 subjects, of
whom no APOE genotype was available, were excluded.
Finally, to ensure that observed associations were not the result of
changing dietary habits due to subclinical dementia, we excluded all subjects
with less than 2 years of follow-up (n = 212). Statistical interactions were
tested by adding a product term to the unstratified model. Because the antioxidative
effects of vitamin C and vitamin E might be synergistic,27
statistical interaction was also tested between vitamin C and vitamin E intake.
All data analyses were performed using SAS statistical software version 6.12
(SAS Institute Inc, Cary, NC). We used a significance level of .05 based on
a 2-sided test.
Table 1 presents the baseline
characteristics of the sample. At baseline, the mean age was 67.7 years, the
majority (59%) were women (n = 3183), 23% (n = 1257) were current smokers,
12% (n = 639) used antioxidative supplements, and 28% (n = 1426) carried at
least 1 APOE*4 allele.
Intake of flavonoids was significantly greater with a higher baseline
MMSE score; every point increase on the MMSE-score intake of flavonoids increased
with 0.24 mg/d (regression coefficient, 0.24 [95% confidence interval {CI},
0.031-0.45]). Intake of beta carotene, vitamin C, and vitamin E were not associated
with baseline MMSE score (regression coefficient, 0.009; 95% CI, −0.004
to 0.022 for beta carotene; −0.19; 95% CI, − 1.12 to 0.75 for
vitamin C; and 0.059; 95% CI, − 0.034 to 0.15 for vitamin E).
After baseline dietary assessment, participants were followed up for
an average of 6 years (32 341 person-years of follow-up). During this
period, 197 participants developed dementia, of whom 146 had Alzheimer disease
(134 without and 12 with cerebrovascular disease). The incidence of Alzheimer
disease did not differ between the sample and the eligible population with
missing data on dietary intake; when adjustments were made for age, sex, and
education, the RR for subjects with dietary data compared with subjects without
dietary data was 0.75 (95% CI, 0.54-1.05).
Table 2 shows the RRs of
Alzheimer disease associated with intake of antioxidants per SD increase.
When adjustments were made for age and sex; age, sex, and baseline MMSE score;
or age, sex, and alcohol intake, intake of beta carotene, flavonoids, or vitamin
E was not related to risk of Alzheimer disease. High intake of vitamin C had
a borderline significant association with risk of Alzheimer disease in all
models. When additional adjustments were made for education, smoking habits,
pack-years of smoking, body mass index, total energy intake, presence of carotid
plaques, and use of antioxidative supplements, high intake of vitamin C was
significantly related to reduced risk of Alzheimer disease: the RR per SD
increase was 0.82 (95% CI, 0.68-0.99). For vitamin E, the inverse relationship
was of borderline significance (RR, 0.82; 95% CI, 0.66-1.00). The results
for beta carotene and flavonoids did not change after extensive adjustment.
Exclusion of supplement users did not substantially alter the results (Table 2).
Table 3 presents RRs of
Alzheimer disease across tertiles of antioxidant intake. When adjustments
were made for age and sex only, antioxidant intake was not related to Alzheimer
disease. However, in the fully adjusted model, higher intake of vitamin E
was significantly associated with lower risk of Alzheimer disease, and higher
intake of vitamin C had a borderline significant association with lower risk
of Alzheimer disease. For vitamin C, the RR of highest compared with lowest
tertile was 0.66 (95% CI, 0.44-1.00) and for vitamin E, it was 0.57 (95% CI,
0.35-0.91). Beta carotene and flavonoids were not associated with Alzheimer
disease across tertiles of intake. Adding supplement users to the highest
tertile of dietary intake did not change the results for any of the 4 antioxidants.
When we performed the analyses with additional adjustments for total fat intake
or saturated fat intake, respectively, the results were similar.
Table 4 shows the relationship
between antioxidant intake and risk of Alzheimer disease across strata of
education. The risk of Alzheimer disease for beta carotene, flavonoids, and
vitamin E did not significantly differ across strata of education and none
of the statistical interaction terms was significant. High vitamin C intake
was related to a lower risk of Alzheimer disease within participants with
intermediate level of education. However, the statistical interaction was
not significant.
Table 5 presents associations
of antioxidants with risk of Alzheimer disease across strata of smoking habits.
The risk of Alzheimer disease associated with higher intake of vitamin C and
vitamin E was lower in current smokers compared with former and never smokers,
but the respective statistical interaction terms were not significant. For
beta carotene, statistical interaction with smoking habits was significant
and of borderline significance for flavonoids: high intake of beta carotene
and flavonoids was associated with reduced risk of Alzheimer disease in current
smokers.
Table 6 shows the relationship
between intake of antioxidants and risk of Alzheimer disease across strata
of APOE*4 allele. In participants with at least 1 APOE*4 allele, higher intake of 3 of the 4 antioxidants
(except for flavonoids) was associated with somewhat lower risk of Alzheimer
disease compared with the risk of Alzheimer disease in participants without
an APOE*4 allele. However, statistical interactions
of intake with APOE genotype were not significant.
We observed no statistical interaction between vitamin C intake and
vitamin E intake with Alzheimer disease. Finally, restriction of the analyses
to participants with at least 2 years of follow-up did not substantially change
the results: RRs per SD increase in intake were 0.80 (95% CI, 0.61-1.06) for
beta carotene, 0.95 (95% CI, 0.77-1.18) for flavonoids, 0.82 (95% CI, 0.66-1.03)
for vitamin C, and 0.85 (95% CI, 0.66-1.08) for vitamin E.
We found that high intake of vitamin C and vitamin E from food may be
associated with a lower incidence of Alzheimer disease after a mean follow-up
period of 6 years. The risk reduction associated with intake of all 4 antioxidants
was consistently largest for current smokers, although the differences in
RRs for beta carotene and flavonoids between smokers and nonsmokers were of
marginal statistical significance, while those for vitamin C and vitamin E
were not significant. Nonetheless, these associations persisted after controlling
for a number of potentially confounding variables, such as use of vitamin
supplements, education, and alcohol use.
Before interpreting the results, some methodological issues should be
considered. First, although we adjusted for a large number of potential confounding
factors, such as age, sex, alcohol intake, education, smoking habits, and
use of supplements, the possibility of residual confounding can never be completely
excluded from an observational study. Second, we cannot completely exclude
the possibility of subclinical dementia at time of dietary assessment, which
may have led to changes in dietary reporting or dietary habits. To minimize
this potential source of confounding, we excluded cognitively impaired subjects
and adjusted for baseline MMSE score. In addition, we also recomputed the
results after excluding the first 2 years of follow-up, which did not alter
the results. Thus, we do not think that our results were affected by the presence
of subclinical dementia. Third, because dietary assessment was performed only
once, it may not have precisely reflected the participants' long-term dietary
habits, which are more likely to influence disease risk. However, this may
have led to dilution and thus an underestimation of the associations of antioxidants
with risk of Alzheimer disease. Finally, we cannot completely rule out the
possibility of confounding by use of dietary supplements. Although only a
small number of participants reported supplement use, we do not have data
on duration of use and dosage of the antioxidative supplements. Nonetheless,
our results were unchanged after either excluding supplement users from the
analysis or after controlling for supplement use, suggesting that our results
are not confounded by supplement use.
The strengths of our study are its prospective design and the population-based
setting. Another important feature is that follow-up with dementia diagnosis
was virtually complete, and thus there was no resulting selection bias.
Several studies have examined the relationship between Alzheimer disease
and intake of vitamin C and vitamin E from supplements.4-6,28,29
A case-control study28 and a prospective study
in men6 showed no association between supplement
intake and Alzheimer disease. Another prospective study found that use of
supplements, in particular vitamin C but not vitamin E, was associated with
a lower risk of Alzheimer disease.5 The only
controlled trial of supplemented antioxidant intake and Alzheimer disease
was performed within patients who were already diagnosed with Alzheimer disease.4 This study reported that patients who took vitamin
E supplements had a slower progression of the disease than patients who took
placebo.
Results on supplement use and risk of dementia, however, may not be
comparable with results on intake from food for several reasons. First, supplement
users are generally a select group of persons with either health problems7 or more health-seeking behaviors.8
Therefore, associations between supplement use and Alzheimer disease may be
biased. Second, intake of antioxidants from food reflects long-term intake,
whereas supplement intake is generally of shorter duration. If duration of
antioxidant intake is more important than the dose, high-lifetime intake from
food would more likely be related to Alzheimer disease than short-term high
intake by supplements. Finally, antioxidants from food are always simultaneously
consumed with other nutrients in a certain proportion, whereas antioxidants
from supplements are consumed in a very high dose either with or without other
substances. This might lead to differences in absorption or biological activity
between antioxidants from food and antioxidants from supplements, though little
is yet known on these issues.30
Previously, the relationship between intake of flavonoids from food
and risk of dementia has been studied.9 This
prospective study found that high flavonoid intake was significantly associated
with a lower risk of dementia. However, the response rate for dietary assessment
was relatively low, only a small part of the study population underwent a
detailed dietary assessment, and confounding or effect modification by smoking
was not examined.
In our study, risk of Alzheimer disease associated with vitamin C and
vitamin E was lowest in current smokers and beta carotene, and flavonoids
seemed inversely related to Alzheimer disease in current smokers only. Because
smoking itself is associated with increased risk of Alzheimer disease,31 high antioxidant intake may partly counteract the
excess risk of Alzheimer disease for smokers. This is supported by the finding
of smokers' increased load of free radicals,25
which may be reduced by antioxidants.
Several biological mechanisms could explain a possible relationship
between antioxidants from food and Alzheimer disease. First, antioxidants
may decrease the level of oxidative stress in the brain. Antioxidants may
thereby reduce the amount of DNA damage, neuronal cell death, and the aggregation
of β-amyloid within the brain.1,2
These phenomena are all important neuropathological features in Alzheimer
disease; by preventing the genesis of these features, the risk of dementia
might be reduced. Second, because Alzheimer disease is associated with both
cardiovascular risk factors and atherosclerosis,32,33
and oxidative processes are involved in atherogenesis,34
high intake of antioxidants could also decrease the risk of dementia by reducing
the risk of atherosclerosis. However, because additional adjustment for carotid
plaques as a measure of atherosclerosis did not change our results, we doubt
that atherosclerosis is an important intermediary in the relationship between
antioxidants and risk of Alzheimer disease.
In conclusion, our results suggest that higher intake of vitamin C and
vitamin E from food may be associated with a lower risk of Alzheimer disease.
Whether this reflects a causal association remains to be elucidated. Randomized
controlled trials can help evaluate a possible causal relationship between
antioxidant intake from supplements and risk of Alzheimer disease. However,
the effect of short-term supplement use in clinical trials may not be comparable
with long-term intake from dietary sources. Therefore, more cohort studies
are needed to further investigate the relationship between dietary antioxidant
intake and risk of Alzheimer disease.
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