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Vitamin E and Cognitive Decline in Older Persons
Martha Clare Morris, ScD;
Denis A. Evans, MD;
Julia L. Bienias, ScD;
Christine C. Tangney, PhD;
Robert S. Wilson, PhD
Arch Neurol. 2002;59:1125-1132.
ABSTRACT
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Background Previous studies raise the possibility that antioxidants protect against
neurodegenerative diseases.
Objective To examine whether intake of antioxidant nutrients, including vitamin
E, vitamin C, and carotene, is associated with reduced cognitive decline with
age.
Design Longitudinal population-based study conducted from September 17, 1993,
to November 20, 2000, with an average follow-up of 3.2 years.
Patients The patients were 2889 community residents, aged 65 to 102 years, who
completed a food frequency questionnaire, on average 18 months after baseline.
Main Outcome Measure Cognitive change as measured by 4 tests (the East Boston Memory Test,
which tests immediate and delayed recall; the Mini-Mental State Examination;
and the Symbol Digit Modalities Test) at baseline and 3 years for all participants,
and at 6 months for 288 randomly selected participants.
Results We used random-effects models to estimate nutrient effects on individual
change in the average score of the 4 cognitive tests. The cognitive score
declined on average by 5.0 x 10-2 standardized units
per year. There was a 36% reduction in the rate of decline among persons in
the highest quintile of total vitamin E intake (-4.3 x 10-2 standardized units per year) compared with those in the lowest
quintile (-6.7 x 10-2 standardized units per
year) (P = .05), in a model adjusted for age, race,
sex, educational level, current smoking, alcohol consumption, total calorie
(energy) intake, and total intakes of vitamin C, carotene, and vitamin A.
We also observed a reduced decline with higher vitamin E intake from foods
(P = .03 for trend). There was little evidence of
association with vitamin C or carotene intake.
Conclusion Vitamin E intake, from foods or supplements, is associated with less
cognitive decline with age.
INTRODUCTION
OXIDATIVE MECHANISMS may play important roles in neurodegenerative diseases,
such as Alzheimer disease1-3
and Parkinson disease,4 and in cellular processes
associated with aging.5-7
The brain is especially vulnerable to free radical damage because of its high
oxygen consumption rate, its abundance of easily peroxidized lipid membranes,
and the presence of relatively few antioxidant enzymes.6
Oxidative reactions induced by reactive oxygen species are thought to cause
the degeneration of neurons. Antioxidant nutrients, including vitamin E, vitamin
C, and carotene, counteract these processes by inhibiting lipid peroxidation,6, 8-9 the generation of reactive
oxygen species,10-11 apoptosis,10-12 mitochondrial dysfunction,11 cytotoxic damage to cell membranes,13
and oxidative damage to proteins14-16
and DNA.17-19
Oxidative processes and the intake of antioxidant nutrients may also
affect the rate of cognitive decline, but epidemiologic investigations20-21 of this issue have been limited.
In a clinical trial22 of patients with Alzheimer
disease, vitamin E supplementation delayed progression to institutionalization
but had no effect on cognitive decline. Whether dietary intake of antioxidants
can prevent cognitive decline earlier in the disease process is not known.
In this report, we describe the association between dietary antioxidants and
3-year change in cognitive function in a large biracial population.
PATIENTS AND METHODS
POPULATION
Study participants are from the Chicago Health and Aging Project (CHAP),
a longitudinal study of a geographically defined community on the south side
of Chicago.23 From September 17, 1993, to May
5, 1997, we conducted a complete census, followed by home interviews with
age-eligible residents that included cognitive testing. A total of 6158 residents
65 years and older participated (79% of eligible residents). Follow-up interviews
were conducted approximately 3 years later for 4320 participants (87% of the
4983 survivors), from January 8, 1997, to February 22, 2000. In addition,
729 randomly selected persons underwent cognitive testing 6 months after the
baseline interview. The Institutional Review Board of Rush-Presbyterian-St
Luke's Medical Center approved the study, and all participants gave written
consent.
Diet was assessed after baseline using a modified Harvard self-administered
food frequency questionnaire (FFQ)24 that measured
usual consumption during the past year of 139 food items and vitamin supplements.25 Of the 4276 persons with cognitive data at the 3-year
interview, 4226 (99%) completed the dietary questionnaire. We excluded 140
persons with incomplete or potentially invalid dietary data and 8 who were
not black or white. Because dietary changes can occur with the onset of illnesses
associated with dementia, we eliminated 1189 persons for whom FFQ completion
exceeded the a priori defined period of 2 years after baseline, leaving
2889 participants for analysis. For these participants, the FFQs were completed
a mean of 18 (SD, ±8) months after baseline and 21 (SD, ±8)
months before the 3-year follow-up. A third cognitive assessment was available
for 288 of these participants, of 729 tested at 6 months. (Of the remaining
sample, 160 died, 134 had incomplete or invalid dietary data, and 147 exceeded
the 2-year time restriction.) Compared with the analyzed group, unanalyzed
participants (36% of whom died before follow-up) were older and less educated,
had lower cognitive scores, and had lower intakes of vitamins E and C (Table 1).
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Table 1. Characteristics of CHAP Participants Including 1177 Who Were
Deceased Before Follow-up*
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COGNITIVE TESTS
Four cognitive tests were administered at each time point: the East
Boston Memory Test,26-27 which
involves immediate and delayed recall of a brief story; the oral form of the
Symbol Digit Modalities Test,28 a measure of
perceptual speed; and the Mini-Mental State Examination.29
Analysis of decline on individual tests is problematic because of floor and
ceiling effects and other sources of measurement error.30
In a previous factor analysis of the data, all 4 tests loaded on a single
factor in a principal components factor analysis, supporting the idea that
a global measure could adequately summarize performance on the 4 tests; a
global measure of cognitive function was formed by averaging the z scores of the 4 individual tests.23
We used this previously established approach in our analyses as well. We computed
the z scores at all time points based on the means
and SDs of the test scores of the entire population at the baseline interview
so that we could examine change in this global measure over time.
DIETARY ASSESSMENT
Daily intake of each dietary component was computed by multiplying the
nutrient content of the food item (from the Harvard nutrient database) by
reported frequency of intake, and summing over all food items. All nutrients
were calorie adjusted using the regression-residual method.31
In a validation study of 232 randomly selected CHAP participants, Pearson
product moment correlation coefficients between nutrient intakes measured
by the FFQ and the average of repeated 24-hour recalls were as follows: r = 0.67 for total vitamin E (r
= 0.41 without supplements) and r = 0.60 for total
vitamin C (r = 0.46 without supplements). The correlation
between total vitamin E intake from the FFQ and serum levels of  -tocopherol
among 56 of these participants was r = 0.63. For
all correlations, P<.001.
COVARIATES
Sex and race were recorded at the census and verified at the baseline
interview. Race questions and categories were those used by the 1990 US census.
Other nondietary covariates were obtained at the baseline interview, and included
age (computed from self-reported birth date and date of the baseline interview),
level of education (years of regular schooling), and current smoking ("Do
you smoke cigarettes now?"). Daily alcohol intake (in grams) was computed
from separate questions on the CHAP FFQ about usual consumption of beer, wine,
and other alcoholic liquor.
STATISTICAL ANALYSES
We used random-effects models32 in SAS
statistical software33 to examine the association
of nutrient intake with change in the global measure of cognitive function,
which was approximately normally distributed, at the baseline, 6-month, and
3-year evaluations. The random-effects model allows for within-person variability
in initial cognitive score and in slope of change, while simultaneously estimating
the linear effects of model covariates on overall level of cognitive score
across the 3 time points (covariate term) and on the rate of change in score
(covariate-time interaction term). Each random-effects model included terms
for time, the main effect term for each covariate, and interaction terms between
time and each covariate. Intakes of the antioxidant nutrients were modeled
in quintiles, with and without intake from vitamin supplements, using the
lowest quintile as the referent category. We used a multivariable model to
simultaneously control for factors potentially related to change in cognitive
function. Confounding by other dietary components was examined by adding continuous
log-transformed terms for these variables to the multivariable model. We examined
effect modification in separate models that included main effect terms from
the multivariable model; 2-way interaction terms between each pair of time,
the effect modifier, and the antioxidant nutrient (continuous); and a 3-way
interaction term between these variables. Model assumptions (eg, normality,
bivariate normality of the random effects, and homoscedasticity) were evaluated
using standard analytical and graphical techniques. P
values were 2 sided, and the type I error rate for statistical significance
() was .05.
RESULTS
Analyzed participants included 1594 black and 1295 white persons, aged
65 to 102 years (mean, 73.9 years), with a mean educational level of 12.5
years (SD, ±3.7 years). The average length of follow-up was 3.2 years
(range, 1.8-5.9 years). The median baseline global z
score was 39 x 10-2 standardized units per year (SU/y).
Cognitive scores declined, on average, by 5.0 x 10-2
SU/y; however, many participants (39%) experienced no change or even an improvement
in scores.
A higher intake of total vitamin E (from foods and supplements) was
associated with less change in cognitive score per year. In the age-adjusted
model, scores for persons in the lowest quintile of total vitamin E intake
declined by 6.5 x 10-2 SU/y (Table 2). The rate decrease for the fifth quintile was statistically
significant, as was the test for linear trend. The rate decreases in the upper
quintiles changed little after adjustment for age, race, sex, educational
level, current smoking, alcohol consumption, and total calorie (energy) intake.
Further adjustment for intakes of total vitamin A, carotene, and vitamin C
had little effect on the results. The rate for persons in the highest vitamin
E quintile (-4.3 x 10-2 SU/y) was lower by 2.4
x 10-2 SU/y compared with that among persons in the
lowest quintile (-6.7 x 10-2 SU/y), a statistically
significant 36% reduction (P = .05). The rate differences
for quintiles of total vitamin C intake were smaller than those for vitamin
E and were nonsignificant in the age-adjusted and multivariable models (Table 2). There was little or no evidence
of an association between carotene intake and cognitive decline. In the multivariable
model, the differences in the rates of cognitive change (x10-2 SU/y) from the lowest to highest quintiles of total carotene intake
were as follows: 0.0, 0.3, 1.1, 0.7, and 0.8 (P =
.77 for trend).
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Table 2. Difference in Annual Change in Cognitive Score by Quintile
of Total Vitamin Intake From Foods and Supplements*
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We observed a linear inverse association with cognitive decline in age-adjusted
analyses considering vitamin E intake from food sources only (Table 3). In this model, rates of decline decreased significantly
by 2.0 x 10-2 SU/y in the fourth quintile and by 2.1
x 10-2 SU/y in the fifth quintile compared with the
first. The rate differences did not change appreciably with adjustment for
other risk factors in the multivariable model, and were slightly increased
with additional adjustment for other antioxidant nutrients. The multivariable
model is presented in Figure 1.
Persons in the upper quintiles of intake had higher predicted baseline scores
than those in the lowest quintile. In addition, the rates of change in score
per year were smaller in quintiles 4 and 5 than in quintile 1. Rates of change
(x10-2) for quintiles 1 through 5 were as follows: -6.7, -5.1, -6.5, -4.6,
and -4.3, respectively (P = .02 for trend).
The protective effect remained when we adjusted for use of multivitamin and
vitamin E supplements in the multivariable model (P
= .04 for trend); however, neither multivitamin use (ß = -.9 x
10-2 SU/y; P = .20) nor vitamin
E supplement use overall (ß = 1.4 x 10-2 SU/y; P = .10) was associated with cognitive change. Further
investigation revealed that the vitamin E supplement users had significantly
less cognitive decline than the nonusers who had low food intake of vitamin
E, but no difference in decline from the nonusers with high food intake of
vitamin E (P = .04 for the interaction term between
supplement use and food intake, modeled continuously in the multivariable
model). There was no association between vitamin C intake from food sources
and change in cognitive function (Table
3). However, vitamin C supplement use was significantly associated
with less cognitive decline, by 1.8 x 10-2 SU/y (P = .03), in a multivariable model adjusted for quintiles
of vitamin C intake from foods and multivitamin use. We found no evidence
of interaction between the use of vitamin E and vitamin C supplements (ß
= .2 x 10-2 SU/y; P = .91)
in the multivariable model, although we had limited power to test this adequately.
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Table 3. Difference in Annual Change in Cognitive Score by Quintile
Vitamin Intake From Food Sources Only*
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Change in global cognitive score (averaged z
score) for persons in quintiles 1 to 5 of vitamin E intake from foods, based
on the multivariable model with antioxidant nutrients (see Table 3). The annual rates of change in cognitive score for quintiles
1 to 5 were as follows: -6.7, -5.1, -6.5, -4.6, and -4.3
x 10-2 standardized units per year, respectively. The
rates were significantly lower for persons in the fourth (P = .03) and fifth (P = .02) quintiles compared
with the rate for persons in the first quintile.
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As seen in Table 4, the
potential confounders were different for vitamin E supplement use and quintiles
of intake from foods. Vitamin E supplement users tended to have more years
of education and a higher intake of other antioxidant nutrients. The lowest
quintile group of vitamin E intake from foods had higher alcohol consumption
and more smokers. Black participants had a somewhat higher intake of vitamin
E from foods, but were less likely to use either vitamin E supplements or
multivitamins.
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Table 4. Baseline Characteristics of Persons According to Quintile
of Vitamin E Intake From Foods, of Multivitamin Users Only, and of Users of
Individual Vitamin E Supplements, Among 2889 Participants of the CHAP (1993-1997)*
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The association between cognitive change and total vitamin E intake
did not change appreciably in separate multivariable models adjusted for intake
of either total fat or different types of fat (polyunsaturated, monounsaturated,
and saturated). We also explored whether the associations with total intakes
of the antioxidant nutrients differed by level of age, sex, race, education,
smoking, alcohol intake, and analyzed dietary components. The only evidence
of effect modification was a marginally significant lower rate of cognitive
decline with high vitamin E intake among smokers compared with nonsmokers
(P = .08 in the multivariable model).
When we reanalyzed the data excluding persons with possible cognitive
impairment at baseline (Mini-Mental State Examination score, <25), the
association with total vitamin E intake was strengthened (a rate difference
of 3.6 x 10-2 SU/y in the fifth quintile compared with
the first; P = .003) in the multivariable model,
adjusting for other antioxidant nutrients. In a reanalysis without the time
restriction on FFQ completion (n = 4072), the vitamin E association was in
the protective direction but not statistically significant. The rate differences
(x10-2 SU/y) for quintiles 2 through 5 of vitamin E
intake from foods in the multivariable model, adjusted for other antioxidant
nutrients, were as follows: 0.5, -0.5, 1.1, and 1.3, respectively (P = .10 for trend).
COMMENT
Vitamin E intake from foods and supplements was associated with reduced
cognitive decline in this older biracial population. In contrast, there was
no association between cognitive decline and carotene intake, and limited
evidence for an association with vitamin C. The effects on cognitive decline
in the highest quintiles of vitamin E intake (total or from foods only) were
equivalent to a corresponding decrease in age of 8 to 9 years. The median
level of vitamin E intake (6.8 IU/d) for the lowest fifth of the CHAP population
was higher than previously reported by other US studies.34-37
This would seem to indicate that increasing vitamin E intake in the population
to at least the recommended levels of 18 to 22 IU/d would have important public
health implications.
We were able to detect small changes in cognitive function in the population
because of the many participants. In addition, the use of a combined measure
of 4 cognitive tests, and up to 3 points of cognitive assessment, provided
a reliable measure of cognitive change. The multiple points of cognitive assessment
allowed for the estimation of within-person changes in cognition, thus reducing
potential confounding from between-person differences in cognitive performance.
The fewer number of participants with a third cognitive assessment may have
resulted in less precise but unbiased estimates of the rates of cognitive
change.
The fact that associations were observed for food and supplement sources
of intake strengthens the inference that vitamin E is associated with reduced
cognitive decline. However, the many participants eliminated from the analyses
and the assessment of diet midway between the cognitive assessments make a
causal interpretation more tenuous. We excluded participants from the analyses
whose dietary assessments were 2 years after baseline because dietary
behaviors can change with onset of conditions and diseases associated with
cognitive decline.38-39 Such bias
due to dietary changes may explain the weakened vitamin E effect in the analyses
of all participants, although it is also possible that the true effect is
smaller than that observed with the exclusion of participants with more cross-sectional
assessments of diet. We also observed secular changes in the use of vitamin
E supplements as the survey progressed; 9% of the participants who completed
the FFQ in 1994 reported taking a vitamin E supplement compared with 19% of
those who completed the FFQ in 1997. Recent supplement use could have weakened
the observed association if the increase occurred among persons who were experiencing
problems in cognition. Further follow-up of the study population will allow
for greater explication of the association between cognitive decline and vitamin
E intake from supplements.
Much of the available epidemiologic evidence on this issue is from cross-sectional
studies. Among 6 cross-sectional studies40-45
that examined vitamin E in serum or plasma, 540-44
found significant protective associations against low cognitive function,
as did one dietary study.45 A cross-sectional
study46 of dietary vitamin E found no association
with cognitive impairment. The findings from cross-sectional studies of vitamin
C have been equivocal, with some reporting protective associations against
low cognitive function45-50
and others reporting no association.20, 40-41,51-52
Inconsistent findings have also been reported for beta carotene, with 542-43,45-46,53
of 8 studies20, 40-43,45-46,53
showing protective associations.
Few epidemiologic studies have examined the association between antioxidant
nutrients and cognitive decline or incident dementia. One study20
observed no association with a 2-point decrease in cognitive score in 53 of
342 men over 3 years. Of 2 other studies that related cognitive score to past
levels of antioxidant nutrients in plasma45
and from diet,48 one observed a protective
association with vitamin E48 and one with beta
carotene and vitamin C.45 All of these studies
were small and likely had low power to detect nutrient effects on small changes
in cognition. Two prospective studies have reported protective associations
between antioxidant vitamin supplements and incident21
and prevalent54 dementia. A study21
of 633 East Boston residents with 91 incident cases of Alzheimer disease found
that 0 of 38 persons consuming vitamin E or C supplements developed incident
disease over 4 years; as in the present study, there was no association
with multivitamin use. Another investigation54
reported lower dementia among men who reported use of vitamin E and C supplements
in earlier surveys. In a clinically evaluated sample of the CHAP population,
we found that vitamin E intake from foods was associated with reduced risk
of developing Alzheimer disease, and the protective benefit appeared to occur
only among persons who were APOE- 4–negative.55
Because APOE genotyping was possible only among the clinically evaluated participants,
we could not examine the interaction between APOE-4 and vitamin E on
cognitive decline in the population.This report provides evidence that high
intakes of vitamin E from food or supplements are associated with a reduced
risk of cognitive decline. The relation is supported by animal studies, in
which rodents fed diets high in vitamin E demonstrated improved cognitive
functioning during aging, with fewer errors in maze tests,6
a greater rate of learning,7 and greater memory
retention.7, 56 A causal interpretation
of the observed findings would require additional evidence by other longitudinal
epidemiologic studies and/or primary prevention trials.
AUTHOR INFORMATION
Accepted for publication March 6, 2002.
Author contributions: Study concept and design (Drs Morris, Evans, Bienias, and Wilson); acquisition of
data (Drs Evans and Tangney); analysis and interpretation
of data (Drs Morris, Evans, Bienias, Tangney, and Wilson); drafting of the manuscript (Drs Morris, Evans, and
Wilson); critical revision of the manuscript for important intellectual
content (Drs Morris, Evans, Bienias, Tangney, and Wilson); statistical expertise (Drs Morris, Bienias, and
Tangney); obtained funding (Dr Morris); administrative,
technical, and material support (Drs Evans and Wilson); and study supervision (Dr Morris).
This study was supported by grants AG11101 and AG13170 from the National
Institute on Aging, Bethesda, Md.
We thank the residents of Morgan Park, Washington Heights, and Beverly,
Ill, for their cooperation and support; the coordinators, Cheryl Bibbs, BA,
Michelle Bos, BA, and Flavio Lamorticella, BA, and their staffs; and the analytic
programmer, Woojeong Bang, MS.
Corresponding author and reprints: Martha Clare Morris, ScD, Rush
Institute for Healthy Aging, Rush-Presbyterian-St Luke's Medical Center, 1645
W Jackson, Suite 675, Chicago, IL 60612 (e-mail: mmorris{at}rush.edu).
From the Departments of Preventive Medicine (Dr Morris), Internal Medicine
(Drs Evans and Bienias), Clinical Nutrition (Dr Tangney), Neurological Sciences
(Dr Wilson), and Psychology (Dr Wilson), the Rush Institute for Healthy Aging
(Drs Morris, Evans, Bienias, and Wilson), and the Rush Alzheimer's Disease
Center (Drs Evans and Wilson), Rush-Presbyterian-St Luke's Medical Center,
Chicago, Ill.
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