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S PECIAL R EPORT

Antioxidant vitamins and Alzheimers disease:

a review of the epidemiological literature
Meredith Harrington1 &
Francine Grodstein1,2
Author

for correspondence
School of Public
Health, Channing
Laboratory, Department of
Medicine, Brigham and
Womens Hospital, Harvard
Medical School and
Department of Epidemiology,
Boston, MA, USA
2Harvard School of Public
Health, Channing Lab, 181
Longwood Avenue, Boston,
MA, USA
Tel.: +1 617 525 2279;
Fax: +1 617 525 2008;
E-mail: fran.grodstein
@channing.harvard.edu
1Harvard

Keywords: Alzheimers
disease, antioxidants,
-carotene, cognitive decline,
dementia, vitamin C,
vitamin E
part of

Identifying ways to prevent Alzheimers disease is becoming increasingly critical in our

aging population. Antioxidant vitamins hold promise for lowering the risk of Alzheimers
disease and cognitive decline in older persons. In animal models and cell lines, these
vitamins, such as vitamins E and C, prevent neuronal damage caused by free radicals,
delaying brain aging and, perhaps, memory loss. However, epidemiological data on
antioxidant vitamins and cognition are conflicting and are not conclusive. This report
reviews current research, in particular, the large, prospective, observational studies and
randomized, controlled trials to assess the evidence regarding the relation of antioxidant
vitamins to dementia or cognitive decline.

As older persons become an increasingly large

segment of the population, the diseases of aging
are becoming increasingly prevalent. Dementia
currently affects approximately 24.3 million
people worldwide and this figure is predicted to
double every 20 years [1]. Clearly a significant
public health concern, there is great interest in
identifying simple interventions to prevent or
delay the onset of dementia, especially Alzheimers disease (AD), the most common type of
dementia [2]. Specifically, estimates indicate that
even delaying the onset of AD by 2 years could
eliminate nearly 2 million cases over the next
50 years [3].
Recently, antioxidant vitamins have become
a focus of research on the prevention of
dementia, as well as cognitive decline (a preclinical precursor of dementia), since oxidative
damage has been implicated in brain aging and
the development of dementia. Antioxidants are
found in a variety of food sources in addition
to supplements (Table 1) [4]. In this review we
will briefly summarize the biological mechanisms that may underlie a potential relationship between antioxidant vitamins and
cognition. Then we will provide a synopsis of
the large, prospective observational as well as
randomized trials that have investigated this
relationship, both via antioxidant supplements
and dietary intake. We will not review the
cross-sectional or casecontrol studies here;
these study designs, in which data are collected
retrospectively from participants with cognitive impairment or dementia, are particularly
difficult to interpret in dietary research, as illness often leads to many changes in diet and
vitamin intake.

10.2217/1745509X.3.1.23 2007 Future Medicine Ltd ISSN 1745-509X

Biology
The free-radical hypothesis of aging was first
proposed in 1956 [5]. The theory, which is now
supported by numerous experiments and observations, suggests that free radicals or oxidants
produced by the body have deleterious, systemic
effects [69]. In particular, brain tissue is a site of
high metabolic activity in which free radicals
(oxygen molecules with unpaired electrons) are
generated. Those oxygen molecules are highly
reactive and cause damage to the surrounding
tissue. Oxidative stress likely acts through additional pathways as well. A recent study indicated
the wide possible variety of mechanisms that
may be involved [10]. In a study of vitamin Edeficient and normally fed rats, gene expression
was explored in the hippocampus; vitamin E
deficiency had a strong impact on genes associated with hormones and hormone metabolism,
nerve growth factor, apoptosis, dopaminergic
neurotransmission and the clearance of amyloid- and advanced glycated end products. In
particular, vitamin E deficiency strongly
affected the expression of an array of genes
encoding proteins directly or indirectly involved
in the clearance of amyloid-.
Indeed, the role of antioxidant vitamins in
protecting against amyloid--induced damage
has been extensively explored. Amyloid-
plaques are one of the neuropathological hallmarks of AD and play a major role in its pathogenesis [11,12]. In transgenic mice, Sung and
colleagues found that vitamin E supplementation in young (5-month-old), but not old
(14-month-old) mice, reduced the level of amyloid- deposition (p < 0.01) [13]. This further
suggests that antioxidant supplementation may
Aging Health (2007) 3(1), 2332

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SPECIAL REPORT Harrington & Grodstein

Table 1. Antioxidant sources, recommended daily values and mean intakes in the USA.
Food sources

Recommended dietary intake

Vitamin E

Vegetable oils, nuts, green leafy vegetables

30 International units

Vitamin C

Citrus fruits, berries, green leafy vegetables

75 mg (adult women)
90 mg (adult men)

-carotene

Yellow, orange, red and dark green fruits and

vegetables

There is no separate dietary reference intake for

-carotene, but it is a form of vitamin A along
with retinol
700 retinol equivalents are recommended for women
and 900 retinol equivalents for men.

Adapted from [4].

be most important at the earlier rather than later

stages of cognitive decline. In addition, in rat
hippocampus, addition of vitamin E prevented
lipid peroxidation and, more importantly, neuronal damage, resulting from amyloid- administration [14]. More direct effects on cognition
have also been reported. Among mice repeatedly
infused with amyloid- protein, those treated
with vitamin E were less prone to learning and
memory deficits as compared with the control
group [15].
An additional possible mechanism by which
antioxidants may protect against brain aging that
has been well-examined is decreased inflammation. Following induction of acute neuroinflammation in rats, antioxidant treatment improved
N-methyl-D-aspartic acid receptor function
(involved in memory and learning) by at least
25% in the hippocampus [16]. In humans, very
high doses (1200 International units [IU]/day) of
-tocopherol (a form of vitamin E) supplementation significantly lowered levels of C-reactive protein and monocyte interleukin-6, after 3 months
of treatment [17]. Data are not totally consistent,
and some studies of inflammation in rats suggest
selective effects of certain antioxidant vitamins.
For example, Jiang and Ames reported that
-tocopherol, but not -tocopherol, inhibits
proinflammatory prostaglandin E2 and attenuates
inflammation-mediated damage in rats [18].
Although few antioxidant vitamins besides
-tocopherol have been well-examined, additional data also suggest that other antioxidants
may be important. For example, while vitamin E
is a fat-soluble vitamin and thus may be key to
protecting the lipid-rich membranes of the
brain, vitamin C (a weaker antioxidant) has the
ability to regenerate -tocopherol from tocopherol radicals. Therefore, the intake of both vitamin E and C together could be key to reducing
oxidative stress [19]. In aged rats, after 60 days of
treatment with vitamin C, vitamin E, or vitamin
24

Aging Health (2007) 3(1)

E plus C, there was no effect of vitamin C on a

memory test, but scores improved by 130% in
the vitamin E group and slightly, but not significantly, more in the group given vitamin E with
vitamin C (160%), compared with controls [20].
In addition, Joseph and colleagues fed rats strawberries, spinach or vitamin E for 8 months, with
equivalent levels of antioxidant activity in each
of the three groups [21]. Neuronal function was
better in rats given the fruit/vegetable diet or
vitamin E than controls, but the fruit/vegetable
diet generally had the strongest effects, indicating that the variety of vitamins in foods may be
more effective than single supplements.
Finally, other studies suggest that additional
details of antioxidant treatment may be critical
to neuroprotection. For example, after 4 months
of treatment with -tocopherol, Socci and colleagues reported that treated rats had better
acquisition rates (p < 0.005) and significantly
greater memory retention (p < 0.05) than
untreated rats [22]. Interestingly, in this study,
there was no effect with short-term treatment
given at older ages, indicating that duration and
timing of treatment may be a factor in any
neuroprotection provided by antioxidants.
Epidemiology
Observational studies
Antioxidant supplements
Many large-scale, prospective, observational
studies have examined the relationship between
antioxidant supplements and incident dementia
or decline of cognitive function (Table 2). As
described below, findings have been somewhat
inconsistent, and together, the literature is
largely inconclusive.
For example, in the Cache County Study,
which included 5092 older men and women, a
very large reduction in risk of AD was reported
(relative risk [RR]: 0.36; 95% confidence
interval [CI]: 0.090.99) for users of vitamin E
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Antioxidant vitamins and Alzheimers disease SPECIAL REPORT

Table 2. Prospective, observational studies of antioxidant supplements and cognition.

Study

Subjects

Outcome

Results (users vs nonusers)

Cache County Study

5092

Incident AD

Vitamin E + C:
RR: 0.36; 95% CI: 0.090.99

Ref.
[23]

Canadian Study of Health

and Aging

894

Cognitive decline,
incident dementia
and AD

Vitamin E + C, cognitive decline:

OR: 0.51; 95% CI: 0.290.90
Vitamin E + C, dementia:
OR: 0.79; 95% CI: 0.481.32
Vitamin E + C, AD:
OR: 1.00; 95% CI: 0.531.87

[24]

Duke Established Population

for Epidemiological Studies of
the Elderly

616

Incident dementia
and AD

Vitamin E and/or C, dementia:

RR: 0.46; 95% CI: 0.111.89
Vitamin E and/or C, AD:
RR: 0.32; 95% CI: 0.042.30

[25]

Nurses Health Study

14,968

Cognitive
performance

Vitamin E + vitamin C:
mean difference in global score, p = 0.07
Long-term (10 years) vitamin E + C:
mean difference in global score, p = 0.03

[26]

HonoluluAsia Aging Study

3385

Incident dementia
and cognitive
performance

Vitamin E + C, AD:
RR: 0.55; 95% CI: 0.281.10
Long-term (10+ years) vitamin E + C, cognitive decline:
RR: 0.57; 95% CI: 0.420.79

[27]

AD: Alzheimers disease; CI: Confidence interval; OR: Odds ratio; RR: Relative risk.

combined with C compared with nonusers of

antioxidant supplements [23]. No association
was found for either vitamin E or C taken
alone, suggesting that the combination of
vitamin E with vitamin C may be important.
However, with 104 cases of incident AD, the
findings for vitamins E and C together were
still fairly unstable and the confidence interval
was extremely wide. Thus, the data were compatible with a wide range of hypotheses,
including a strong relationship between antioxidants and AD (i.e., the lower bound of the
CI was a RR of 0.09) as well as almost no relationship (i.e., the upper bound of the CI was a
RR of 0.99).
The Canadian Study of Health and Aging
(n = 894) examined supplement use in relation
to several cognitive outcomes, including cognitive decline, incident AD and incident
dementia [24]. They also found an association
between combined use of vitamin E and vitamin
C and cognition. Supplement users had a 49%
reduction in odds of cognitive decline as compared with nonusers (95% CI: 0.290.90), with
cognitive decline defined as a 10 point or more
decrease in Modified Mini-Mental State Examination; again, however, the confidence interval
was fairly wide and the results had limited accuracy. Moreover, unlike the Cache County Study
there was no significant reduction in risk

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observed for incident dementia (odds ratio

[OR]: 0.79; 95% CI: 0.481.32) or AD
(OR: 1.00; 95% CI: 0.531.87) for users of
vitamin E and C combined.
In a smaller study among 616 older persons
from the Duke Established Population for the
Epidemiological Studies of the Elderly, use of
vitamin C and/or E supplements at study enrolment did not significantly reduce risk of developing dementia (RR: 0.46, 95% CI: 0.111.89)
or AD (RR: 0.32; 95% CI: 0.042.30) [25].
Again, however, the data from this study were
somewhat difficult to interpret as a very small
proportion of subjects reported taking vitamin
supplements (<10%).
Few studies have specifically examined the
duration of vitamin supplementation, although
the animal data indicate that long-term exposure to antioxidant vitamins may be required for
neuroprotection. In the largest investigation of
cognitive function, among 14,968 older women
from the Nurses Health Study, data were collected on supplementation with vitamins C and
E over 15 years, after which a battery of cognitive tests was administered [26]. There was
slightly better mean cognitive performance
among current users of vitamin E combined
with vitamin C, compared with women who
did not take antioxidant supplements, which
was of borderline statistical significance

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SPECIAL REPORT Harrington & Grodstein

(p = 0.07). However, significantly better performance was found specifically for the longestterm users of vitamin E with C, compared with
nonusers (for >10 years of use; p = 0.03).
Similarly, in the HonoluluAsia Aging Study
(HAAS), which explored both dementia and cognitive function among 3385 older men, the overall data on antioxidant supplements and cognitive
outcomes were weak [27]. There was no statistically
significant relationship observed between antioxidant supplements and AD (RR: 0.55; 95%
CI: 0.281.10). However, the HAAS reported
similar results to the Nurses Health Study, in that
long-term users (10 years) of vitamin E with
vitamin C had 43% lower odds (RR: 0.57;
95% CI: 0.420.79) of poor cognitive performance on the Cognitive Abilities Screening Instrument, as compared with participants who
reported no use of these supplements.
Summary

Overall, the large-scale observational studies of

antioxidant supplementation do not provide
strong support for a relationship between antioxidant supplements and cognitive function or
dementia. Those studies that report positive findings are generally based on a limited number of
cases with supplement use, and thus the results
are generally statistically unstable and should not
be considered conclusive. However, consistent
with animal studies, there is some evidence to
suggest that combined vitamin E and C use, or
long-term use of supplements, may decrease the
risk of cognitive impairment, and these are
certainly areas that need further investigation.
Dietary antioxidants

Antioxidants can be consumed in food, not only

via supplements, and some studies have also
examined the potential of dietary antioxidants to
reduce dementia risk (Table 3). Specifically, as
noted above, food contains a larger variety of
antioxidant vitamins than supplements (e.g.,
dietary vitamin E can be consumed as -, -, -,
and -tocopherol, whereas vitamin E supplements usually include only -tocopherol).
Unfortunately, dietary data can be more difficult
to collect than supplement data, thus few epidemiological studies of cognition have examined
the impact of diet on cognitive outcomes. Typically, dietary intake has been assessed using food
frequency questionnaires (FFQ). In older persons, who may eat prepared food or institutional
food more often than younger persons, or may
have difficulty completing the FFQ owing to
26

Aging Health (2007) 3(1)

health or cognitive issues, there may be more

misclassification of diet on FFQs; thus, studies
of dietary antioxidants may provide biased estimates of the relationship between vitamin intake
and cognitive status. Nonetheless, a validation
study among older persons indicated that the
FFQ performed similarly in those with cognitive
or other health problems as in those with better
health [28], thus misclassification of diet in studies of older persons is most likely random,
leading to bias to the null.
In the Rotterdam Study (n = 5395), dietary
antioxidant intake and risk of AD was
explored [29]. It appeared that a high dietary
intake of vitamin E or vitamin C reduced the
risk of AD, with borderline significant RRs of
0.66 (95% CI: 0.441.00) for vitamin E and
0.57 (95% CI: 0.350.91) for vitamin C, comparing the top and bottom tertiles. This study
included very few subjects taking vitamin supplements (12%) as supplement use is less common in Europe than in the USA, but the
findings were similar in analyses that included
or excluded those reporting antioxidant supplementation. Thus, any apparent benefits of antioxidants were not the result of greater
supplement use in the highest categories of
antioxidant intake.
The Chicago Health and Aging Project
(CHAP) determined dietary habits at baseline,
and then followed 2889 community residents for
an average of 3.2 years to examine dietary antioxidants and both cognitive decline or AD [30]. Using
a battery of four cognitive tests, administered at
three points in time, participants in the highest
quintile of total vitamin E intake had a 36% lower
rate of cognitive decline compared with those in
the lowest quintile (p = 0.05); unlike the Rotterdam study, no relations were noted for vitamin C
intake, or for -carotene intake. Consistent with
the Rotterdam study, findings remained similar
after excluding supplement use (p-trend across
quintiles of diet alone = 0.03); thus, these data do
not support any clear benefits of vitamin E supplementation independent of diet. In separate
analyses
of
AD
development
among
815 participants, the results were similar [31]. The
study of AD had less statistical power than analyses of cognitive decline, but those in the highest
quintile of vitamin E intake from foods appeared
to have a reduced risk of AD as compared with the
lowest quintile (RR: 0.30; 95% CI: 0.100.92).
There was no relationship between supplement
use and AD risk, and no relationship for the other
antioxidant vitamins either.
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Antioxidant vitamins and Alzheimers disease SPECIAL REPORT

Table 3. Prospective, observational studies of dietary antioxidants and cognition.

Study

Subjects

Outcome

Results

Rotterdam Study

5395

Incident AD

Highest versus lowest tertile:

Vitamin E: RR: 0.66; 95% CI: 0.441.00
Vitamin C: RR: 0.57; 95% CI: 0.350.91

[29]

Chicago Health and

Aging Project

2889

Cognitive decline

Highest versus lowest quintile*:

Vitamin E: mean difference in rate of decline: 2.4;
95% CI: 0.04.9
Vitamin C: mean difference in rate of decline: 1.6;
95% CI: 0.084.0

[30]

815

Incident AD

Highest versus lowest quintile:

Vitamin E: RR: 0.30; 95% CI: 0.100.92
Vitamin C: RR: 1.03; 95% CI: 0.412.56
-carotene: RR: 0.55; 95% CI: 0.221.35

[31]

1041

Incident AD and
cognitive decline

Mean difference in cognitive decline per 5 mg/day

increase in intake:
Vitamin E: 0.0049; 95% CI: 0.00180.0080
-tocopherol: 0.0082; 95% CI: 0.00230.0141
-tocopherol equivalents: 0.0109;
95% CI: 0.00320.0249
-tocopherol: 0.0065; 95% CI: 0.00060.0124
Vitamin E, AD: RR: 0.74; 95% CI: 0.620.88
-tocopherol equivalents, AD: RR: 0.56;
95% CI: 0.320.98

[35]

Paquid Cohort

1367

Incident dementia

>75 vs <75 mg/day

Vitamin C: RR: 1.29; 95% CI: 0.682.45

[32]

Washington HeightsInwood Cognitive

Aging Project

980

Incident AD

Highest versus lowest quartiles:

Vitamin E: RR: 0.76; 95% CI: 0.521.13
Vitamin C: RR: 0.71; 95% CI: 0.491.04

[33]

HonoluluAsia Aging
Study

2459

Incident dementia

Highest versus lowest quartiles:

Vitamin E: RR: 1.33; 95% CI: 0.901.96
Vitamin C: RR: 1.25; 95% CI: 0.871.78
-carotene: RR: 1.08; 95% CI: 0.741.57

[27]

*Data

Ref.

given as regression coefficients x 102 standard units. AD: Alzheimers disease; CI: Confidence interval; RR: Relative risk.

Nonetheless, four other prospective studies

report no association between antioxidant
intake and dementia. The Paquid cohort
(n = 1367) examined only vitamin C intake,
and found no significant relationship between
dietary vitamin C and incident dementia
(RR: 1.29; 95% CI: 0.682.45, comparing >75
vs <75 mg/day) [32] This study did not report
results for intake of any other antioxidants. Similarly, the Washington HeightsInwood Columbia Aging Project (WHICAP), involving
980 men and women observed no significant
decrease in risk of AD development for high
compared with lower dietary antioxidant
intake [33]. With 242 incident cases of AD, there
was a nonsignificant 24% lower rate of AD
(RR: 0.76; 95% CI: 0.521.13) comparing the
highest to lowest quartile of vitamin E intake,
with a RR of 0.71 (95% CI: 0.491.04) for
vitamin C intake, which also did not reach
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statistical significance. However, in this innercity population, relatively low levels of antioxidants vitamins were consumed; for instance, the
highest category of vitamin E intake
(mean: 7 IU/day) in this study was similar to
the
lowest
category
in
CHAP
(mean: 6.8 IU/day), thus it may be difficult to
compare the findings from WHICAP to those
of other studies with different populations. In
the HAAS cohort, no relationship was found
between midlife intake of vitamin E (RR: 1.33;
95% CI: 0.901.96), vitamin C (RR: 1.25;
95% CI: 0.871.78) or -carotene (RR: 1.08;
95% CI: 0.741.57) and risk of late-life dementia, comparing the highest to lowest quartiles
[34]. However, this study had fairly high loss to
follow-up (29.9%) and utilized a single 24-h
dietary recall to represent long-term antioxidant
intake, both of which may result in particularly
diminished ability to detect associations.
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SPECIAL REPORT Harrington & Grodstein

Finally, to explore whether any possible differences in the effect of supplements and the
effect of dietary vitamin E may be attributable
to their different tocopherol forms, one study
specifically examined the four tocopherol
forms in relation to AD and cognitive decline
[35]. The investigators found that a reduced risk
of AD was associated with a higher dietary
intake of vitamin E (RR: 0.74 for every
5 mg/day
increase
in
intake;
95%
CI: 0.620.88) and -tocopherol equivalents
(RR: 0.56 for every 5 mg/day increase; 95%
CI: 0.32, 0.98). In addition, a slower rate of
cognitive decline was associated with intakes of
vitamin E, -tocopherol equivalents, and and -tocopherols. Therefore, it appears that a
combined intake of the tocopherol forms, not
just the -tocopherol found in supplements,
may be important in providing protection
against AD and cognitive decline.
Summary

Overall, there are relatively few studies of dietary antioxidant vitamins and cognitive function or dementia. But the limited evidence
may suggest that dietary vitamin E could specifically have the potential to reduce the risk of
dementia or cognitive impairment. However,
there are insufficient data to make any firm
conclusions, and it could also be possible that
the studies of dietary vitamin E simply better
represent long-term intake than studies of supplement use, since diet generally does not
change substantially over time, but supplement use can be more sporadic over time. This
is clearly an area that needs substantial
additional research.
Randomized clinical trials

Often considered a gold-standard in research,

randomized, controlled trials eliminate the confounding inherent to observational studies. Trials can be important in dietary research, since
dietary studies can be particularly subject to confounding variables; specifically, those who
choose to take supplements or to eat a healthy
diet may be more likely to lead a generally
healthier lifestyle as well. Still, trials present
other difficulties, such as maintaining long-term
compliance, and most clinical trials only examine vitamin supplements and tend to include a
short to moderate duration of follow-up. A total
of six large-scale trials have explored the relationship between antioxidant vitamins and cognitive
outcomes (Table 4).
28

Aging Health (2007) 3(1)

In the only trial of AD prevention, among

769 subjects with mild cognitive impairment,
participants were randomized to 2000 IU of
vitamin E or to placebo [36]. After 3 years of follow-up, there was no evidence of benefits in the
treatment group; those assigned to vitamin E
supplements had similar risk of progression to
AD as the placebo group (hazard ratio: 1.02;
95% CI: 0.741.41), as well as similar mean
cognitive
performance
across
several
psychometric tests.
In a study of patients with AD of moderate
severity, 341 patients were randomized for
2 years to a selective monoamine oxidase inhibitor, selegiline (10 mg/day), -tocopherol
(2000 IU/day), both selegiline and -tocopherol, or placebo [37]. In addition to cognitive
decline, one outcome was the time to occurrence
of death, institutionalization, loss of the ability
to perform activities of daily living, or severe
dementia. Although there was no change in cognitive function among any of the groups, there
were significant delays in institutionalization for
all groups compared with placebo (selegiline:
p = 0.012; selegiline plus -tocopherol:
p = 0.001; -tocopherol: p = 0.049).
Four randomized trials have been conducted
of cognitive function in generally healthy
participants. In the Age-Related Eye Disease
Study, 2166 subjects were randomly assigned to
receive a combination of daily antioxidants
(vitamin C: 500 mg; vitamin E: 400 IU;
-carotene: 15 mg) or placebo [38]. After a
median of 6.9 years of treatment, a cognitive
battery of six tests was administered to the participants. Mean performance on each cognitive
test was similar in the treatment group compared
with the placebo group (p > 0.05 for all tests).
Similarly, in the Medical Research Council/British Heart Foundation Heart Protection
Study (n = 20,536), participants were randomized to either a placebo or a combination of
vitamin E (600 mg [900 IU]), vitamin C
(250 mg) and -carotene (20 mg) daily [39]. At
the close of the trial, the Telephone Interview of
Cognitive Status (TICS) was administered.
There was no evidence of treatment differences
after 5 years of follow-up between the placebo
group and the group given the antioxidant vitamins (mean difference in TICS score: 0.09;
95% CI: -0.05 to 0.23). Similarly, the Womens
Health Study, with 6377 women given 600 IU
of vitamin E every other day or placebo for
almost 10 years, also reported no cognitive benefits with supplementation across a battery of
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Antioxidant vitamins and Alzheimers disease SPECIAL REPORT

Table 4. Randomized clinical trials of antioxidant supplements.

Study

Subjects

Outcome

Duration of
study

Results (treatment vs placebo)

Ref.

Alzheimers Disease
Cooperative Study

769

AD development among those

with mild cognitive impairment

3 years

Vitamin E (2000 IU/day): RR: 1.02;

95% CI: 0.741.41

[36]

Alzheimers Disease
Cooperative Study

341 with
moderately
severe AD

Cognitive decline, and disease

progression

2 years

Cognitive decline:
No relations observed
Median time to disease progression:
Placebo: 440 days
Selegiline (10 mg/day): 655 days,
p = 0.012
Selegiline (10 mg/day) + vitamin E
(2000 IU/day): 670 days, p = 0.001
Vitamin E (2000 IU/day): 585 days,
p = 0.049

[37]

Age-Related Eye
Disease Study

2166

Cognitive performance,
modified MMSE

6.9 years

Vitamin E (400 IU/day) + vitamin C

(500 mg/day) + -carotene (15 mg/day):
mean difference: 0.6;
95% CI: -0.021.40

[38]

MRC/BHF Heart
Protection Study

20,536

Cognitive performance, TICS

5 years

Vitamin E (600 mg/day*) + vitamin C

(250 mg/day) + -carotene (20 mg/day):
mean difference: 0.09;
95% CI: -0.050.23

[39]

Womens Health
Study

6377

Cognitive function and decline,

summary score across battery of
cognitive tests

510 years

Vitamin E (600 IU on alternate days),

cognitive function: mean
difference: 0.00; 95% CI: -0.040.04
Vitamin E (600 IU on alternate days),
cognitive decline: mean
difference: 0.02; 95% CI: -0.010.05

[40]

Physicians Health
Study II

5956

Cognitive performance,
summary score across battery of
cognitive tests

Long-term
(mean 18 years)
Short-term
(mean 1 year)

Long:term: -carotene (50 mg on

alternate days): mean difference: 0.047;
95% CI: 0.00400.091
Short-term: -carotene (50 mg on
alternate days):
mean difference: -0.014;
95% CI: -0.0740.046

[41]

*Vitamin E 600 mg = 900 IU of Vitamin E. AD: Alzheimers disease; BHF: British Heart Foundation; CI: Confidence interval; IU: International unit(s);
MMSE: Mini-mental state exam; MRC: Medical Research Council; RR: Relative risk; TICS: Telephone interview of cognitive status.

cognitive tests [40]. The vitamin E supplement

group had similar mean cognitive function after
approximately 5 years of treatment compared
with the placebo group (on a global score combining all cognitive tests, mean difference: 0.00;
95% CI: -0.04 to 0.04) as well as similar rates of
cognitive decline through the close of follow-up
(mean difference in decline over three points in
time: 0.02; 95% CI: -0.01 to 0.05).
Finally, the only clinical trial with more than
10 years of follow-up was the Physicians Health
Study II, including 5956 men randomized to
antioxidant supplements for 2 months up to
20 years; this trial is particularly interesting as
the observational data suggest that cognitive
benefits may be most notable after at least
10 years of supplementation [41]. The men were
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randomized to placebo or -carotene 50 mg on

alternate days. One group of men was given only
short-term -carotene supplementation (mean
duration: 1 year), and this regimen was not associated with any cognitive benefits at the close of
treatment (mean difference on global score of
cognitive function: -0.014; 95% CI: -0.074 to
0.046). However, among those participants who
were assigned to long-term treatment (mean
duration: 18 years), significantly better cognitive
performance was found for the treatment compared with placebo group at the close of the trial.
Those taking -carotene had, on average, a significantly higher global score (by 0.047 standard
units) than the placebo group (95%
CI: 0.00400.091). This mean difference was
equivalent to the mean difference observed for
29

SPECIAL REPORT Harrington & Grodstein

subjects 1 year apart in age, thus the data from

this trial indicate that long-term supplementation delays cognitive aging by 1 year. Although
this was the only trial focusing on high doses of
-carotene supplementation, the observational
epidemiological data indicate no particular benefits of -carotene over other antioxidant vitamins, thus it seems more likely that the duration
rather than type of treatment was the critical
issue here.
Summary

The data from all these randomized trials

clearly demonstrates that short to moderate
duration of antioxidant supplementation has
no effects on cognitive function, although may
impact disease progression in some dementia
patients. Nonetheless, the Physicians Health
Study suggests that long duration of antioxidant supplementation may be required to
achieve significant neuroprotection.

Conclusion
Despite strong biological evidence supporting a
role for antioxidant treatment in the prevention
of brain aging, overall, the epidemiological evidence regarding possible benefits of antioxidants on cognitive function are inconsistent,
and largely unconvincing. Most of the observational studies, even the larger studies, have
somewhat limited statistical power, and their
results are fairly unstable. Very limited data suggest that dietary antioxidants, especially vitamin E, might have greater potential to decrease
risk of cognitive impairment than antioxidant
supplements, but this area needs substantially
more investigation before any conclusions or
recommendations can be made. However,
growing data, including randomized clinical
trials, indicate that the duration of exposure
might be a critical factor in neuroprotection,
with long-term, but not shorter-term, antioxidant intake holding the greatest promise for

Executive summary
Introduction
Alzheimers disease, dementia and general cognitive decline are significant public health issues. Antioxidant vitamins may provide
a means for delaying or preventing these conditions.
Biology
Animal and cell culture studies suggest that antioxidants, such as vitamin E, prevent oxidative damage, which may play a role in
brain aging and cognitive impairment.
Animal data indicate that long-term exposure to antioxidants may be required to provide neuroprotection.
Observational epidemiological studies of antioxidant supplements
Several large-scale, prospective studies have examined the relationship between antioxidant supplements and cognitive decline or
dementia. Results are largely null, with positive findings tending to be statistically unstable.
Limited studies of long-term intake of supplements suggest that at least 10 years of supplementation with vitamins E and C
combined could reduce cognitive impairment and dementia.
Observational epidemiological studies of antioxidant vitamins in diet
There are very limited studies examining dietary intake of antioxidants and cognitive impairment. Two studies suggest that dietary
vitamin E may have the potential to decrease risk of cognitive decline and dementia, but this area needs significantly more
research attention, in particular regarding the various forms of vitamin E that are available in foods.
Randomized clinical trials of antioxidant supplements
Several randomized, controlled trials of less than 10 years duration report no association between several antioxidant
supplements (i.e., vitamin E, vitamin C, -carotene) and cognitive function or dementia development.
One large trial, including up to 1520 years of treatment with -carotene supplements, found that those assigned to -carotene
had significantly better cognitive function than those assigned to placebo. Thus, the duration of treatment may be a critical factor
in any potential neuroprotection from antioxidant vitamins.
Conclusions
Overall, the epidemiological literature indicates few cognitive benefits of antioxidant vitamins.
Specific data on antioxidants available in foods and on long-term use of antioxidant supplements demonstrate the most
promising results on brain aging.
Future perspective
Future studies will need to better focus on the role of diet on cognition, as well as the varying impacts of different durations of
antioxidant intake.

30

Aging Health (2007) 3(1)

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Antioxidant vitamins and Alzheimers disease SPECIAL REPORT

delaying, or preventing, the onset of cognitive
decline and potentially dementia. Long-term
studies, with a large enough sample size to specifically examine the duration of antioxidant
intake, are required to better understand
whether and how antioxidant vitamins may
have public health utility for maintaining cognitive function and reducing dementia risk
with aging.
Future perspective
In our demographically aging population, there
is a tremendous need to identify ways to delay
or prevent the onset of cognitive decline and
dementia. Although diet has been identified as
an important component in reducing the risk
of many chronic diseases, including Type 2 diabetes and cardiovascular disease, there has been
little research on how diet may affect cognitive
aging. Future studies of dementia prevention
will need to better focus on many aspects of
diet, including vitamins, as well as food groups,
so that a basis can be formed for developing
public health recommendations regarding diet
and cognition.
Much of the existing epidemiological data
on dietary risk factors for cognitive outcomes
have examined the impact of antioxidant
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