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Antioxidant vitamins and Alzheimers disease:
a review of the epidemiological literature
Meredith Harrington1 &
Francine Grodstein1,2
Author for correspondence
1Harvard 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
Keywords: Alzheimers
disease, antioxidants,
-carotene, cognitive decline,
dementia, vitamin C,
vitamin E
part of
10.2217/1745509X.3.1.23 2007 Future Medicine Ltd ISSN 1745-509X
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 Biology
segment of the population, the diseases of aging The free-radical hypothesis of aging was first
are becoming increasingly prevalent. Dementia proposed in 1956 [5]. The theory, which is now
currently affects approximately 24.3 million supported by numerous experiments and obser-
people worldwide and this figure is predicted to vations, suggests that free radicals or oxidants
double every 20 years [1]. Clearly a significant produced by the body have deleterious, systemic
public health concern, there is great interest in effects [69]. In particular, brain tissue is a site of
identifying simple interventions to prevent or high metabolic activity in which free radicals
delay the onset of dementia, especially Alzhe- (oxygen molecules with unpaired electrons) are
imers disease (AD), the most common type of generated. Those oxygen molecules are highly
dementia [2]. Specifically, estimates indicate that reactive and cause damage to the surrounding
even delaying the onset of AD by 2 years could tissue. Oxidative stress likely acts through addi-
eliminate nearly 2 million cases over the next tional pathways as well. A recent study indicated
50 years [3]. the wide possible variety of mechanisms that
Recently, antioxidant vitamins have become may be involved [10]. In a study of vitamin E-
a focus of research on the prevention of deficient and normally fed rats, gene expression
dementia, as well as cognitive decline (a pre- was explored in the hippocampus; vitamin E
clinical precursor of dementia), since oxidative deficiency had a strong impact on genes associ-
damage has been implicated in brain aging and ated with hormones and hormone metabolism,
the development of dementia. Antioxidants are nerve growth factor, apoptosis, dopaminergic
found in a variety of food sources in addition neurotransmission and the clearance of amy-
to supplements (Table 1) [4]. In this review we loid- and advanced glycated end products. In
will briefly summarize the biological mecha- particular, vitamin E deficiency strongly
nisms that may underlie a potential relation- affected the expression of an array of genes
ship between antioxidant vitamins and encoding proteins directly or indirectly involved
cognition. Then we will provide a synopsis of in the clearance of amyloid-.
the large, prospective observational as well as Indeed, the role of antioxidant vitamins in
randomized trials that have investigated this protecting against amyloid--induced damage
relationship, both via antioxidant supplements has been extensively explored. Amyloid-
and dietary intake. We will not review the plaques are one of the neuropathological hall-
cross-sectional or casecontrol studies here; marks of AD and play a major role in its patho-
these study designs, in which data are collected genesis [11,12]. In transgenic mice, Sung and
retrospectively from participants with cogni- colleagues found that vitamin E supplementa-
tive impairment or dementia, are particularly tion in young (5-month-old), but not old
difficult to interpret in dietary research, as ill- (14-month-old) mice, reduced the level of amy-
ness often leads to many changes in diet and loid- deposition (p < 0.01) [13]. This further
vitamin intake. suggests that antioxidant supplementation may
Aging Health (2007) 3(1), 2332 23
SPECIAL REPORT Harrington & Grodstein
Table 1. Antioxidant sources, recommended daily values and mean intakes in the USA.
Food sources
Vitamin E Vegetable oils, nuts, green leafy vegetables
Vitamin C Citrus fruits, berries, green leafy vegetables
-carotene Yellow, orange, red and dark green fruits and
vegetables
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, neu-
ronal damage, resulting from amyloid- admin-
istration [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 inflamma-
tion. Following induction of acute neuroinflam-
mation 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) supplementa-
tion significantly lowered levels of C-reactive pro-
tein 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, addi-
tional 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 tocophe-
rol radicals. Therefore, the intake of both vita-
min 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)
Recommended dietary intake
30 International units
75 mg (adult women)
90 mg (adult men)
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.
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 signifi-
cantly, more in the group given vitamin E with
vitamin C (160%), compared with controls [20].
In addition, Joseph and colleagues fed rats straw-
berries, 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, indicat-
ing 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 col-
leagues 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) Ref.
Cache County Study 5092 Incident AD Vitamin E + C: [23]
RR: 0.36; 95% CI: 0.090.99
Canadian Study of Health 894 Cognitive decline, Vitamin E + C, cognitive decline: [24]
and Aging incident dementia OR: 0.51; 95% CI: 0.290.90
and AD Vitamin E + C, dementia:
OR: 0.79; 95% CI: 0.481.32
Vitamin E + C, AD:
OR: 1.00; 95% CI: 0.531.87
Duke Established Population 616 Incident dementia Vitamin E and/or C, dementia: [25]
for Epidemiological Studies of and AD RR: 0.46; 95% CI: 0.111.89
the Elderly Vitamin E and/or C, AD:
RR: 0.32; 95% CI: 0.042.30
Nurses Health Study 14,968 Cognitive Vitamin E + vitamin C: [26]
performance mean difference in global score, p = 0.07
Long-term (10 years) vitamin E + C:
mean difference in global score, p = 0.03
HonoluluAsia Aging Study 3385 Incident dementia Vitamin E + C, AD: [27]
and cognitive RR: 0.55; 95% CI: 0.281.10
performance Long-term (10+ years) vitamin E + C, cognitive decline:
RR: 0.57; 95% CI: 0.420.79
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 com-
patible with a wide range of hypotheses,
including a strong relationship between anti-
oxidants and AD (i.e., the lower bound of the
CI was a RR of 0.09) as well as almost no rela-
tionship (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 cogni-
tive 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 com-
pared with nonusers (95% CI: 0.290.90), with
cognitive decline defined as a 10 point or more
decrease in Modified Mini-Mental State Exami-
nation; again, however, the confidence interval
was fairly wide and the results had limited accu-
racy. Moreover, unlike the Cache County Study
there was no significant reduction in risk
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 enrol-
ment did not significantly reduce risk of devel-
oping 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 expo-
sure 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 col-
lected on supplementation with vitamins C and
E over 15 years, after which a battery of cogni-
tive 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

future science group www.futuremedicine.com 25

SPECIAL REPORT Harrington & Grodstein
(p = 0.07). However, significantly better per-
formance was found specifically for the longest-
term 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 cog-
nitive function among 3385 older men, the over-
all data on antioxidant supplements and cognitive
outcomes were weak [27]. There was no statistically
significant relationship observed between antioxi-
dant 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 perform-
ance on the Cognitive Abilities Screening Instru-
ment, 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 antioxi-
dant supplements and cognitive function or
dementia. Those studies that report positive find-
ings 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 supple-
ments usually include only -tocopherol).
Unfortunately, dietary data can be more difficult
to collect than supplement data, thus few epide-
miological studies of cognition have examined
the impact of diet on cognitive outcomes. Typi-
cally, dietary intake has been assessed using food
frequency questionnaires (FFQ). In older per-
sons, 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 esti-
mates 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 stud-
ies 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, com-
paring the top and bottom tertiles. This study
included very few subjects taking vitamin sup-
plements (12%) as supplement use is less com-
mon in Europe than in the USA, but the
findings were similar in analyses that included
or excluded those reporting antioxidant supple-
mentation. Thus, any apparent benefits of anti-
oxidants 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 antioxi-
dants 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 Rotter-
dam 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 sup-
plementation 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 analy-
ses 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 Ref.
Rotterdam Study 5395 Incident AD Highest versus lowest tertile: [29]
Vitamin E: RR: 0.66; 95% CI: 0.441.00
Vitamin C: RR: 0.57; 95% CI: 0.350.91
Chicago Health and 2889 Cognitive decline Highest versus lowest quintile*: [30]
Aging Project 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
815 Incident AD Highest versus lowest quintile: [31]
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
1041 Incident AD and Mean difference in cognitive decline per 5 mg/day [35]
cognitive decline 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
Paquid Cohort 1367 Incident dementia >75 vs <75 mg/day [32]
Vitamin C: RR: 1.29; 95% CI: 0.682.45
Washington Heights- 980 Incident AD Highest versus lowest quartiles: [33]
Inwood Cognitive Vitamin E: RR: 0.76; 95% CI: 0.521.13
Aging Project Vitamin C: RR: 0.71; 95% CI: 0.491.04
HonoluluAsia Aging 2459 Incident dementia Highest versus lowest quartiles: [27]
Study 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
*Data 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. Sim-
ilarly, the Washington HeightsInwood Colum-
bia 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
statistical significance. However, in this inner-
city population, relatively low levels of antioxi-
dants 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 demen-
tia, 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.

future science group www.futuremedicine.com 27

SPECIAL REPORT Harrington & Grodstein
Finally, to explore whether any possible dif-
ferences 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 die-
tary antioxidant vitamins and cognitive func-
tion or dementia. But the limited evidence
may suggest that dietary vitamin E could spe-
cifically 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 sup-
plement use, since diet generally does not
change substantially over time, but supple-
ment 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 con-
founding inherent to observational studies. Tri-
als can be important in dietary research, since
dietary studies can be particularly subject to con-
founding 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 exam-
ine vitamin supplements and tend to include a
short to moderate duration of follow-up. A total
of six large-scale trials have explored the relation-
ship 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 fol-
low-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 inhibi-
tor, selegiline (10 mg/day), -tocopherol
(2000 IU/day), both selegiline and -tocophe-
rol, 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 cog-
nitive 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 par-
ticipants. 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 Coun-
cil/British Heart Foundation Heart Protection
Study (n = 20,536), participants were rand-
omized 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 vita-
mins (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 ben-
efits 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 Results (treatment vs placebo) Ref.
study
Alzheimers Disease 769 AD development among those 3 years Vitamin E (2000 IU/day): RR: 1.02; [36]
Cooperative Study with mild cognitive impairment 95% CI: 0.741.41
Alzheimers Disease 341 with Cognitive decline, and disease 2 years Cognitive decline: [37]
Cooperative Study moderately progression No relations observed
severe AD 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
Age-Related Eye 2166 Cognitive performance, 6.9 years Vitamin E (400 IU/day) + vitamin C [38]
Disease Study modified MMSE (500 mg/day) + -carotene (15 mg/day):
mean difference: 0.6;
95% CI: -0.021.40
MRC/BHF Heart 20,536 Cognitive performance, TICS 5 years Vitamin E (600 mg/day*) + vitamin C [39]
Protection Study (250 mg/day) + -carotene (20 mg/day):
mean difference: 0.09;
95% CI: -0.050.23
Womens Health 6377 Cognitive function and decline, 510 years Vitamin E (600 IU on alternate days), [40]
Study summary score across battery of cognitive function: mean
cognitive tests 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
Physicians Health 5956 Cognitive performance, Long-term Long:term: -carotene (50 mg on [41]
Study II summary score across battery of (mean 18 years) alternate days): mean difference: 0.047;
cognitive tests Short-term 95% CI: 0.00400.091
(mean 1 year) Short-term: -carotene (50 mg on
alternate days):
mean difference: -0.014;
95% CI: -0.0740.046
*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 randomized to placebo or -carotene 50 mg on

group had similar mean cognitive function after
approximately 5 years of treatment compared
with the placebo group (on a global score com-
bining 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
alternate days. One group of men was given only
short-term -carotene supplementation (mean
duration: 1 year), and this regimen was not asso-
ciated 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 com-
pared with placebo group at the close of the trial.
Those taking -carotene had, on average, a sig-
nificantly 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

future science group www.futuremedicine.com 29

SPECIAL REPORT Harrington & Grodstein

subjects 1 year apart in age, thus the data from Conclusion

this trial indicate that long-term supplementa-
tion 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 bene-
fits of -carotene over other antioxidant vita-
mins, 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 antioxi-
dant supplementation may be required to
achieve significant neuroprotection.
Despite strong biological evidence supporting a
role for antioxidant treatment in the prevention
of brain aging, overall, the epidemiological evi-
dence regarding possible benefits of anti-
oxidants on cognitive function are inconsistent,
and largely unconvincing. Most of the observa-
tional studies, even the larger studies, have
somewhat limited statistical power, and their
results are fairly unstable. Very limited data sug-
gest that dietary antioxidants, especially vita-
min 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, anti-
oxidant 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) future science group

 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 spe-
cifically examine the duration of antioxidant
intake, are required to better understand
whether and how antioxidant vitamins may
have public health utility for maintaining cog-
nitive 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 dia-
betes 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
vitamins, especially supplements, and the bio-
logical literature supports the hypothesis that
oxidative damage contributes to cognitive
impairment.
This focus on vitamin supplements is largely
due to the relative ease of collecting data on
supplements, compared with dietary habits.
Moreover, since long-term studies are difficult
to conduct and since data on long-term habits
are difficult to collect, most of the epidemio-
logical investigations have explored overall use
of antioxidant supplements and cognition, and
have not examined the specific duration of
their use. Results from these studies have gen-
erally been inconclusive and do not strongly
indicate that antioxidant vitamin supplements
can reduce risk of cognitive impairments.
However, the most promising data regard the
potential of antioxidants in foods to lower rates
of cognitive aging, and the possibility that long
durations (i.e., >10 years) of antioxidant sup-
plementation are required to provide
neuroprotection. Thus, important aspects of
future research on antioxidant vitamins and
dementia will include prospective studies that
have the ability to specifically explore anti-
oxidant in the diet, as well as long-term
patterns of diet and supplementation.

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