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231CANADIAN GERIATRICS JOURNAL, VOLUME 18, ISSUE 4, DECEMBER 2015
ABSTRACT
Background
Observational studies have suggested that various nutrients,
dietary supplements, and vitamins may delay the onset of
age-associated cognitive decline and dementia. We system-
atically reviewed recent randomized controlled trials inves-
tigating the effect of nutritional interventions on cognitive
performance in older non-demented adults.
Methods
We searched MEDLINE, CINAHL, Embase, and the Co-
chrane Library for articles published between 2003 and 2013.
We included randomized trials of ≥ 3 months’ duration that
examined the cognitive effects of a nutritional intervention in
non-demented adults > 40 years of age. Meta-analyses were
done when sufcient trials were available.
Results
Twenty-four trials met inclusion criteria (six omega-3 fatty
acids, seven B vitamins, three vitamin E, eight other interven-
tions). In the meta-analyses, omega-3 fatty acids showed no
signicant effect on Mini-Mental State Examination (MMSE)
scores (four trials, mean difference 0.06, 95% CI -0.08 – 0.19)
or digit span forward (three trials, mean difference -0.02, 95%
CI -0.30 – 0.25), while B vitamins showed no signicant
effect on MMSE scores (three trials, mean difference 0.02,
95% CI -0.22 – 0.25). None of the vitamin E studies reported
signicant effects on cognitive outcomes. Among the other
nutritional interventions, statistically signicant differences
between the intervention and control groups on at least one
cognitive domain were found in single studies of green tea
extract, Concord grape juice, chromium picolinate, beta-
carotene, two different combinations of multiple vitamins, and
a dietary approach developed for the control of hypertension.
Conclusions
Omega-3 fatty acids, B vitamins, and vitamin E supplementa-
tion did not affect cognition in non-demented middle-aged and
older adults. Other nutritional interventions require further
evaluation before their use can be advocated for the prevention
of age-associated cognitive decline and dementia.
Key words: nutrition, micro-nutrients, macro-nutrients,
dementia
INTRODUCTION
By 2050, the number of individuals with dementia worldwide
is projected to reach 135 million.(1) Dementia, a devastating
condition, adversely affects the cognitive abilities, indepen-
dence, and quality of life of those affected and leads to health
costs equivalent to those of heart disease and cancer.(2) In
2012, the World Health Organization declared dementia a
public health priority.(3)
The mechanisms underlying the development of age-
associated cognitive decline and dementia are felt to be oper-
ant 10–15 years or more before the development of clinical
symptoms.(4 ,5 ) Recent reports suggest that there is a decline
in the age-specic prevalence of dementia,(6-8) providing
indirect evidence of potentially modiable risk factors.(5)
Effective strategies that can ameliorate the anticipated
Effect of Nutrients, Dietary Supplements and
Vitamins on Cognition: a Systematic Review
and Meta-Analysis of Randomized
Controlled Trials
Scott C. Forbes, PhD1, Jayna M. Holroyd-Leduc, MD4,5, Marc J. Poulin PhD, DPhil1,2, David B. Hogan MD2,3,4,5
1Department of Physiology and Pharmacology, Faculty of Medicine, University of Calgary, Calgary, AB; 2Hotchkiss Brain
Institute, Faculty of Medicine, University of Calgary, Calgary, AB; 3Brenda Stafford Foundation Chair in Geriatric Medicine,
Faculty of Medicine, University of Calgary, Calgary, AB; 4Departments of Medicine, Clinical Neurosciences and Community
Health Sciences, Faculty of Medicine, University of Calgary, Calgary, AB; 5Alberta Seniors Health Strategic Clinical
Network, Alberta Health Services, Calgary, AB
DOI:http://dx.doi.org/10.5770/cgj.18.189
SYSTEMATIC REVIEWS/META-ANALYSIS
© 2015 Author(s). Published by the Canadian Geriatrics Society. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial
No-Derivative license (http://creativecommons.org/licenses/by-nc-nd/2.5/ca/), which permits unrestricted non-commercial use and distribution, provided the original work is properly cited.
CANADIAN GERIATRICS JOURNAL, VOLUME 18, ISSUE 4, DECEMBER 2015
FORBES: NUTRITION AND COGNITION
232
dramatic growth in the number of individuals affected by
dementia brought on by population aging are needed.(3,5 ) In
the absence of curative treatment,(9) preventing or postponing
the onset of dementia is of critical importance.(5) A ve-year
delay in the development of Alzheimer’s disease (the most
common neurodegenerative cause of late-life dementia)
would reduce its prevalence by 50%.(10)
While to date no interventions have been shown to
conclusively decrease the risk of age-associated cognitive
decline or the development of Alzheimer’s disease,(9) there
is a large body of evidence from observational studies sug-
gesting that vitamins, nutrients, and dietary supplements
(e.g., omega-3 fatty acids,(11,12) folic acid,(13) vitamins B6,(13)
B12,(13) C,(14,15) D,(16) and E(14,15) may delay the onset of age-
associated cognitive decline and various forms of dementia
including Alzheimer’s disease.(17,18) A variety of mechanisms
including correction of metabolic derangements or dietary
deciencies have been proposed by which they may affect
cognitive health.(19)
The purpose of this systematic review is to summarize
the ndings of recent randomized controlled trials (RCTs)
investigating the cognitive impact of nutritional interven-
tions (e.g., nutrients [including macro-nutrients, vitamins, or
minerals], diet, dietary supplement, fortied food, or medical
food) of three months or longer in middle-aged and older (>
40 years) non-demented adults. We performed meta-analyses
of the effects where possible.
METHODS
The approach outlined in the Cochrane Handbook for
Systematic Reviews of Interventions(20) was followed
and the reporting was done in accordance with PR ISMA
(Preferred Reporting Items for Systematic Reviews and
Meta-Analyses).(21)
Data Sources and Search Strategy
Literature searches were performed in June 2013 on MED-
LINE, Embase, CINAHL, and the Cochrane Database of
Systematic Reviews. For the MEDLINE search, the Medi-
cal Subject headings (MeSH) terms (exploded) Delirium,
Dementia, Amnestic, and Cognitive Disorders with the
subheading “prevention and control” were combined with
the terms Nutrition Assessment, Nutrition Therapy, Diet,
Micronutrients and Food, plus Nutrition as a keyword. De-
lirium, dementia, and other related terms were searched with
the diet therapy subheading as a separate set. A supporting
keyword search was also done: (cognition disorder* or Al-
zheimer* or mild cognitive decline) AND (food* or diet* or
nutrition* or apolipoprotein* or lipoprotein* or micronutri-
ent* or mineral*). Searches were limited to meta-analyses,
systematic reviews, or RCTs performed on middle-aged and/
or older human study populations and published between
2003 and June 2013. Other systematic reviews surveyed the
literature prior to 2006.(22-24) Our systematic review was
intended to update this prior work. We wanted to focus on
those nutritional interventions attracting the greatest current
interest. A concern we had in including older studies was the
change that that has occurred in typical food intake over the
last 20+ years(2 5) as there is evidence that baseline dietary
intake may impact on the effect that dietary supplements have
on cognitive function. The other databases were searched by
similar strategies using terms from their specic thesauri.
The search was not limited to articles written in any specic
language. The full search strategy is attached in Appendix 1.
Other articles included in our systematic review were either
known by the authors or identied by manually searching
the bibliographies of retrieved articles.
Study Selection
Two of the authors independently screened the titles and
abstracts of each of the articles identied in the search for
possible inclusion in our systematic review. Articles were
selected for full-text review if they met the following criteria:
(i) RCT where participants were allocated to either a dietary
intervention (e.g., nutrient [including macro-nutrients, vita-
mins, or minerals], diet, dietary supplement, fortied food,
or medical food) or a control arm; (ii) all participants were
40 years of age or older and judged to have normal cognition
or mild cognitive impairment (note: if it was not explicitly
noted that all cases of diagnosed or suspected dementia were
excluded, a study was not selected for full-text review); (iii)
intervention duration three or more months (to exclude studies
that dealt with the acute effects of nutritional interventions);
and, (iv) included cognition as an outcome measure. Discrep-
ancies were resolved either by consensus or the involvement
of a third author if necessary.
Full-text articles were reviewed independently by two of
the authors for their eligibility of inclusion in the systematic
review. Study quality, based on the procedures used for ran-
domization, allocation concealment and blinding,(20) and ex-
cluding persons with an underlying condition that could affect
cognition, was considered during the study selection process.
Data Extraction
Full-text articles selected for inclusion had the following
information extracted: authors, country where the study
was done, date of publication, information on specic
inclusion and exclusion criteria, sample size, proportion
of total sample that was female, proportion of total sample
completing the study, mean age, other characteristics of the
study population, nutritional intervention used (including
information on dose and frequency of a supplement), dura-
tion of study, intervention and control adherence, outcome
measures, and results. We focused on examining the out-
come measure(s) results as reported for the entire group.
As mean (standard deviation [SD]) change in the cognitive
CANADIAN GERIATRICS JOURNAL, VOLUME 18, ISSUE 4, DECEMBER 2015
FORBES: NUTRITION AND COGNITION
233
outcome(s) from baseline was frequently not reported, we
noted the nal mean value, SD, and number of participants
in each group. If a trial had two or more intervention arms,
combining their data was considered if the arms were judged
similar (e.g., they used the same nutritional intervention
except for dosage)(20) and the same control group was util-
ized. This was done with one study(26) where we pooled
two intervention arms (moderate and higher dosages of the
same nutritional intervention).
Two authors extracted the data independently with any
disagreements resolved by consensus or the involvement of
a third author if necessary.
Assessment of the Risk for Bias in Included Studies
Two of the authors independently assessed and rated the
trials for their risk of bias based on criteria derived from
the Cochrane Handbook for Systematic Reviews of Inter-
ventions.(20) The methods used for randomization and
blinding were examined. A low risk of bias was considered
present when the approach taken was deemed adequate
for both randomization and blinding, moderate if the ap-
proach taken was either unclear or only partially met the
pre-determined criteria for adequacy, and high risk when
these pre-determined criteria were not met. Disagreements
were resolved by consensus or the involvement of a third
author if necessary.
Data Analysis
A meta-analysis was done if three or more studies examined
the same intervention with the same outcome measure. We
did not encounter any situations where two studies examined
the same intervention with the same outcome measure where
a meta-analysis could have been performed. A xed effect
model was used. A summary measure of the mean differ-
ence with a 95% condence interval (CI) was calculated.
Statistical analysis for heterogeneity was assessed using chi-
square test for heterogeneity and the I2 statistic to quantify
total variation across studies attributable to heterogeneity.
Meta-analysis results are presented as forest plots. Funnel
plots of the meta-analyses were visually inspected to look for
evidence of publication bias, but statistical testing was not
done because of the small number (< 10 / meta-analysis) of
included studies. Statistical analyses were performed using
the software program Review Manager (Review Manager
5.2; The Nordic Cochrane Centre, Copenhagen, Denmark).
RESULTS
Study Characteristics
Two hundred and sixty citations, excluding duplicate entries,
were identied as potentially relevant. After the initial screen-
ing of titles and abstracts, 49 full-text articles were retrieved
for detailed review (Figure 1). Twenty-four articles met our
inclusion criteria for the systematic review (Appendix 2 lists
retrieved full-text articles excluded from the systematic re-
view). While most studies had multiple cognitive outcomes,
ten had a single or designated primary outcome.
Six trials examined the effects of omega-3 fatty acid
supplementation (Table 1). Among these studies, there was
a large amount of heterogeneity with regards to the dosage
used (400 mg to 2200 mg) and duration of the intervention (6
months to 3.3 years). Three found a modest benecial effect
on memory and/or executive functioning,(27-29) while the other
three reported none.(26,30,31)
Meta-analyses of omega-3 fatty acid studies were per-
formed for the outcomes of MMSE scores and digit span
forward results (Figure 2(a) and (b)). The summary mean
difference for MMSE scores was non-signicant at 0.06 (95%
CI -0.08 to 0.19, p = .40), and the summary mean difference
for digit span forward was non-signicant at -0.02 (95% CI
-0.30 to 0.25, p = .87).
Seven trials investigated the effects of various combina-
tions of folate, B6 and/or B12 vitamins (Table 2). There was
substantial heterogeneity between trials with regards to dose,
intervention duration (12 weeks to 6.6 years), participant
health status (suffering from or at risk for cardiovascular
disease to healthy community-dwelling individuals), and
cognitive outcomes assessed. Inconsistent results were seen
with some studies reporting modest benets in at least one
cognitive domain,(32-35) while others found no effect.(36-38)
Three studies were pooled to examine the impact on
MMSE scores of folate combined with vitamins B6 and/or B12
(Figure 3). The summary mean difference for MMSE scores
was non-signicant at 0.02 (95% CI -0.22 to 0.25, p = .90).
Three trials investigated vitamin E supplementation
(Table 3). They were relatively large (769 to 6377 participants)
(39-41) and of long duration (3 to 9.6 years). One trial was lim-
ited to participants with amnestic mild cognitive impairment.
(39) No statistically signicant effect on any of the cognitive
outcomes examined was found.(39-41)
Among the other nutritional interventions examined
(Table 4), statistically signicant differences between the in-
tervention and control groups on at least one cognitive domain
were found for green tea extract,(42) Concord grape juice,(43)
chromium picolinate,(44) beta-carotene,(45) two different
combination therapies including multiple vitamins,(46,47) and
a dietary approach developed for the control of hypertension.
(48) No benecial effects were found for calcium carbonate
combined with vitamin D3.(49)
A variety of approaches were used to assess adher-
ence to the nutritional interventions including counting
capsules,(26,27,31,32,35,37,42-44,47) weighing pills,(49) question-
naires,(33,45) diaries,(32,46) interviews,(34,49) and/or blood analy-
ses.(28,30,37,38) All studies reporting on adherence described it
as good or better (e.g., consumption of 2/3+ of all capsules)
with the intervention.(30,31,33,35,37,40,41,49) Two studies did not
attempt to assess adherence.(29,48)
CANADIAN GERIATRICS JOURNAL, VOLUME 18, ISSUE 4, DECEMBER 2015
FORBES: NUTRITION AND COGNITION
234
Risk of Bias and Evidence of Publication Bias
Ten trials were considered low,(26-28,31,34-39) ten moder-
ate,(29,32,33,40- 42,46-49) and four high risk(30,43 -45 ) of bias (Tables
1–4). Funnel plots for each meta-analysis were visually in-
spected and showed no evidence of publication bias.
DISCUSSION
This systematic review and meta-analysis presents data on
recent RCTs of the cognitive impact of nutritional interven-
tions in non-demented middle-aged and older adults. Our main
nding is that there is no convincing evidence of benet for
any of the nutritional interventions included in this review.
Meta-analyses of two nutritional interventions, omega-3 fatty
acids, and select B vitamins (folate, B6 and/or B12) didn’t
demonstrate signicant effects. The promising results of
generally small single studies with moderate to high risk of
bias reporting on other nutritional interventions will require
conrmation.
In general, observational studies have been more positive
than experimental ones. For example, though several obser-
vational studies(50-53) suggest that a high intake of omega-3
might lead to improve cognition, the RCTs examined showed
no benet(26,30,31) or at most a modest one.(27-29) Observa-
tional studies can lead to erroneous conclusions and must be
interpreted cautiously.(54) The risk of a confounding variable
leading to the groups being compared (e.g., those following a
particular diet versus those not) differing in their probability of
the outcome of interest (e.g., developing cognitive problems)
for reasons other than the intervention is a major limitation
with them. This can occur if one is unaware of potential con-
founders, does not measure them, or does not measure them
adequately. In many circumstances, to more rmly establish
causality, a RCT is required.
Biologically plausible mechanisms are present for most
of the nutritional interventions examined. Omega-3 fatty acids
play a critical role in central nervous system development,
structure, and function.(55) Folate, vitamin B6, and/or vitamin
B12 are considered essential for normal brain function as we
Figure 1: Literature Search Flow Diagram
Recordsidentifiedthrough
databasesearching
(n=242)
Screening
Included
Eligibility
Identification
Additionalrecordsidentified
throughothersources
(n=18)
Recordsafterduplicatesremoved
(n=260)
Records screened
(n=260)
Recordsexcluded
(n=211)
Fulltextarticlesassessed
foreligibility
(n=49)
Fulltextarticlesexcluded(n=25)
Review/commentaryn=3
Abstract onlyn=1
Patientsagedidnotmeetcriterian=4
Randomizationnotsufficientn=2
Shorttermstud yn=4
Patients w/dementia oruncle arn=7
Notanutritionalordietaryinterventionn=1
Didnotmeasurecognitionn=2
Studyproposaln=1
Studiesincludedin
qualitativesynthesis
(n=24)
Studiesincludedin
quantitativesynthesis
(metaanalysis;
Omega3 n=6;Folate+/
VitaminsB6/12n=7)
FIGURE 1. Literature search ow diagram
CANADIAN GERIATRICS JOURNAL, VOLUME 18, ISSUE 4, DECEMBER 2015
FORBES: NUTRITION AND COGNITION
235
TABLE 1.
Studies of omega-3 fatty acid supplementation on cognitive function
First Author
(year)
Study
Population
(n)
Design and
Duration
Intervention Outcome Measure Results Risk of
Bias
Geleijnse
et al.(30)
N=2,911
coronary heart
disease patients
(22% women);
60–80 yrs.
RCT; 40
mths.
20 g of a margarine that contained
either a supplement (400 mg/d of
EPA–DHA at a ratio of 3:2,
2 g/d of ALA, 400 mg/d of EPA–DHA
plus 2 g/d of ALA (EPA–DHA 1 ALA))
or a placebo (i.e., non-supplemented
margarine)
Global
(MMSE)
↔ Global cognitive decline (Mean ± SD: PLA=28.2±1.7
vs. Omega-3 =28.3±1.6)
High
Lee
et al.(27)
N=36;
(27 women);
>60 yrs.; low
SES with MCI
RCT; 12
mths.
3 x/d 430 mg of DHA and 150 mg
of EPA/d or an isocaloric placebo
(0.6 g linoeic acid)
Memory (Auditory Verbal
Learning Test and Digit span
backward), executive function,
attention, psychomotor speed,
and global (MMSE)
# Digit Span (Mean (95%CI): PLA = 8.0 (6.877 -9.113)
vs. Omega-3 = 9.6 (8.437-10.749);
VR-I (PLA = 23.1 (19.154-26.952) vs.
Omega-3 = 29.2 (25.207-33.269); RAVLT delayed recall
(PLA = 5.0 (3.587-6.312) vs. Omega-3 = 8.1 (6.645-
9.462);
↔ MMSE (PLA = 26.5 (25.6-27.4) vs.
Omega-3 = 26.6 (25.7-27.6); RAVLT immediate recall
(PLA = 40.1 (37.384-42.785) vs.
Omega-3 = 45.5 (42.706-48.291);
VR-II (PLA = 18.0 (12.943-23.143) vs.
Omega-3 = 20.8 (15.564-26.110); CDT (PLA = 7.8
(7.145-8.436) vs. Omega-3 (7.8 (7.142- 8.477); Digit
Symbol substitution
(PLA = 4.9 (3.254-6.634) vs. Omega-3 = 5.5 (3.723-
7.218)
Low
Van de Rest
et al.(26)
N=302
(45% women);
> 65 yrs.
(mean=70 yrs.)
RCT; 26
wks.
1,800 mg/d EPA–DHA,
400 mg/d EPA–DHA or placebo
(high-oleic sunower oil)
Cognitive domains of attention,
sensorimotor
speed, memory,
and executive function
↔ Mean ± SD: Trail Making part A (PLA = 40.9±16.2 vs.
Low Omega-3 = 42.3±14.0 vs. High Omega-3 =
43.4±15.1);
Trail Making Test Part B – Part A / Part A (PLA =
0.66±0.51 vs.
Low Omega-3 = 0.62±0.46 vs. High Omega-3 =
0.73±0.62);
15 Word Learning-immediate recall – 75 words (PLA
= 44.8±9.4 vs. Low Omega-3 = 46.1±10.1 vs. High
Omega-3 = 44.9±9.9);
Digit span Forward (PLA = 8.5±2.0 vs. Low Omega-3 =
8.6±1.8;
High Omega-3 = 8.6±2.0)
Low risk
CANADIAN GERIATRICS JOURNAL, VOLUME 18, ISSUE 4, DECEMBER 2015
FORBES: NUTRITION AND COGNITION
236
TABLE 1.
Continued
First Author
(year)
Study
Population
(n)
Design and
Duration
Intervention Outcome Measure Results Risk of
Bias
Dangour
et al.(31)
N=867
(45% women);
70-79 yrs.
RCT; 2 yrs. 200 mg EPA plus
500 mg DHA/d or placebo
(olive oil)
Primary: California Verbal
Learning Test (CVLT)
Secondary: Cognitive domains
for global cognitive function,
memory, processing speed,
executive function,
global delay score
↔ Mean ± SD: Primary: CVLT
(PLA = 24.4±6.4 vs. Omega-3 = 24.1±6.7)
on any secondary cognitive outcome
Low risk
Yurko-
Mauro
et al.(28)
N=485
(58% women);
≥ 55 yrs.
RCT; 24
wks.
900 mg/d DHA or placebo
(50% corn oil and 50% soy oil)
Primary: CANTAB Paired
Associate Learning -
visuospatial learning,
and episodic memory
Secondary: CANTAB Pattern
and Verbal Recognition
memory, CANTAB Stockings
of Cambridge, CANTAB
spatial working memory,
Frequency of forgetting-10
scale, MMSE
# Mean ± SD: CANTAB Paired Associate Learning
(PLA = 9.7±10.4 vs. Omega-3 = 8.8±9.9);
# Verbal Recognition memory -immediate
(PLA = 10.9±1.4 vs. Omega-3 = 11.0±1.4) and delayed
(PLA = 10.7±1.8 vs. Omega-3 = 10.7±1.8 ) and Stockings
of Cambridge - Executive function
(PLA = 3.7±1.3 vs. Omega-3 = 3.5±1.3);
↔ on any other cognitive outcome: VRM free recall
(PLA = 5.8±2.1 vs. Omega-3 = 5.8±2.1); PRM delayed,
number correct (PLA = 8.8±1.8 vs. Omega-3 = 8.6±2.0);
MMSE (PLA = 27.9±1.9 vs. Omega-3 = 28.0±1.9)
Low
Witte
et al.(29)
N=65
(31% women);
50-75 yrs.
RCT; 26
wks.
2.2 g/d (1320 mg EPA plus
880 mg DHA) or placebo
(sunower oil)
Executive function (phonemic
uency, semantic uency,
TMT-B/TMT-A, Stroop) and
memory (AVLT learning,
delayed recall, recognition,
digit span backwards)
# Executive function#; ↔ memory#
(Data presented as a gure).
Moderate
# = signicantly better (p<.05) in the omega-3 condition; ↔ = no difference between omega-3 and control conditions; # = corrected for multiple comparisons; RCT = randomized
controlled trial; EPA = eicosapentaenoic acid; DHA = docosahexaenoic acid; ALA = alpha-linolenic acid; SES = socio-economic status; MCI = mild cognitive impairment; MMSE =
Mini-Mental State Examination; CVLT = California Verbal Learning Test; CANTAB = Cambridge neuropsychological test automated battery; TMT-A = Trail Making Test part A; TMT-B
= Trail Making Test part B; AVLT = auditory verbal learning task.
Range of scores of each outcome tool: MMSE = 0–30, Digit Span = 1–19, VR-I = 0–11. VR-II = 0–41, RAVLT delayed recall = 0–15, RAVLT immediate = 0–75, Digit Symbol
Substitution = 1–19, CDT = 0–10, Digit Span Forward = 1–16, CVLT = 0–30, CANTAB PAL = 21 potential outcome measures, CANTAB VRM = 5 potential outcome measures,
CANTAB Stockings of Cambridge = 3 potential outcome measures, TMT-A, TMT-B, Stroop are timed in seconds. Higher scores indicate better performance except for TMT-A, TMT-B,
and Stroop (i.e., more time to complete the tasks represents poorer performance).
CANADIAN GERIATRICS JOURNAL, VOLUME 18, ISSUE 4, DECEMBER 2015
FORBES: NUTRITION AND COGNITION
237
age(56) as a result of their effect on homocysteine metabo-
lism(56,57) and other mechanisms.(58,59) Vitamin E and several
of the other nutrients examined are felt to have anti-oxidant
effects. Long-term oxidative stress has been implicated in the
pathogenesis of cognitive decline and dementia.(60) Consump-
tion of anti-oxidants, such as vitamin E, could potentially
decrease free radical mediated damage in neuronal cells and
reduce beta amyloid toxicity.(61) An in vitro model of green
tea extract was found to attenuate cell death induced by beta
amyloid.(62) Insulin resistance is associated with cognitive
impairment,(63) and chromium may improve insulin sensitiv-
ity.(64) Determining, though, how much weight to give these
purported mechanisms is difcult, cannot be done in isola-
tion from other forms of evidence (e.g., clinical studies), and
ultimately is often subjective.(65)
B vitamins have attracted particular interest as a possible
nutritional intervention.(56) Folate acts as a donor of methyl
groups in a reaction catalyzed by the enzyme methionine
synthase to produce methylcobalamin, which is required for
methylation of homocysteine to methionine.(56) B-vitamin de-
ciency leads to an increase in blood concentrations of homo-
cysteine.(66) High intra-neuronal levels of homocysteine could
disturb brain metabolism and cause cognitive impairment.(56)
Additionally, folate increases nitric oxide availability in the
brain,(58) and deciency of this molecule impairs DNA repair
in neurons and sensitizes neurons to oxidative damage and
the toxicity of amyloid beta-peptide.(59) A cohort study of 965
older adults demonstrated a lower incidence of Alzheimer’s
disease in the highest quartile of total dietary folate intake
after controlling for other factors.(67) We identied seven
RCTs investigating the inuence of B vitamins on cognition
(Table 2). Our meta-analysis showed no signicant effect of
supplementation on MMSE scores. One study did show better
cognitive performance with active therapy but only in women
with low baseline dietary folate intake.(33) Future RCTs should
consider initial nutritional status, as benets may be limited
to those with relative deciencies.(33)
Our ndings are congruent with the previous systematic
reviews. While Manders et al.,(22) in an examination of the
available literature on the cognitive effects of nutritional
supplements in older individuals concluded that their use
might lead to improvements without causing any harm, the
two more recent systematic reviews on this topic found little
if any evidence of a benecial effect.(23,24)
A number of systematic reviews have dealt with specic
nutritional interventions. One examined population-based
cohort studies of anti-oxidant nutrients and reported a possible
effect on age-related cognitive decline though the available
evidence was limited.(68) Recent Cochrane systematic reviews
concluded that both omega-3(69) and folate (± vitamin B12)(70)
had no consistent benecial effect on cognitive functioning
in healthy older individuals.
Limitations of this review include the limited extent
and quality of the available literature. Even when there are a
number of studies dealing with the same nutritional interven-
tion, the results do not necessarily show a consistent picture.
While this may be due to differences in study population and/
or outcome measures, an issue requiring attention is the vari-
ability in the composition, dose, duration, and timing (during
the participant’s life span) of the intervention. For example,
the ratio of omega-6 to -3 may be an important consideration
for omega-3 trials.(71) There is increasing evidence that a
A
B
FIGURE 2. Meta-analyses of polyunsaturated omega-3 studies for the outcomes of (A) Mini-Mental State Examination (MMSE) score and
(B) digit span forward
A
B
Figure2AandB.
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FORBES: NUTRITION AND COGNITION
238
TABLE 2.
Studies of B vitamins (vitamin B6, vitamin B12, and folate) on cognitive function
First author
(year)
Study Population (n) Design and
Duration
Intervention Outcome Measure Results Risk of Bias
Ford
et al.(32)
N=299 hypertensive
males; >75 yrs.
RCT (computer
generated random
permuted blocks);
2 yrs.
400 μg B12, 2 mg
folic acid, and 25 mg
B6 or placebo
Primary: ADAS-cog.
Secondary: CVLT, MMSE,
Digit Cancellation Test,
Clock Drawing Test, TICS
Primary: (Mean change ± SD (PLA = -0.8±4.0 vs. B
vitamins = -0.7±3.4) ↔ ADAS-cog Secondary: ↔
Clock Drawing Test, and MMSE; # Digit Cancellation
test @ 12 mths; # CVLT @ 24 mths; ↔ in cognitive
impairment and dementia risk over 8-yr follow-up
Moderate
Kang
et al.(33)
N=2009 women with
CVD or vascular
risk factors
RCT; 6.6 yrs. of
treatment and 5.4
yrs. of follow up
Folic acid 2.5 mg,
Vitamin B6 50 mg,
Vitamin B12 1 mg/d
or placebo
Primary: Global cognitive
composite score
Secondary: Verbal memory
composite score; TICS; Category
Fluency
↔ Mean change in global score (95%CI):
Cognitive decline = 0.03 (-0.03-0.08);
↔ Verbal memory; TICS; Category uency
Moderate
Sub-group analysis: # cognition in women
with low baseline intake of B vitamins
van Uffelen
et al.(36)
N=152 (44%
women); 70-80 yrs.;
community dwelling
RCT; 1 yr. 2X2 factorial design:
2x/wk. moderate
exercise; 2x/wk. low
exercise with either
5 mg folic acid,
0.4 mg vitamin B12,
50 mg vitamin B6
or placebo
MMSE, Verbal Fluency Test,
Digit symbol substitution test, and
Abridged Stroop Color Word Test
↔ MMSE: Men: PLA = 29 (28-29) vs. B vitamins = 28
(27-30), Women: PLA = 29 (27-30) vs. B vitamins = 29
(27-30); AVLT 1-5 – words: Men: PLA = 31.5±9.3 vs. B
vitamins = 29.1±8.9, Women: PLA = 31.2±6.6 vs.
B vitamins = 33.7±10); DSST: Men: PLA = 38.1±9.1 vs.
B vitamins = 36.2±12.1, Women: PLA = 33.5±7.7 vs.
B vitamins = 36.6±10.3); Verbal Fluency Test:
Men: PLA = 36.0±13.3 vs. B vitamins 31.8±10.3,
Women: PLA = 36.7±12.1 vs. B vitamins = 33.8±10.1)
Low
Walker
et al.(34)
N=900 with elevated
psychological
distress (60%
women); 60-74 yrs.
RCT; 2 yrs. 400 μg folic acid +
100 μg vitamin B-12
or Placebo
Telephone interview for Cognitive
Status-Modied (TICS-M),
processing speed, and informant
questionnaire on cognitive decline
# In cognitive function
(immediate and delayed memory):
Data presented as gures
Low
McMahon
et al.(37)
N=276
(44% women);
> 65 yrs.
RCT; 2 yrs. Folate (1 mg) and
vitamins B12
(500 μg) and
B6 (10 mg)
or placebo
Global cognition (MMSE);
Rey Auditory Verbal Learning
Test; Verbal and Semantic Fluency;
Processing Speed; Reasoning
Ability
↔ Mean ± SD: MMSE (PLA = 29.32±1.10 vs.
B vitamins = 29.29±1.41); Wechsler Paragraph Recall
test (PLA = 20.76±7.21 vs. B vitamins = 18.67±6.55);
Category Word Fluency test (PLA = 68.78±13.71 vs.
B vitamins = 65.72±14.96); Rey Auditory Verbal
Learning (PLA 44.22±9.90 vs. B vitamins = 43.90±9.70);
Raven’s Progressive Matrices (PLA = 11.90±3.05
vs. B vitamins = 11.60±2.92); Controlled Oral Word
Association (PLA = 41.00±12.44 vs.
B vitamins = 40.11±14.08)
Low
CANADIAN GERIATRICS JOURNAL, VOLUME 18, ISSUE 4, DECEMBER 2015
FORBES: NUTRITION AND COGNITION
239
TABLE 2.
Continued
First author
(year)
Study Population (n) Design and
Duration
Intervention Outcome Measure Results Risk of Bias
De Jager
et al.(35)
N=223
(64% women);
≥70 yrs.
RCT; 2 yrs. 0.8 mg folic acid,
0.5 mg vitamin B12,
20 mg vitamin B6 or
Placebo (vitamin free
tablets)
MMSE, HVLT-DR; episodic
memory, semantic memory,
executive function (CLOX), and
cognitive decline (IQCODE)
↔ MMSE, HVLT-DR or Category Fluency;
# Executive Function; $ Cognitive decline (i.e., slow
the rate of cognitive decline): data presented for
sub-analyses only.
Low
Stott
et al.(38)
N=185
(52% women);
> 65 yrs. with
ischemic disease
RCT; 12 wks. Folic acid (2.5 mg)
plus vitamin B-12
(500 μg), vitamin B-6
(25 mg) and riboavin
(25 mg) or placebo
Letter Digit Coding Test;
TICS-M
Mean change ± SD: ↔ Letter Digit Coding test
(PLA = 1.0±3.2 vs. B vitamins = -1.2±5.6) and
TICS-M (PLA = -0.4±2.7 vs. B vitamins = 0.7±3.8)
Low
# = signicantly better (p<.05) in the B-vitamin condition; ↔ = no difference between B-vitamin and control conditions; $ = signicantly lower (p<.05) in the B-vitamin condition;
RCT = randomized controlled trial; ADAS-cog = Alzheimer’s disease assessment scale – cognition; MMSE = Mini-Mental State Examination; TICS = telephone interview for
cognitive status; TICS-M = telephone interview for cognitive status – modied; CVLT = California Verbal Learning Test; CVD = cardiovascular disease; HVLT-DR = Hopkins Verbal
Learning Test – Delayed Recall; CLOX = Clock Drawing Task; IQCODE = Informant Questionnaire on Cognitive Decline in the Elderly.
Range of scores of each outcome tool: ADAS-Cog = 0-70, CDR = 0-5, MMSE = 0-30, CVLT = 0-30, TICS-M = 0-30, AVLT immediate = 0-75, AVLT delayed = 0-15, DSST and
Verbal Fluency Test = number of correct responses. Higher scores indicate better performance except for ADAS-cog.
FIGURE 3. Meta-analysis of folate, B6, and B12 studies for the outcome of Mini-Mental State Examination (MMSE) score
CANADIAN GERIATRICS JOURNAL, VOLUME 18, ISSUE 4, DECEMBER 2015
FORBES: NUTRITION AND COGNITION
240
lifetime of accumulated exposures are predictive of cogni-
tive function in late-life.(4) An intervention limited to later in
the person’s life may be beyond the critical period when it
may be benecial. More thought about the inuence of the
specic characteristics of the intervention is needed during
the planning stage of these studies. Also relatively neglected
is assessing the initial nutritional status of participants. Ben-
ets may be limited to those with relative deciencies.(72) In
one of the B vitamin studies reviewed,(33) better cognitive
performance was seen with active therapy but only in women
with low baseline dietary folate intake. Another issue might
be the relative insensitivity of the outcome measures utilized
(e.g., MMSE).
Recent research suggests that considering the per-
son’s “whole” diet may be needed to better understand the
nutrient-cognition link.(7 3) Supplements cannot replicate
the complexity of natural food and provide all its potential
benets. Conducting rigorous long-term studies of the ef-
fect of diet on cognition will be a difcult challenge.(74)
One of the dietary approaches that might be considered
is caloric restriction. This may have a benecial impact
by increasing insulin sensitivity.(75) One of our included
studies examined a dietary approach developed for hy-
pertension.(48) Risk factors for Alzheimer’s disease and
vascular dementia overlap with those for heart disease.(4,76)
A recent meta-analysis of observational studies found high
adherence to a Mediterranean diet was associated with a
lower risk of developing cognitive impairment,(7 7,78) but no
interventional studies that met our inclusion criteria were
found. While the PREDIMED-Navarra investigators found
small but statistically signicant differences in favour of
those assigned to a Mediterranean diet supplemented with
TABLE 3.
Studies of vitamin E supplementation on cognitive function
First author
(year)
Study Population
(n)
Design and
Duration
Intervention Outcome Measure Results Risk of Bias
Kang
et al.(41)
N=2824 women;
> 65 yrs.;
≥ 3 coronary
risk factors
RCT; 5.4 yrs.
follow up time
Vitamin E 402 mg
every other day +
500 mg of vitamin
C daily and 50 mg
of B-carotene every
other day or placebo
Telephone interview
for Cognitive Status-
Modied (TICS-M)
↔ Rates of cognitive
change; data presented as
gures
Moderate
Kang
et al.(40)
N= 6377 women;
> 65 yrs.
RCT;
follow up at
~5.6 yrs. and
at ~9.6 yrs.
Vitamin E (600 IU)
or placebo
Primary:
Global composite score
(TICS)
Mean ± SE: ↔ Global
cognitive scores
(PLA = 0.02±0.01 vs.
Vitamin E = 0.02±0.01);
↔ verbal memory
at both follow-ups
Moderate
Secondary:
Verbal memory
(TICS & East Boston
Memory Test)
Petersen
et al.(39)
N=769
(46% women);
72.9±7.3 yrs.;
Amnestic MCI
RCT; 3 yrs. Vitamin E (2000 IU)
or Donepezil (10 mg)
or placebo
Primary: Possible or
probably AD
Secondary: MMSE;
ADAS-Cog; global CDR;
CDR sum of boxes; Global
Deterioration Scale;
New York University
paragraph-recall test; the
symbol digit modalities
test; category-uency test;
a number cancellation
test; Boston Naming Test;
Digits-backward test; clock
drawing test; maze-tracing
task.
↔ Probability of
progression from MCI
to AD (hazard ratio,
1.02; 95% CI,
0.74 – 1.41); ↔ in any
of the secondary
outcome variables
after 3 yrs.
Low
↔ = no difference between vitamin E and control conditions; RCT = randomized controlled trial; ADAS-cog = Alzheimer’s disease
assessment scale – cognition; MMSE = Mini-Mental State Examination; TICS = telephone interview for cognitive status; TICS-M =
telephone interview for cognitive status – modied; AD = Alzheimer’s disease; CDR = clinical dementia rating.
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TABLE 4.
Studies of other nutritional or dietary supplements on cognitive function
First author
(year)
Study Population
(n)
Design and
Duration
Intervention Outcome Measure Results Risk of
Bias
Park
et al.(42)
N=91 (73% women);
subjective memory
complaints including those
with MCI
RCT (balanced
blocked
randomization); 16
wks.
360 mg of Green Tea Extract
and 60 mg of L-theanine or
placebo (maltodextrin and
lactose)
MMSE-Korean;
Rey-Kim memory test;
Stroop color-word reading test
Mean change ± SD: ↔ Stoop (PLA
= 0.67±2.41 vs. Green Tea Extract =
2.47±12.25); Rey-Kim Memory Test (PLA
= 11.26±9.10 vs. Green Tea Extract =
10.60±10.51)
Moderate
Krikorian
et al.(43)
N=12; (33% women);
78.2±5.0 yrs.
RCT; 12 wks. 100% Concord grape juice
(~6-9 mL/kg) or isocaloric
placebo
Verbal (CVLT) and non-verbal
memory (SPALT)
↑verbal learning (PLA = 33.2 vs. Concord
juice = 38.6); ↔ recall PLA = 5.0 vs.
Concord juice = 7.2)
High
Smith
et al.(48)
N=124 (64% women);
hypertensive;
52.3±9.6 yrs.
RCT; 4 mths Dietary Approaches to
Stop Hypertension (DASH),
DASH + weight management,
or usual diet
Trail making test B-A,
Stroop interference, Digit
span, Verbal Fluency test,
Verbal paired associations,
Word Association, and
Psychomotor speed
# Executive function-memory-learning and
psychomotor speed on DASH + weight
management; # psychomotor speed on
DASH alone: Data presented as gures
Moderate
Krikorian
et al.(44)
N=26 (54% women);
71± 6 yrs.
RCT; 3 mths Chromium picolinate
(1000 mcg) or placebo
Clinical Dementia Rating;
CVLT
↔ Learning rate and retention; # semantic
interference on learning, recall, and
recognition memory tasks: Data presented
as gures
High
Grodstein
et al.(45)
N=5956 (n=1904 mean
treatment time = 1 yr.
[new recruits];
n=4052 mean treatment
time = 18 yrs.
[continuing recruits]);
> 65 yrs.
RCT; New recruits
(1 yr.); Continuing
participants
(18 yrs.)
B-carotene every other day
(50 mg) or placebo
Primary: Global composite
score (global cognition, verbal
memory, and category uency)
Secondary: Verbal memory
score
New recruits: (1 yr. treatment) ↔ Global
composite score and verbal uency
Continuing Participants (18 yrs. treatment):
# global composite score and verbal
memory in the continuing participants
(PLA = -0.024±0.71 vs.
Beta Carotene = 0.023±0.69)
High
CANADIAN GERIATRICS JOURNAL, VOLUME 18, ISSUE 4, DECEMBER 2015
FORBES: NUTRITION AND COGNITION
242
TABLE 4.
Continued
First author
(year)
Study Population
(n)
Design and
Duration
Intervention Outcome Measure Results Risk of
Bias
Rossom
et al.(49)
N=4143;
71 yrs. (65-80); women
RCT; Mean
follow-up of
7.8 yrs.
2 tablets/d (1,000mg of
calcium carbonate and 400 IU
of vitamin D3) or placebo
Primary: development of
dementia or MCI
Primary: ↔ Incidence of cognitive
impairment (Hazard ratio: 1.11, 95% CI,
0.71 – 1.74 for dementia)
Moderate
Secondary: 3MSE, Digit
Span Forward and backwards,
Primary Mental Abilities
Vocabulary Test, Card Rotation
Test, Letter and Semantic
uency test, California Verbal
Learning Test, the Benton
Visual Retention Test, and
Finger Tapping Test
Secondary: ↔ 3MSE; ↔ on any
domain-specic cognitive scores
Wolters
et al.(46)
N=220 women;
60-91 yrs.
RCT; 6 mths Vitamin and mineral capsule
(150 mg vitamin C, 50 mg
magnesium, 36 mg vitamin
E, 34 mg niacin, 16 mg
pantothenic acid, 9 mg
B-carotene, 3.4 mg pyridoxine,
3.2 mg riboavin, 2.4 mg
thiamine, 400 μg folic acid,
200 μg biotin, 60 µg selenium,
and 9 μµg cobalamin) or
placebo (soy oil)
Symbol search test, Wechsler
Adult Intelligence Scale,
and pattern recognition and
intelligence
Mean (5-95th percentiles):
↔ Pattern recognition
(PLA = 7.4 (5.0-10.0) vs.
multi-vitamin = 7.6 (5.0-10.0)) and
intelligence (PLA = 110 (90.0-129) vs.
multi-vitamin = 109 (93.4-131));
# symbol search test (PLA = 33.0 (23-42)
vs. multi-vitamin = 35.0 (25-48)
Moderate
Macpherson
et al.(47)
N=56 women; 64-82 yrs. RCT; 16 wks. Multivitamin (contains folic
acid, B6, B12), antioxidant
and mineral formula with
added herbal and antioxidant
plant extracts (Swiss Women’s
Ultivite 50+) or placebo
Primary: memory and
attention composite score
Secondary: Simple Reaction
Time; Complex Reaction
Time; Immediate and Delayed
Recognition Memory; Stroop
Congruent; Contextual
Recognition Memory;
CVLT-II
Primary data is presented as gures.
# Spatial working memory;
↔ any other cognitive test
Moderate
# = signicantly better (p<.05) in the experimental condition; ↔ = no difference between conditions; RCT = randomized controlled trial; MMSE = Mini-Mental State Examination; IU
= international units; MCI = mild cognitive impairment; TICS-M = telephone interview for cognitive status – modied; CVLT = California Verbal Learning Test.
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FORBES: NUTRITION AND COGNITION
243
extra-virgin olive oil on several cognitive measures after an
average of 6.5 years,(79,8 0) cognitive testing was not done at
baseline. As a result, change in cognition in response to the
intervention could not be evaluated. As well, the testing was
done only on sub-groups of participants randomized at one
PREDIMED recruitment site. Other components of a healthy
lifestyle, such as exercise, may be important modulators of
the relationship between dietary intake and cognition.(81)
Their inuence should also be considered in future research.
Much of the research demonstrating a potential link
between nutrition and cognition is observational, done on
animals, or in vitro and may not be relevant to clinical prac-
tice. Our meta-analyses demonstrated no overall effect of
omega-3 fatty acids or select B-vitamin supplementation on
cognition. Green tea extract, chromium, anti-oxidants, and
the DASH (Dietary Approaches to Stop Hypertension) diet
deserve further exploration but cannot be recommended at
this juncture. Future research should utilize rigorous study
methods that incorporate baseline dietary assessments, con-
sider potential modulation by other components of a healthy
lifestyle, and use common and robust outcome measures.
ACKNOWLEDGEMENTS
The authors gratefully acknowledge the support received
from the Brenda Stafford Centre on Aging (SCF), the Brenda
Strafford Foundation Chair in Geriatric Medicine (DBH), the
Brenda Strafford Foundation Chair in Alzheimer Research
(MJP; SCF) of the University of Calgary, and the Canadian
Institutes of Health Research (Funding Reference Number
MOP-93717; MJ Poulin PI). The funders played no role in
the design and conduct of the study, analysis of the data, or
the drafting of this submission.
CONFLICT OF INTEREST DISCLOSURES
The authors have no competing interests to declare.
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Correspondence to: David B. Hogan, md, HSC-3330 Hospital
Dr. NW, Calgary, AB T2N 4N1, Canada
E-mail: dhogan@ucalgary.ca