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Introduction
The Mediterranean Diet is characterized by olive oil as the
main culinary fat, high intake of plant-based foods (fruits, nuts,
vegetables, legumes and minimally processed cereals),
moderate-to-high consumption of fish and seafood, low-to-
moderate intake of dairy products and low intake of meat or
meat products (1, 2). It also included regular but moderate
intake of alcohol in the form of red wine during meals (1, 2).
Compelling evidence supports a protective effect of the
MedDiet on cardiovascular disease (CVD) (1, 3, 4), cancer (4,
5) and total mortality (2-4, 6, 7).
Oxidative stress (8), inflammation (9) and vascular
comorbidity (10) are related to food habits and potentially
involved not only in the pathogenesis of CVD, but also they
could play a role in neurodegenerative disorders. Therefore, the
antioxidant (11) and anti-inflammatory (12) properties of
MedDiet and its cerebrovascular protective effect (1) are
reasons for expecting a protective effect on cognition. Some
observational studies are favorable to this hypothesis, but
consistency is not complete. Inverse associations observed in
some studies (13, 14, 16-20) could not be replicated in others
(15, 21-23). The only available randomized trial evaluating the
effect of MedDiet on cognition found inconsistent results, the
small sample size (n=27) and short duration (10 days) make
difficult to translate its results into sound evidence (24).
Therefore, we aimed to evaluate cognitive function and mild
cognitive impairment (MCI) or dementia in a randomized trial
that compared two MedDiets versus a low-fat diet.
Methods
Study design
The PREDIMED study is a randomized, primary prevention
trial conducted in Spain (May 2005-December 2010) to assess
the potential protective effect of two interventions with
MedDiet (supplemented with EVOO or mixed nuts) compared
to a control (low-fat) diet. The design of the PREDIMED trial
has been the subject of specific publications (1, 11). The
stopping boundary for the benefit of the MedDiets on the
primary end point was crossed at the fourth interim evaluation
VIRGIN OLIVE OIL SUPPLEMENTATION AND LONG-TERM COGNITION:
THE PREDIMED-NAVARRA RANDOMIZED, TRIAL
E.H. MARTINEZ-LAPISCINA1,2, P. CLAVERO3, E. TOLEDO1,4, B. SAN JULIAN1, A. SANCHEZ-TAINTA1,
D. CORELLA4,5, R.M. LAMUELA-RAVENTOS4,6, J.A.MARTINEZ4,7, M.Á. MARTINEZ-GONZALEZ1,4
1. Department of Preventive Medicine and Public Health, Medical School-Clinica, University of Navarra, Pamplona, Spain; 2. Center for Neuroimmunology, Institute of Biomedical
Research August Pi Sunyer (IDIBAPS), Hospital Clinic of Barcelona, Barcelona, Spain; 3. Department of Neurology, Complejo Hospitalario de Navarra, Pamplona, Spain; 4. CIBER
Fisiopatología de la Obesidad y Nutrición (CIBERobn), Instituto de Salud Carlos III (ISCIII), Spain; 5. Department of Preventive Medicine, University of Valencia, Valencia, Spain;
6. Nutrition and Food Science Department, XaRTA, INSA. Pharmacy School, University of Barcelona, Spain; 7. Department of Nutrition.University of Navarra, Spain. Corresponding
author: Elena H Martínez-Lapiscina, Departamento de Medicina Preventiva y Salud Pública, Facultad de Medicina-Clínica Universidad de Navarra, Universidad de Navarra, C/ Irunlarrea
n1 1, Pamplona, Navarra, E-31008, Spain. Tel.: +34-948 425 600, ext. 6463, Fax: +34-948 425 740, E-mail address: elenahmlapiscina@gmail.com or ehernand2@alumni.unav.es
Abstract: Objective: to assess the effect on cognition of a controlled intervention testing Mediterranean diets
(MedDiet). Design: randomized trial after 6.5 years of nutritional intervention. Setting: Eight primary care
centers affiliated to the University of Navarra. Participants: A random subsample of 285 participants (95
randomly allocated to each of 3 groups) of the PREDIMED-NAVARRA trial. All of them were at high vascular
risk (44.8% men, 74.1± 5.7 years at cognitive evaluation). Interventions: Nutritional intervention comparing two
MedDiets (supplemented with extra-virgin olive oil [EVOO] or mixed nuts) versus a low-fat control diet.
Participants received intensive education to increase adherence to the intended intervention. Participants allocated
to the MedDiet groups received EVOO (1 l/week) or 30 g/day of mixed nuts. Dietary habits were evaluated using
a validated 137-item food frequency questionnaire (FFQ). Additionally, adherence to MedDiet was appraised
using a 14-item questionnaire both at baseline and yearly thereafter. Measurements: cognitive performance as a
main outcome and cognitive status (normal, mild cognitive impairment [MCI] or dementia) as a secondary
outcome were evaluated by two neurologists blinded to group assignment after 6.5 years of nutritional
intervention. Results: Better post-trial cognitive performance versus control in all cognitive domains and
significantly better performance across fluency and memory tasks were observed for participants allocated to the
MedDiet+EVOO group. After adjustment for sex, age, education, apolipoprotein E genotype, family history of
cognitive impairment/dementia, smoking, physical activity, body mass index, hypertension, dyslipidaemia,
diabetes, alcohol and total energy intake, this group also showed lower MCI (OR=0.34 95% CI: 0.12-0.97)
compared with control group. Participants assigned to MedDiet+Nuts group did not differ from controls.
Conclusion: A long-term intervention with an EVOO-rich MedDiet resulted in a better cognitive function in
comparison with a control diet. However, non-significant differences were found for most cognitive domains.
Participants allocated to an EVOO-rich MedDiet had less MCI than controls.
Key words: Mediterranean diet, olive oil, randomized controlled trial, cognition, mild cognitive impairment.
1
J Nutr Health Aging
THE JOURNAL OF NUTRITION, HEALTH & AGING©
Received December 12, 2012
Accepted for publication January 29, 2013
MARTINEZ _04 LORD_c 04/03/13 09:38 Page1
and the Data Safety Monitoring Boards recommended to stop
the trial (July, 2011). No relevant diet-related adverse effects
were reported. The study population for the present study was
randomly drawn as a subsample from one of the recruitment
centers (PREDIMED-Navarra). This center completed the
recruitment earlier (May 2005) than other centers (2009) and
thus allowed for longer intervention and induction period for
the effect of nutritional changes on cognition.
Study Population
Eligible subjects were community-dwelling men (55–80
years old) and women (60–80 years old) without CVD but at
high vascular risk because they met one of the inclusion
criteria: (1) type 2 diabetes mellitus or (2) three or more
vascular risk factors, as detailed elsewhere (11). Exclusion
criteria include previous history of CVD, illiteracy and any
severe chronic diseases or conditions that may limit the
compliance with the study protocol (11).
Participants were recruited by general practitioners and
signed an informed consent. Tables of random allocation were
elaborated using a computer-generated random-number
sequence and participants were randomly assigned into blocks
of 50 participants balanced by center, sex, and age group to
three groups (allocation ratio 1:1:1). We concealed allocation
by using closed envelopes with correlative numbers by pre-
specified subgroups of sex and age (11). The PREDIMED-
Navarra center recruited 1,055 participants between 2003 and
2005. A random subsample of 285 of our 969 participants who
were alive after a 6.5-year of nutritional intervention was
selected for this substudy. A total of 271 participants accepted
to participate. Three out of 271 participants were excluded due
to an incomplete neuropsychological examination. As we
applied an intention to treat principle for analysis, all
participants were included in the trial irrespective of their
continuity or adherence to the dietary intervention. Fortunately,
participants randomly selected for the subsample did not have
any serious health problem that impaired them to participate in
the cognitive assessment. The local Institutional Review Board
approved this protocol.
Sample size
An individually randomized trial would require 63
participants per group to detect a difference of the size of 0.5
SD between each of MedDiet groups and the control group for
a two-sided 5% alpha error with 80% statistical power.
Nutrition interventions and dietary assessment
A previously described behavioral intervention promoting
the MedDiet or a low fat diet was implemented during 6.5 years
(11, 25). At inclusion and quarterly thereafter, dietitians gave
intensive education to increase adherence to the intended
intervention. Participants assigned the MedDiet intervention
groups received free allotments of either EVOO (1l/week) or
raw, unprocessed mixed nuts (15g walnuts+7.5g almonds+7.5g
hazelnuts/day). Energy restriction was not advised, nor physical
activity promoted. There was no ethical problem in not
promoting energy restriction or physical activity according to
Institutional Review Boards of all centres. The rationale for this
decision was that the trial was not designed to avoid or replace
the usual care, but as an add-on intervention, assuming that
energy restriction (when needed) and physical activity were
promoted by the usual medical care at the Primary Care Health
Centres with the same intensity in the three groups. Moreover,
the randomized design ensured a balanced distribution of the
three groups in these aspects. In fact, no between-group
clinically significant changes in energy expenditure or energy
intake were observed during the trial.
At baseline and yearly thereafter, a trained dietitian
administered a validated 137-item FFQ and a brief 14-item
questionnaire of adherence to the MedDiet dietary pattern (26,
27). Furthermore, to obtain an objective assessment, some
biomarkers of compliance with MedDiet were assessed in
random samples of participants as detailed elsewhere (25). The
assessment of these biomarkers supports a good adherence to
the intended intervention (25).
Cognitive assessment
A neurologist who was blinded to group allocation
conducted a structured in-person neurological and
neuropsychological examination. The Mini-Mental State
Examination (28, 29) (MMSE) and Clock Drawing Test (30,
31) were used to evaluate global cognition. The
neuropsychological memory test were the verbal paired
associates (32) (Wechsler Memory Scale) to evaluate episodic
memory; the Rey Auditory Verbal Learning Test (33) to assess
immediate (sum of words recalled on the five learning trials)
and delayed verbal memory and Rey-Osterrieth Complex
Figure (ROCF) (34-36) with both immediate and delayed-recall
trials to measure visual memory. Visual-spatial abilities were
evaluated with the copy assay of ROCF (34-36). The
instruments used to assess language were the Boston Naming
Test (37, 38) for naming and animals fluency task (39, 40) and
FAS test (41, 42) to evaluate semantic and phonemic fluency,
respectively. Executive function was measured with the digit
span (43, 44) of the Wechsler Adult Intelligence Scale (WAIS)
and Trail Making Test (TMT) (44, 45) to assess attention and
immediate memory (digits forward and TMT-A) and working
memory (digits backward and TMT-B) and similarities test (31,
46), a subtest of WAIS-IIIR to evaluate abstract reasoning. A
global summary score on the Clinical Dementia Rating (CDR)
scale (47) was also administered. Evidence of impairment in
daily living functioning and in social or occupational functions
was assessed by the Barthel index (48), the Instrumental
Activities of Daily Living scale of Lawton and Brody (49) and
Blessed Dementia Rating Scale (BDRS) (50). The complete
neuropsychological examination lasted two hours so it was
performed in two different days (time interval<1 week). This
first day included a structured in-person neurological
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examination to collect cognitive and mood symptoms and to
perform a standard neurological examination. This first day
also included the administration of the global cognitive scores
(MMSE, CDT and CDR) and tests to appraise the potential in
the daily living functioning and in social or occupational
functions (Barthel, Lawton and Brody and BDRS). The second
day included the complete neuropsychological battery to assess
each specific cognitive domain.
MCI was diagnosed according to the International Working
Group on MCI criteria (51): (1) cognitive decline complaints
reported by participants and/or informants; (2) objective
impairment in at least 1 of the 4 cognitive domains. Impairment
was defined based on the average of the scores on the
neuropsychological tests within that domain and a -1.5SD
cutoff using corrections for sex, age and schooling (28-46); (3)
preserved basic activities of daily living with minimal or no
impairment in complex instrumental functions (47-50) and (4)
absence of dementia. Amnestic and no amnestic MCI were
considered. Diagnosis of dementia was made according to the
DSM-IV criteria (52). Two experienced neurologists who were
blinded to group allocation reviewed the cognitive data in order
to establish a diagnosis of normal cognition, MCI or dementia
by consensus.
Covariate assessment
The baseline questionnaire provided information about
socio-demographic features, lifestyle and health-related habits,
medical history and family history of cognitive impairment or
dementia. Anthropometric measurements were performed by
standard methods (11). Physical activity was assessed with a
validated Spanish version of the Minnesota physical activity
questionnaire (53, 54). The apolipoprotein E (APOE) genotype
was measured by the method proposed by Hixson and Vernier
(55). Only one participant of the 268 analysed was
homozygous for E4, so APOE genotype was considered
dichotomously: presence of at least one E4 allele (sum of E4/3
and E4/4 genotypes) vs. absence of E4 allele and APOE E2/4
genotype was excluded.
Statistical analyses
Analyses were performed based on an intention-to-treat
(ITT) principle. First, we estimated unadjusted mean cognitive
test scores according to the intervention group after a mean of
6.5 years of nutritional intervention. Then, multivariable-
adjusted cognitive relative differences (expressed as
percentages) versus control (95% confidence intervals) in each
group were estimated using general linear models adjusting for
sex, age, education, family history of cognitive impairment or
dementia, APOE4 genotype, hypertension, dyslipidemia,
diabetes, smoking status, alcohol intake, body mass index,
physical activity and total energy intake. To address the
relative role in cognition of the two MedDiet interventions, we
also compared one versus the other MedDiet groups for
cognitive performance using the same method. Finally, we
fitted a logistic regression model adjusted for the mentioned
confounders to estimate the odds ratios for MCI in the
MedDiets groups compared to controls.
Two-tailed p-values <0.05 were considered statistically
significant. We used Benjamini-Hochberg method (56) to
correct for multiple comparisons. Statistics were performed
with SPSS version 17.0 (SPSS Inc,Chicago, IL) software.
Results
Study population
A total of 271 of the 285 participants randomly selected for
this study accepted to participate. We excluded three patients
with an incomplete cognitive examination. Two participants
who accepted to participate in the cognitive substudy, finally
refused to complete the second part of the examination. The
long duration of the study was the reason to refuse argued by
these two participants. The other participant died suddenly
before completing the cognitive study. Finally, 268 participants
were included. Figure 1 shows the flow of participants
throughout the study. The mean age of the study population at
cognitive evaluation was 74.1±5.7 years and 44.8% were men.
Table 1 shows the distribution of participants according to
sociodemographic, medical, anthropometric and life-style
variables at baseline by intervention group. The groups were
well balanced with respect to these characteristics with a non-
significantly higher proportion of current smokers in the
control group. The intervention in the PREDIMED-
NAVARRA centre achieved a substantial contrast between the
2 groups allocated to the MedDiet and the control group. The
average values for the 14-item questionnaire after 5-year
intervention were 10.5(SD:3.3) in MedDiet+EVOO,
9.1(SD:4.9) in MedDiet+Nuts and 5.8(SD:4.7) in the control
group (p<0.001). After 6-year intervention, these figures were
10.8(SD:2.7) in MedDiet+EVOO; 10.1(SD:4.0) in
MedDiet+Nuts and 6.3(SD:4.7) in the control group (p<0.001).
Figure 1
Flow Chart of Participants
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Enrollment
Allocation
Follow-up
Randomly selected
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J Nutr Health Aging
VIRGIN OLIVE OIL SUPPLEMENTATION AND LONG-TERM COGNITION
Table 1
Baseline characteristics* of participants according to
intervention group. Subsample of participants in the
PREDIMED-Navarra trial
VARIABLES MedDiet MedDiet Control P value**
+ EVOO + Nuts (low-fat diet)
(n=91) (n=88) (n=89)
Family history of dementia†, n [%] 25 (27.5) 27 (30.7) 22 (24.7) 0.674
Apolipoprotein E4 genotype‡, n [%] 12 (13.2) 17 (19.3) 14 (15.7) 0.533
Sex male, n [%] 38 (41.8) 35 (39.8) 47 (52.8) 0.170
Age (years) 67.18±5.61 67.33±5.96 67.52±5.67 0.921
Education (years) 8.87±2.08 8.57±2.84 8.75±3.34 0.770
Hypertension, n [%] 68 (74.7) 70 (79.5) 71 (79.8) 0.652
Dyslipidaemia, n [%] 72 (79.1) 67 (76.1) 59 (66.3) 0.124
Diabetes, n [%] 29 (31.9) 30 (34.1) 29 (32.6) 0.949
Body mass index (BMI) (kg/m2) 28.68±3.6 28.83±3.2 29.12±3.5 0.687
Smoking
Current smoker, n [%] 13 (14.3) 9 (10.2) 20 (22.5) 0.074
Former smoker, n [%] 16 (17.6) 18 (20.5) 23 (25.8) 0.390
Alcohol intake (g/day) 16±24 11±15 14±19 0.217
Physical Activity (MET-min/day)∫302±219 249±188 276±220 0.238
Total energy intake (Kcal/day) 2334±531 2246±446 2202±485 0.184
* Mean and Standard Deviation unless otherwise stated. † Family history of dementia or
cognitive impairment in first-degree relatives, ‡Sum of E4/3 and E4/4 genotypes (E2/4
excluded). ∫ Minutes at a given metabolic equivalent level (units of energy expenditure in a
physical activity, 1 MET-min roughly equivalent to 1Kcal). **Chi-squared test
(percentages) or one-way ANOVA (means).
Primary Outcome: cognitive performance
Participants allocated to the MedDiet+EVOO group had
better post-trial cognitive performance in all cognitive tests in
comparison with the control group but these crude differences
did not reach statistical significance after correcting for
multiple comparisons. Favorable differences were also present
in some but not in all cognitive tasks for participants allocated
to the MedDiet+Nuts group (Table 2).
Then, multivariable-adjusted relative differences (expressed
as percentages) versus control (95% confidence intervals)
showed that cognitive performance remained better for
participants allocated to MedDiet+EVOO group. Post-trial
MMSE, ROCF immediate and delayed, FAS and digit forward
scores were significantly higher for these participants compared
with controls (Figure 2). Participants assigned to
MedDiet+Nuts group did not differ from controls (Figure 3).
Multivariable-adjusted relative differences (expressed as
percentages) between the two MedDiet intervention groups
showed that cognitive performance was better for participants
allocated to MedDiet+EVOO group than for those allocated to
MedDiet+Nuts. Participants allocated to MedDiet+EVOO
group had a significantly better performance on both visual
(ROCF immediate and delayed) and verbal (VPA) memory
domains compared to those allocated to MedDiet+Nuts (Figure
4).
Secondary Outcome: cognitive status
We identified 34 participants with MCI at the end of follow-
up (table 3). After adjusting for all confounding factors
mentioned before, participants allocated to the
MedDiet+EVOO had significantly less MCI [OR for MCI, 0.34
95%CI: 0.12 to 0.97] compared to the control group (table 3).
To assess the influence of sex, education and APOE genotype
on the association between MCI and a MedDiet intervention,
we included interaction terms in the logistic regression models
and found no interaction with sex, education or ApoE4
genotype. We found only 5 cases of dementia (1-
MedDiet+EVOO; 3-MedDiet+Nuts; 1-Control).
Table 2
Unadjusted means (95% Confidence Intervals) in cognitive tests after 6.5-year follow-up according to intervention group. The
PREDIMED-Navarra trial
MedDiet + EVOO MedDiet + Nuts Control (low-fat diet) ANOVA P <0.05
(n=91) (n=88) (n=89) P value after correcting for
multiple comparisons
Mean 95% CI Mean 95% CI Mean 95% CI
MMSE 28.14 27.72-28.56 28.83 27.36-28.30 27.48 27.07.27.90 0.130 NO
CDT 5.53 5.19-5.86 5.20 4.85-5.56 5.07 4.72-5.42 0.160 NO
RAVLT (immediate) 32.90 31.06-34.74 31.28 29.04-33.53 30.62 28.61-32.63 0.266 NO
RAVLT (delay) 5.81 5.25-6.37 5.17 4.53-5.81 5.21 4.59-5.84 0.250 NO
VPA 13.43 12.66-14.20 12.05 11.25-12.84 12.81 12.01-13.61 0.047 NO
ROCF (immediate) 13.88 12.49-15.27 10.94 9.54-12.34 11.95 11.47-13.03 0.008 NO
ROCF (delay) 13.27 11.70-14.84 10.83 9.44-12.22 11.13 9.84-12.43 0.033 NO
Similarities 10.90 9.78-12.03 10.64 9.44-11.83 10.11 9.19-11.03 0.582 NO
TMT-A 65.50 58.84-72.16 71.57 64.59-78.55 70.79 63.60-77.98 0.409 NO
TMT-B 199.58 171.48-227.69 232.41 206.91-257.91 220.19 195.51-244.88 0.206 NO
Digit (forward) 7.80 7.38-8.22 7.40 7.01-7.79 6.90 6.55-7.24 0.005 NO
Digit (backward) 4.44 4.03-4.86 4.51 4.09-4.94 4.20 3.91-4.49 0.487 NO
SVFT-Animals 13.05 12.20-13.91 12.17 11.27-13.07 12.16 11.32-12.99 0.244 NO
FVFT-FAS 25.66 23.58-27.74 23.34 21.14-25.54 21.29 19.44-23.14 0.012 NO
BNT 47.27 45.66-48.88 45.43 43.69-47.17 47.19 45.91-48.48 0.175 NO
ROCF (copy) 29.87 28.62-31.11 28.13 26.63-29.62 28.13 26.85-29.41 0.112 NO
Abbreviations: MedDiet, Mediterranean Diet; EVOO, Extra Virgin Olive Oil; MMSE, Mini-Mental State Examination; CDT, Clock Drawing Test; RAVLT, Rey Auditory Verbal
Learning Test; VPA, Verbal Paired Associates; ROCF, Rey-Osterrieth Complex Figure; TMT-A, Trail Making Test A; TMT-B, Trail Making Test B; SVFT Semantic Verbal Fluency
Test; FVFT, Phonemic Verbal Fluency Test; BNT, Boston Naming Test.
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Figure 2
Multivariable-adjusted relative differences (expressed as
percentages) versus control (95% confidence intervals) after 6.5
years of nutritional intervention in MedDiet+EVOO group.
General Linear Models
Adjusted for sex, age, education, apolipoprotein E genotype, family history of cognitive
impairment or dementia, smoking, physical activity, body mass index, hypertension,
dyslipidaemia, diabetes, alcohol and total energy intake. Abbreviations: MedDiet,
Mediterranean Diet; EVOO, Extra Virgin Olive Oil; MMSE, Mini-Mental State
Examination; CDT, Clock Drawing Test; RAVLT, Rey Auditory Verbal Learning Test;
VPA, Verbal Paired Associates; ROCF, Rey-Osterrieth Complex Figure; TMT-A, Trail
Making Test A; TMT-B, Trail Making Test B; SVFT Semantic Verbal Fluency Test;
FVFT, Phonemic Verbal Fluency Test; BNT, Boston Naming Test.
Figure 3
Multivariable-adjusted relative differences (expressed as
percentages) versus control (95% confidence intervals) after 6.5
years of nutritional intervention in MedDiet+Nuts group.
General Linear Models
Adjusted for sex, age, education, apolipoprotein E genotype, family history of cognitive
impairment or dementia, smoking, physical activity, body mass index, hypertension,
dyslipidaemia, diabetes, alcohol and total energy intake. Abbreviations: MedDiet,
Mediterranean Diet; EVOO, Extra Virgin Olive Oil; MMSE, Mini-Mental State
Examination; CDT, Clock Drawing Test; RAVLT, Rey Auditory Verbal Learning Test;
VPA, Verbal Paired Associates; ROCF, Rey-Osterrieth Complex Figure; TMT-A, Trail
Making Test A; TMT-B, Trail Making Test B; SVFT Semantic Verbal Fluency Test;
FVFT, Phonemic Verbal Fluency Test; BNT, Boston Naming Test.
Figure 4
Multivariable-adjusted relative differences (expressed as
percentages) between the two MedDiet intervention groups
after 6.5 years of nutritional intervention. General Linear
Models
Adjusted for sex, age, education, apolipoprotein E genotype, family history of cognitive
impairment or dementia, smoking, physical activity, body mass index, hypertension,
dyslipidaemia, diabetes, alcohol and total energy intake. Abbreviations: MedDiet,
Mediterranean Diet; EVOO, Extra Virgin Olive Oil; MMSE, Mini-Mental State
Examination; CDT, Clock Drawing Test; RAVLT, Rey Auditory Verbal Learning Test;
VPA, Verbal Paired Associates; ROCF, Rey-Osterrieth Complex Figure; TMT-A, Trail
Making Test A; TMT-B, Trail Making Test B; SVFT Semantic Verbal Fluency Test;
FVFT, Phonemic Verbal Fluency Test; BNT, Boston Naming Test.
Discussion
An intervention with EVOO-rich MedDiet was associated
with better cognition especially across fluency and memory
tasks and less MCI as compared to controls after 6.5 years of
nutritional intervention. This is the first study that finds such
results in a randomized trial. The association with better
cognitive function was independent of potential confounders
such as age, family history of cognitive impairment or
dementia, APOE genotype, education, physical activity,
vascular risk factors, and energy intake. Participants assigned to
MedDiet+Nuts group did not differ from controls.
The MedDiet may exert protective effects on cognition
through different mechanisms. First, inflammatory processes
have been considered to be an underlying pathogenic
mechanism of cognitive decline (9). The MedDiet (57) and
some of its nutrients (58) have been related to lower serum
concentrations of inflammatory biomarkers. EVOO, the
hallmark of the MedDiet, contains a large amount of oleic acid
which has been associated with lower inflammatory markers
such as CRP (1) and TNF-α (59). Moreover, EVOO has also
some minor components such as phytosterols, vitamin E and
phenolic compounds with anti-inflammatory properties (60).
Second, oxidative stress is another mechanism related to
cognitive impairment (8). Typical MedDiets include many
nutrients with antioxidant properties, such as fruits, vegetables,
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olive oil, vitamins C and E, and carotenoids (11, 61, 62). In
fact, a previous assessment from the PREDIMED-NAVARRA
found that participants allocated to MedDiet had higher levels
of plasma antioxidant capacity (63). Recently, a cross-sectional
analysis at baseline in another PREDIMED subgroup
(Barcelona) found that total urinary polyphenol excretion as a
biomarker of antioxidant polyphenol-rich food such as EVOO
and walnuts was directly related with better memory function
(64). Finally, the protective effect of the MedDiet on cognition
could also be mediated via cerebrovascular protection, since
compliance with MedDiet seems to improve vascular risk
factors (1). At the same time, there is accruing evidence
relating these conditions with cognitive decline (10).
No previous randomized trial has prospectively assessed the
long-term effect of a MedDiet intervention on cognition.
However, six prospective observational cohorts have focused
on this topic. Our results are in accordance with observational
population based studies conducted in Mediterranean countries.
A non-significant association between greater adherence to the
MedDiet and better global cognition was found in the EPIC-
Greek cohort study (13). Reduced rates of cognitive decline
associated with greater adherence to the MedDiet were reported
in the Three-City French cohort (14). However, results from
French participants who agreed to participate in a
postsupplementation observational follow-up of the SUVIMAX
trial showed only very slight improvements in some analyses,
but did not support an overall beneficial effect of the MedDiet
on cognition (15). Our findings are also in line with some but
not all observational studies conducted in populations outside
the Mediterranean basin. Two large American cohorts
consistently reported lower rates of cognitive decline for
participants with greater compliance to MedDiet (16, 17).
However, another American cohort (21) and an Australian
cohort (22, 23) failed to find this association. Finally, the only
randomized controlled trial to date evaluating the effect of
MedDiet on cognition provided inconclusive results, since it
reported improved visuo-spatial working memory with the
MedDiet while the opposite was seen for numeric working
memory and word recognition, where controls improved with
respect to MedDiet group (24). These findings can be partly
explained by some methodological limitations such as a small
sample size (27 participants) and inordinately short follow up
(10 days). Furthermore, three observational studies have
evaluated adherence to MedDiet and MCI providing
inconsistent results. In an American cohort study, adherence to
the MedDiet was marginally associated with a reduced risk of
MCI (18). Contrarily, another American (19) and an Australian
cohort (22, 23) failed to detect any inverse association.
Considering the nutritional supplements of the trial, namely
EVOO and nuts, participants allocated to EVOO
supplementation group had a significantly better performance
on both visual and verbal memory domains compared to those
allocated to nuts supplementation. These results support an
inverse association between the consumption of extra-virgin
olive oil and amnestic cognitive impairment. This type of
cognitive impairment is the one most commonly associated
with the risk of Alzheimer's Disease (the first cause of dementia
worldwide). Our results are in consistency with previous cross-
sectional findings whereby a higher olive oil intake was
associated with better memory function (64). Our results
especially concur with the better performance on fluency and
visual memory tasks for those with moderate to intensive
consumption of olive oil in the Three-City French cohort (65).
We did not find any association for participants allocated to the
MedDiet+Nuts group. Epidemiological evidence relating nuts
and cognition is scarce and not conclusive as to expect a
protective effect. Previous cross-sectional observations only
reported a moderate effect for walnuts (and not for other nuts)
on working memory but not on other cognitive domains (64). In
the same direction, a higher intake of nuts was associated with
better performance in all cognitive domains at baseline, but not
after 4 years of follow-up in the longitudinal analyses in the
Doetinchem Cohort Study (66).
These discrepancies might be partly explained by intrinsic
limitations of observational studies: (1) the country-specific
dietary pattern and the use of sample-specific cut-off points for
scoring MedDiet that may lead to misclassification between the
low and high MedDiet adherence of Mediterranean and US
populations. Therefore, the groups classified as having the
highest adherence to MedDiet in US or Australian cohorts may
be similar to groups classified as poorly adherent if they were
part of a Mediterranean cohort. Their level of intake of typical
foods of the MedDiet might be not high enough to experience a
protective effect on cognition (19, 22, 23); (2) the intake of
VIRGIN OLIVE OIL SUPPLEMENTATION AND LONG-TERM COGNITION
J Nutr Health Aging
6
Table 3
Mild Cognitive Impairment after 6.5 years of nutritional intervention in each intervention group
Cognitive Status MedDiet MedDiet Control P value P value
+ EVOO (1) + Nuts (2) (low-fat diet) (3) (1-3) (2-3)
(n=90) (n=85) (n=88)
MCI n [%] A-MCI NA-MCI A-MCI NA-MCI A-MCI NA-MCI
6 (6.6) 1 (1.1) 9 (10.6) 1(1.1) 14 (15.9) 3 (3.4)
MCI* n [%] 7 (7.8) 10 (11.8) 17 (19.3) 0.024 0.171
OR** for MCI (all types) 0.341 (0.120-0.969) 0.563 (0.222-1,427) Reference 0.044 0.226
95% CI
*Including mild cognitive impairment of all subtypes. A-MCI (Amnestic MCI), NA-MCI (No Amnestic MCI). ** Adjusted for sex, age, education, apolipoprotein E genotype, family
history of cognitive impairment or dementia, smoking, physical activity, body mass index, hypertension, dyslipidaemia, diabetes, alcohol and total energy intake.
MARTINEZ _04 LORD_c 04/03/13 09:38 Page6
other foods not measured in the MedDiet adherence score that
can be responsible for residual confounding; (3) the nutritional
assessment tools frequently used in observational studies which
are prone to measurement errors that usually tend to lead to null
associations. Additionally, it is important to consider other
factors: (1) a short length of follow-up in many of the previous
studies (21, 22, 24); (2) the differences in the outcome and the
neuropsychological tools which may limit the comparability
across different studies.
Limitations of this study should be discussed. First, the most
important limitation of the study is that cognitive status was not
measured at baseline. However the fact that the presence of any
chronic disease or condition that may limit the compliance with
the study protocol was an exclusion criterion argues for the
likely absence of relevant cognitive decline at baseline. More
importantly, the random allocation of participants to the 3
intervention arms resulted in well-balanced groups with respect
to the overall baseline characteristics. This is a good reason to
confide that cognitive status was also similar at baseline among
groups. In addition, our analysis included a wide array of
potential confounders, so even though small between-group
differences in cognition at baseline might had existed, it would
be unlikely that they remained after multivariate adjustment,
because that alternative possibility would imply also statistical
independence from all covariates that we adjusted for.
Nonetheless, we acknowledge that the lack of baseline
cognitive status is a major limitation, especially because it
precludes our ability to repeatedly evaluate cognitive decline
over time. Second, sample size was relatively small. Finally,
due to the study design, only participants at high vascular risk
were included so caution is needed in the extrapolation of these
results to the general population
Confidence in our results is strengthened by the following
factors. First, the nutritional interventions and
neuropsychological evaluations were assessed with validated
diet measurement tools (26, 27), standardized
neuropsychological tests (28-50) and well-established
diagnostic criteria (51, 52). Second, potential confounders were
carefully recorded and controlled for in the analyses so along
with randomization, our fully-adjusted results allow us to allay
the threat of relevant residual confounding. Third, the
randomized design prevents us from some intrinsic biases of
observational studies such as the “healthy person bias” or
“reverse causation bias”. The former may reduce the validity of
observational studies since a general healthier lifestyle of
subjects adhering to a MedDiet pattern can contribute to the
protective effect on cognition (13, 18). The latter is referred to
the possibility that a lower compliance to the MedDiet may
represent a consequence and not a contributing factor of an
undiagnosed cognitive decline (13, 18). The randomization and
the ITT analysis almost completely avoid this bias since the
lack of compliance with the intended intervention would in any
case bias the estimate toward the null (67).
In conclusion, a randomized intervention with EVOO-rich
MedDiet was associated with better cognitive performance
especially across fluency and memory domains and less MCI
after 6.5-year of nutritional intervention compared with a low-
fat diet intervention. Future randomized studies with larger
sample size and both baseline and follow-up cognitive
assessments will provide stronger evidence on the role of
EVOO-rich MedDiet on cognition.
Acknowledgements: The authors thank the participants for their enthusiastic
collaboration, the PREDIMED personnel for excellent assistance, and the personnel of all
affiliated primary care centers.
Original prococol: The original protocol has been published in an open access at
http://www.unav.es/departamento/preventiva/predi_thematic (Research Plan of the
PREDIMED trial).
Author contributions: EHML, MAMG, had full access to all the data in the study and
take full responsibility for the integrity and accuracy of the data analysis. Study concept
and design: MAMG, ET, PC, EHML. Analysis and interpretation of data: EHML, PC,
MAMG. Drafting of the manuscript: EHML, MAMG, PC. Funding and administrative
support: ET, MAMG, BSL, AST, DC, RMLR, IAM. Critical revision of the manuscript for
important intellectual content: All the authors.
The PREDIMED Study Investigators: University of Navarra, Primary Care Division
Centres, Pamplona, Spain: P. Buil-Cosiales, J. Díez-Espino, A. García-Arellano, E. Goñi,
V Extremera Urabayen, C Arroyo Azpa, L García Pérez, I. Zazpe, J. Basterra-Gortari, M.
Serrano-Martínez, N. Ortuño, N. Berrade, C. Razquin, J. Villanueva Tellería, F. Cortés
Ugalde, T. Sagredo Arce, Mª D. García de la Noceda Montoy, Mª D. Vigata López, Mª T.
Arceiz Campo, A. Urtasun Samper, Mª V. Gueto Rubio, and B. ChurioBeraza. University
of Valencia, Valencia, Spain: P. Carrasco, O. Portolés. School of Pharmacy, University of
Barcelona, Barcelona, Spain: M.C. López-Sabater, A. Tresserra-Rimbau. Hospital Clinic,
Institutd’InvestigacionsBiomèdiques August Pi i Sunyer, Barcelona, Spain: R.Estruch, E.
Ros, M. Serra, A. Pérez-Heras, C. Viñas, R. Casas, L. De Santamaría, S. Romero, J.M.
Baena, M. García, M. Oller, J. Amat, I. Duaso, Y. García, C. Iglesias, C. Simón, Ll.
Quinzavos, Ll. Parra, M. Liroz, J. Benavent, J. Clos, I. Pla, M. Amorós, M.T. Bonet, M.T.
Martin, M.S. Sánchez, J. Altirruba, E. Manzano, A. Altés, M. Cofán, C. Valls-Pedret, A.
Sala-Vila, and M. Doménech. University Rovira I Virgili, Reus, Spain: J. Salas-Salvado,
R. González, C. Molina, F. Sorli, J. García Roselló, F. Martin, R. Tort, A. Isach, B. Costa,
J.J. Cabré, and J. Fernández-Ballart. Institute de Recerca Hospital del Mar, Barcelona,
Spain: M.I. Covas, S. Tello, J. Vila. University Hospital of Alava, Vitoria, Spain: F. Aros,
I. Salaverría, T. del Hierro. University of Málaga, Málaga, Spain: E. Gómez-Gracia, J.
Wärnberg, J. Martínez-González, J Fernández-Crehuet. Instituto de la Grasa, Consejo
Superior de Investigaciones Científicas, Sevilla, Spain: V. Ruiz-Gutiérrez, J. Sánchez
Perona, E. Montero Romero. Institute of Health Sciences IUNICS, University of Balearic
Islands, and Hospital Son Espases, Palma de Mallorca, Spain: M.Fiol, D. Romaguera, M.
Moñino. Department of Family Medicine, Primary Care Division of Sevilla, Sevilla, Spain:
J Lapetra, M. Leal, M. Ortega-Calvo. University of Las Palmas de Gran Canaria, Las
Palmas, Spain: L. Serra-Majem, A Sánchez-Villegas, J. Álvarez-Pérez. Hospital
Universitario de Bellvitge, Hospitalet de Llobregat, Barcelona, Spain: X Pinto, A. Galera,
E. Corbella. Other investigators of the PREDIMED network: A. Marti (University of
Navarra), M.P. Portillo (University of Basque Country), G. Sáez (University of Valencia),
J. Tur (University of Balearic Islands) and M.T. Mitjavila (University of Barcelona).
Conflict of interest statement: Elena H Martínez-Lapiscina has received travel and
accommodation expenses from Novartis, Biogen, Teva, Sanofi Aventis, Lundbeck and
Bayer for national and international congress. Pedro Clavero has received payment for
lectures from UCB Pharma, GlaxoSmithkline and Lundbeck and travel and
accommodation expenses for congress from Lundbeck, Esteve and UCB Pharma. All
other authors declare that they have no conflict of interest.
Funding: This study was funded by the official agency for funding biomedical research
of the Spanish Government (ISCIII) through the following competitive grants: PI1001407,
PI1002293 PI081943, PI070240, PI050976, Thematic Network Nutrition & Cardiovascular
disease G03/140 (Coordinator Ramón Estruch), Thematic Network PREDIMED
RD06/0045 (Coordinator Miguel A. Martínez-Gonzalez), FEDER (FondoEuropeo de
Desarrollo Regional) and CIBERobn (Virtual Center for Biomedical Research on Obesity
and Nutrition). CIBERobn is an initiative of ISCIII, Spain. Additional funding was
provided by the Government of Navarra (PI41/2005, PI36/2008, PI27/2012). Estefania
Toledo is supported by a Rio Hortega post-residency fellowship of ISCIII, Ministry of
Economy and Competitiveness, Spanish Government. None of the funding sources played
a role in the design, collection, analysis or interpretation of the data, or in the decision to
submit the manuscript for publication. Fundación Patrimonio Comunal Olivarero and
Hojiblanca SA, California Walnut Commission, Borges SA, and Morella Nuts SA
generously donated the olive oil, walnuts, almonds, and hazelnuts, respectively, used in the
THE JOURNAL OF NUTRITION, HEALTH & AGING©
J Nutr Health Aging
7
MARTINEZ _04 LORD_c 04/03/13 09:38 Page7
study. None of the mentioned food companies played or will play any role in the design,
collection, analysis or interpretation of the data or in the decision to submit manuscripts for
publication.
Trial Registration: ISRCT:35739639.
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