mediterranean diet and cognitive health: an update of available knowledge

8/19/2019 Mediterranean diet and cognitive health: an update of available knowledge

1/12Copyright © Lippincott Williams Wilkins. Unauthorized reproduction of this article is prohibited.

CURRENTOPINION Mediterranean diet and cognitive health: an updateof available knowledge

Catherine Feart, Cécilia Samieri, and Pascale Barberger-Gateau

Purpose of review

Nutrition constitutes an interesting approach for the prevention of age-related brain disorders. The objectiveof this review was to examine the most recent evidence on the association between adherence to aMediterranean diet (MeDi) and cognitive health among elderly individuals.

Recent findings

Based on available epidemiological studies, two meta-analyses published in 2013 have underlined aprotective effect of a greater MeDi adherence on cognitive health, including a reduced risk of Alzheimer’sdisease and cognitive impairment. Since then, six additional studies, from longitudinal cohorts or post-hoc

analyses of randomized controlled trials conducted in the USA and Europe, have been published andprovided mixed results. Potential reasons for such discrepancies include methodological limitations inherentto observational studies, and interactions between diet, environmental factors, such as those enhancingcognitive reserve, chronic diseases, and genetic factors.

Summary

Overall, available evidence suggests that the MeDi might exert a long-term beneficial effect on brainfunctioning. However, more high-powered observational studies with long-term follow-up for cognition andrandomized controlled trials assessing the impact of shifting to a MeDi on cognitive functions are stillneeded in various populations.

Keywords

aging, cognitive functions, Mediterranean diet

INTRODUCTION

Progressive cognitive decline and neurodegenera-tive diseases associated with aging are responsiblefor a considerable public health challenge becauseof the rapid growth of the proportion of olderpeople all over the world and the limited efficacyof pharmacological therapies to date [1]. The pre-valence of dementia, whose most frequent causeis Alzheimer’s disease, increases with age fromapproximately 1.0% in the age group 65–69 years

to 30% in the older than 90 years age group [2]. Themanagement of older people with dementia gener-ates a huge financial burden for society, estimated at$41 000–$56 000 per dementia case per year in 2010in the USA [3]. Therefore, strategies to prevent ordelay the entry into the neurodegenerative process,to slow down its progression, and avoid conversionto dementia must be developed. In this context,prevention by modifiable lifestyle factors, such asnutrition, has been suggested as potential effectivestrategy [4–7]. More specifically, there has been arecent interest in healthy dietary patterns, which

consider the synergistic effect of foods and nutrientsconsumed together [8]. Initially described as thetypical dietary pattern of populations living aroundthe Mediterranean basin [9], the so-called ‘Mediter-ranean diet’ (MeDi) has gained increasing interest –thanks to its many benefits on health [10]. Sincethe first published benefit of higher MeDi adher-ence n the risk of Alzheimer’s disease [11], a rapidaccumulation of knowledge has promoted thisdietary pattern as one of the healthiest for cognitive

health, as confirmed by recent critical reviews[10,12,13&

,14,15].

INSERM, ISPED and University Bordeaux, ISPED, Centre INSERM

U897-Epidemiologie-Biostatistique, Bordeaux, France

Correspondence to Catherine Feart, Equipe Epidémiologie de la nutrition

et des comportements alimentaires, INSERM, U897, Université de

Bordeaux, ISPED, 146 rue Léo-Saignat, CS61292, F-33076 Bordeaux,

Cedex, France. Tel: +33 5 47 30 42 04; fax: +33 5 57 57 14 86; e-mail:

[email protected]

Curr Opin Clin Nutr Metab Care 2015, 18:51–62

DOI:10.1097/MCO.0000000000000131

1363-1950 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins www.co-clinicalnutrition.com

REVIEW

mailto:[email protected]:[email protected]



The purpose of this article was to updateprevious reviews with the most recent availableevidence (from 2013 to mid-2014) from longitudi-nal epidemiological studies and randomized con-trolled trials (RCTs) addressing the relationshipbetween MeDi adherence and cognitive healthamong elderly people.

First introduced by Ancel Keys in the Seven-Country study, the concept of MeDi was describedas a collection of eating habits traditionally fol-

lowed by the populations of the Mediterraneanbasin [9,16]. This dietary pattern has remainedrelatively constant over time and space, and consistmainly of high consumption of plant foods (i.e.,fresh or dried fruits and vegetables, legumes, andcereals), high intake of olive oil as the main sourceof added fat, moderate amount of fish, low-to-moderate intake of dairy products, low consump-tion of meat and poultry and many condiments andspices, all accompanied by infusions, or wine inlow-to-moderate amounts during meals, alwaysrespecting beliefs of each community [9]. There is

no single MeDi, but a scientific consensus hasnow been reached on what constitutes a typicalMeDi today [17]. Beyond dietary habits, theMeDi is also part of a lifestyle, constitutes a setof traditional practices, skills, knowledge, andtraditions, from generation to generation, rangingfrom the landscape to the table, and providing asense of belonging and continuity to the concernedcommunities [17]. These features have led to theinscription of the MeDi on the representative list of the Intangible Cultural Heritage of Humanity byUNESCO in 2010.

OVERALL HEALTH BENEFITS OF THE

MEDITERRANEAN DIET: ACCRUING

RECENT EVIDENCE

A protective effect of greater MeDi adherence ongeneral health, and in particular chronic diseases,has been suggested for a long time. A meta-analysis,which has been updated with more recent published

studies in 2013, reported that a 2-point increase inMeDi adherence, assessed by a 10-point scale, wassignificantly associated with lower mortality rates[relative risk (RR)¼0.91, 95% confidence interval(CI) 0.89– 0.93], and reduced risks for fatal and non-fatal cardiovascular diseases (RR¼0.90, 95% CI0.87–0.92) and cancers (RR¼0.95, 95% CI 0.93–0.97) [18

&

]. Regarding vascular outcomes, a recentprimary prevention multicenter RCT conducted inSpain (PREvencion con DIeta MEDiterranea, PRE-DIMED) reported that individuals at high cardiovas-cular risk allocated to a MeDi supplemented with

extra virgin olive oil (EVOO) (1 l/week) or mixednuts (30 g/day of walnuts, almonds, and hazelnuts)for 4.8 years had a lower risk of stroke comparedwith a low-fat diet [19

&&

]. Finally, the MeDi has alsobeen suggested as a protective dietary approachagainst the risk of type 2 diabetes mellitus [20].

RATIONALE FOR A PROTECTIVE ROLE OF

THE MEDI IN BRAIN AGING

The potential benefit of a greater MeDi adherenceon cognitive health has only recently emerged,although this dietary pattern provides foods or

nutrients (i.e., virgin olive oil, provider of mono-unsaturated fatty acids and polyphenols, fish, richin long-chain v-3 polyunsaturated fatty acids andvitamin D, fruits and vegetables, rich in antioxi-dants, vitamins C and E, carotenoids, folate, andpolyphenols) that alone may contribute to delayage-related cognitive decline [21–23]. Altogether,these nutrients could have a beneficial impact oncognition through various mechanisms includingvascular, antioxidant and anti-inflammatory path-ways [24]. For instance, the MeDi provides long-chain v-3 polyunsaturated fatty acids, which have

well documented anti-inflammatory effects via theirderivatives (i.e., eicosanoids such as prostaglandinsand leukotrienes and docosanoids such as neuro-protectin D1) [25,26]. By providing foods rich inpowerful antioxidants, the MeDi may contribute todecrease oxidative stress and lipid peroxidation, asindicated by reported associations between higherMeDi adherence and lower plasma F2-isoprostanelevels and higher ascorbic acid concentrations[27,28]. A favorable effect of the MeDi on cardio-vascular risk factors (reduced total cholesterol andlow-density lipoproteins) has also been reported in

KEY POINTS

There is a strong biological rationale for a protectiverole of the MeDi in brain aging.

Results from previous meta-analyses mostly convergetoward a beneficial effect of the MeDi on cognitivehealth, whereas conclusions from last published

longitudinal observational studies are inconsistent.

To date, there is a lack of scientific evidence to ensurethat the MeDi is an optimal dietary strategy of theprevention of the age-related neurodegeneration.

There is a need for large-scale studies in variouspopulations with common methodology beforeproviding convincing conclusions.

The promotion of the healthy MeDi should beextended, at least for maintaining overall health,but keeping in mind special features of elderlyindividuals.

Ageing: biology and nutrition

52 www.co-clinicalnutrition.com Volume 18 Number 1 January 2015



seven RCTs conducted in healthy adults and adultsat high risk of cardiovascular diseases [29]. Inaddition, a meta-analysis of prospective studiesand RCTs including more than 530 000 individualshas shown that MeDi adherence was associated withreduced risk of metabolic syndrome [30], itself associated with dementia risk, in particular vascular

dementia [31]. Altogether, these data suggest thatthe MeDi could be a particularly promising dietarypattern for lowering dementia risk, by direct orindirect ways.

LAST PUBLISHED LONGITUDINAL STUDIES

IN THE FIELD

Since 2006 and the first large-scale evidence of aprotective association between MeDi adherence andthe risk of Alzheimer’s disease among participantsfrom the Washington Heights-Inwood ColumbiaAging Project [11], many longitudinal studies havebeen published, including six studies on the associ-ation between MeDi adherence and cognitivedecline [32–37], five studies on the incidence of mild cognitive impairment (MCI) [38–42] and threestudies on the risk of Alzheimer’s disease or demen-tia [32,40,43]. To help in summarizing the abundantexisting literature, three reviews [13

&

,14,44] andtwo meta-analyses have already been conducted[45

&&

,46&&

].The first meta-analysis published in 2013

focused on cognitive impairment as outcome,defined as mild or severe cognitive performances,

risk of MCI or Alzheimer’s disease, and includingeight case–control, cross-sectional, and longitudi-nal studies [45

&&

]. Higher adherence to a MeDi wassignificantly inversely associated with lower risk of cognitive impairment (pooled effect, RR¼0.60, 95%CI 0.43–0.83). The magnitude of this associationwas slightly decreased when moderate MeDi adher-ence was considered (pooled effect, RR¼0.79, 95%CI 0.62–0.95). Similar findings were reported withAlzheimer’s disease, despite some heterogeneity inthe methods of diagnosis across eligible studies[45

&&

]. The second meta-analysis examined the

association between MeDi adherence and cognitivehealth focusing on incident cognitive impairment,which included any incident outcomes (either MCIor Alzheimer’s disease in cognitively normal sub-jects, or Alzheimer’s disease in MCI subjects), risk of MCI from cognitively normal subjects at baseline,and risk of Alzheimer’s disease f rom cognitivelynormal subjects at baseline [46

&&

]. This meta-analysis reported that the highest MeDi tertile, com-pared with the lowest tertile, was associated withsignificantly reduced risks of MCI, Alzheimer’s dis-ease, and cognitive impairment (hazard ratio¼0.73,

95% CI 0.56–0.96; hazard ratio¼0.64, 95% CI 0.46–0.89 and hazard ratio¼0.67, 95% CI 0.55–0.81respectively), with only a dose-response eff ectregarding the risk of cognitive impairment [46

&&

].These findings add to the growing body of evidenceof a protective effect of the MeDi on cognitivehealth, despite the small number of studies included

in both meta-analyses (no more than five longitudi-nal cohort studies).Six additional longitudinal studies, not included

in previous meta-analyses, have been publishedduring the last 18 months [33,34,36,37,39,40].These studies, including four reports from theUSA and two from Europe, are described in detailhere, and summarized in Table 1.

Reports from the USA

Four studies have recently reported the associationbetween MeDi adherence and cognitive perform-ances over time among US people, as describedbelow.

Women’s Health Study

The relationship between adherence to the MeDiand cognitive change was examined in an ancillarycognitive substudy of the Women’s Health Study(an RCT for the primary prevention of cardiovascu-lar diseases and cancer with low-dose aspirin andvitamin E supplements in women; N ¼6174, ages70 years and older from the cognitive substudy wereanalyzed) [33]. An average 5.6 years after the dietary

survey, which served to ascertain MeDi adherence, acognitive examination was performed by telephone.Two repeated visits were conducted at approxi-mately 2-year intervals. There was no significantassociation between higher adherence to the MeDiand the trajectories of cognitive change or averagedcognition in this sample of older women. Thespecific characteristics of the population studied,with a high socioeconomic level and a narrow rangeof score of MeDi adherence in this US-based popu-lation, might in part explain these null findings.

Nurse’s Health StudyThe association between long-term MeDi adherencesince midlife and cognitive decline in late life wasalso investigated in a very large sample of US womenenrolled in the cognitive substudy of the Nurse’sHealth Study (N ¼16 058, ages 70 years and olderand free of stroke at the time of first cognitiveexamination) [34]. The long-term MeDi adherencewas assessed from repeated dietary surveys con-ducted every 4 years for 13 years, on average.Cognition was assessed by telephone four times at2-year intervals, using a validated cognitive battery.

Mediterranean diet, cognitive decline and dementia Feart et al.

1363-1950 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins www.co-clinicalnutrition.com 53

http://-/?-http://-/?-



T a b l e 1 .

A d h e r e n c e t o a M e

d i t e r r a n e a n - l i k e

d i e t a n

d c o g n i t i v e

h e a

l t h : s

u m m a r y o

f m a i n l o n g i t u

d i n a

l s t u

d i e s p

u b l i s h e

d f r o m

2 0 1 3 t o m i d - 2 0 1 4

S t u d y ,

l o c a t i o n ,

a u t h o r s ( r e f e r e n c e )

P a r t i c i p a n t s

F o l l o w - u p ( m e a n ( S D )

a n d / o r r a n g e )

M

e D i a d h e r e n c e :

m e t h o d o f a s s e s s m e n t

O u t c o m e s

A d j u s t m e n t v a r i a b l e s

M

a i n f i n d i n g s

W o m e n ’ s H e a l t h S t u d y ,

U S A , S a m i e r i e t a l .

[ 3 3 ]

6 1 7 4 w o m e n

, m e a n

( S D ) a g e 7 2 . 0 ( 4 . 1 )

y e a r s a t b a

s e l i n e o f

t h e R C T ( d i e t a r y

a s s e s s m e n t )

4 y e a r s o n a v e r a g e

S e

m i q u a n t i t a t i v e F F Q t o

c o m p u t e t h e a l t e r n a t e

M e D i a d h e r e n c e s c o r e

F i v e q u i n t i l e s w e r e

c o n s i d e r e d

C o m p o s i t e s c o r e s o f g l o b a l

c o g n i t i o n a n d

v e r b a l

m e m o r y a s s e s s e d b y a

b a t t e r y o f f i v e

t e s t s ( T I C S ,

i m m e d i a t e a n d d e l a y e d

r e c a l l s o f t h e E a s t B o s t o n

M e m o r y T e s t ,

d e l a y e d

r e c a l l o f t h e T

I C S 1 0 -

w o r d l i s t , a n d

c a t e g o r y

f l u e n c y ) ( t h r e e

r e p e a t e d

m e a s u r e s a t a

p p r o x i -

m a t e l y 2 - y e a r

i n t e r v a l s )

A g e , r a c e , e d u c a t i o n ,

i n c o m e , R C T t r e a t m e n t

a r m , r e g u l a r v i g o r o u s

e x e r c i s e , B M I , s m o k i n g ,

d i a b e t e s , h i s t o r y o f

d e p r e s s i o n , h y p e r t e n -

s i o n , h y p e r c h o l e s t e r o l e -

m i a , a n d

p o s t m e n o p a u s a l h o r -

m o n e u s e

N

o e v i d e n c e o f a n a s s o c i -

a t i o n b e t w e e n g r e a t e r

a l t e r n a t e M e D i s c o r e

a n d b e t t e r t r a j e c t o r i e s o f

g l o b a l c o g n i t i o n a n d v e r -

b a l m e m o r y ( P f o r q u i n -

t i l e s m e d -

i a n t i m e ¼

0 . 2 6 f o r 4 -

y e a r t r a j e c t o r i e s o f m e a n

r e p e a t e d g l o b a l c o g n i -

t i v e s c o r e s a n d P f o r

q u i n t i l e s m e d -

i a n t i m e ¼

0 . 4 0 f o r 4 -

y e a r t r a j e c t o r i e s o f m e a n

r e p e a t e d v e r b a l m e m o r y

s c o r e s )

T h e o v e r a l l c o g n i t i v e s t a t u s

( a v e r a g e d m e a s u r e o f

g l o b a l c o g n i t i v e f u n c t i o n

a n d o f v e r b a l m e m o r y )

w a s n o t s i g n i f i c a n t l y

a s s o c i a t e d w i t h a l t e r n a t e

M e D i s c o r e ( P f o r

t r e n d ¼ 0 . 6 3 a n d 0 . 4 4 ,

r e s p e c t i v e l y )

N u r s e ’ s H e a l t h S t u d y ,

U S A , S a m i e r i e t a l .

[ 3 4 ]

1 6 0 5 8 w o m e n , m e a n

( S D ) a g e 7 4 . 3 ( 2 . 3 )

y e a r s a t b a

s e l i n e

1 3 y e a r s o n a v e r a g e

S e

m i q u a n t i t a t i v e F F Q

a s s e s s e d a t m i d l i f e i n

1 9 8 4 , 1 9 8 6 , 1 9 9 0 ,

1 9 9 4 , a n d 1 9 9 8

C o m p o s i t e s c o r e s o f g l o b a l

a n d v e r b a l m e m o r y

a s s e s s e d b y a

b a t t e r y o f

s i x t e s t s ( T I C S , i m m e d i a t e

a n d d e l a y e d r e c a l l s o f

t h e E a s t B o s t o

n M e m o r y

T e s t , d e l a y e d

r e c a l l o f

t h e T I C S 1 0 - w

o r d l i s t ,

c a t e g o r y f l u e n

c y a n d

d i g i t s p a n b a c k w a r d )

( f o u r r e p e a t e d

m e a s u r e s

b e t w e e n 1 9 9 5 a n d

2 0 0 1 )

A g e , e d u c a t i o n , l o n g - t e r m

p h y s i c a l a c t i v i t y a n d

e n e r g y i n t a k e , B M I ,

s m o k i n g , m u l t i v i t a m i n

u s e , h i s t o r y o f d e p r e s -

s i o n , d i a b e t e s , h y p e r t e n -

s i o n , h y p e r c h o l e s t e r o l e -

m i a , a n d m y o c a r d i a l

i n f a r c t i o n

N

o a s s o c i a t i o n b e t w e e n

a l t e r n a t e M e D i a d h e r -

e n c e a n d c h a n g e i n c o g -

n i t i o n o v e r t i m e i n t h e

T I C S ( P f o r t r e n d ¼

0 . 3 7 ) ,

g l o b a l c o g n i t i v e s c o r e ( P

f o r t r e n d ¼

0 . 3 3 ) a n d

v e r b a l m e m o r y ( P f o r

t r e n d ¼ 0 . 3 6 )





L o

n g - t e r m a l t e r n a t e M e D i

s c o r e w a s c o m p u t e d a s

t h e m e a n o f s c o r e s

a c r o s s a l l d i e t a r y a s s e s s -

m e n t s . F i v e q u i n t i l e s

w e r e c o n s i d e r e d

T h e o v e r a l l c o g n i t i v e s t a t u s

w a s s i g n i f i c a n t l y h i g h e r

w i t h h i g h e r l o n g - t e r m

a l t e r n a t e M e D i a d h e r -

e n c e . P a r t i c i p a n t s

b e l o n g i n g t o t h e q u i n t i l e

f i v e o f a l t e r n a t e M e D i

a d h e r e n c e s c o r e h a v e

m e a n p e r f o r m a n c e s o f

þ 0 . 0 6 ( 9 5 % C I 0 . 0 1 –

0 . 1 1 ) i n t h e T I C S ( P f o r

t r e n d ¼ 0 . 0 0 4 ) , þ 0 . 0 5

( 9 5 % C I 0 . 0 1 – 0 . 0 8 ) i n

t h e g l o b a l s c o r e o f c o g -

n i t i o n ( P f o r

t r e n d ¼ 0 . 0 0 2 ) a n d

þ 0 . 0 6 ( 9 5 % C I 0 . 0 3 –

0 . 1 0 ) i n t h e v e r b a l m e m -

o r y s c o r e ( P f o r t r e n d

< 0 . 0 0 1 ) c o m p a r e d w i t h

t h o s e o f f i r s t q u i n t i l e

C a c h e C o u n t y S t u d y o n

M e m o r y , H e a l t h a n d

A g i n g , U S A , W e n -

g r e e n e t a l . [ 3 6 ]

3 8 3 1 c o m m u

n i t y - b a s e d

n o n d e m e n t e d i n d i v i d -

u a l s a g e s 6

5 y e a r s

a n d o l d e r a t b a s e l i n e

1 0 . 6 y e a r s f o r t h e w h o l e

c o h o r t , n o d a t a f o r t h e

s u b s a m p l e s t u d i e d

S e

l f - a d m i n i s t e r e d F F Q

a s s e s s e d a t b a s e l i n e i n

1 9 9 5 a n d c a l o r i c -

d e r i v e d r e s i d u a l s

F i v e q u i n t i l e s w e r e

c o n s i d e r e d

3 M S a s s e s s e d f o u r t i m e s

d u r i n g f o l l o w - u p

A g e , s e x , B M I , f r e q u e n c y

o f m o d e r a t e p h y s i c a l

a c t i v i t y , m u l t i v i t a m i n a n d

m i n e r a l s u p p l e m e n t u s e ,

h i s t o r y o f s m o k i n g a n d

d r i n k i n g , h i s t o r y o f d i a -

b e t e s , h e a r t a t t a c k , a n d

s t r o k e

A

t b a s e l i n e , h i g h e r M e D i

s c o r e s w e r e a s s o c i a t e d

w i t h h i g h e r m e a n 3 M S

s c o r e s . P a r t i c i p a n t s

b e l o n g i n g t o t h e q u i n t i l e

f i v e o f M e D i s c o r e h a v e

m e a n p e r f o r m a n c e s o f

þ 0 . 9 4 ( S E 0 . 2 9 ) c o m -

p a r e d w i t h t h o s e o f

f i r s t q u i n t i l e ( P f o r t r e n d

¼

0 . 0 0 2 )

T h e s e d i f f e r e n c e s w e r e

m a i n t a i n e d o v e r t i m e

a n d t h e r a t e s o f 3 M S

c h a n g e o v e r t i m e w e r e

n o t s i g n i f i c a n t l y d i f f e r e n t

a c r o s s t h e q u i n t i l e

g r o u p s

( C o n t i n u e d )





T a b l e 1 ( C o n t i n u e

d )

S t u d y ,

l o c a t i o n ,





M



O u t c o m e s


M


R E G A R D S , U S A , T s i v -

g o u l i s e t a l . [ 3 9 ]

1 7 4 7 8 c o m m

u n i t y -

b a s e d n o n d e m e n t e d

i n d i v i d u a l s

a g e s 4 5

y e a r s a n d o l d e r a t

b a s e l i n e

4 . 0 y e a r s ( 1 . 5 ) o n a v e r a g e S e

l f - a d m i n i s t e r e d F F Q a n d

c a l o r i c - d e r i v e d r e s i d u a l s

t o c o m p u t e t h e M e D i

s c o r e ( 0 – 9 p o i n t s c a l e )

T w

o c a t e g o r i e s :

L o w a d h e r e n t s

( s c o r e s 0 – 4 )

H i g h a d h e r e n t s

( s c o r e s 5 – 9 )

1 2 4 8 i n c i d e n t c

o g n i t i v e

i m p a i r m e n t c a

s e s ,

a s s e s s e d b y t h e S i x - I t e m

S c r e e n e r

A g e , r a c e , s e x , r e g i o n o f

r e s i d e n c e , B M I , w a i s t c i r -

c u m f e r e n c e , h o u s e h o l d

i n c o m e , e d u c a t i o n ,

s m o k i n g s t a t u s , a l c o h o l

u s e , p h y s i c a l a c t i v i t y

l e v e l , h i s t o r y o f h e a r t d i s -

e a s e , d i a b e t e s , a t r i a l

f i b r i l l a t i o n , S B P , D B P ,

h i g h c h o l e s t e r o l , a n t i h y -

p e r t e n s i v e r e g i m e n , p e r -

c e i v e d g e n e r a l h e a l t h ,

a n d d e p r e s s i v e s y m p -

t o m s

H

i g h e r M e D i a d h e r e n c e

w a s a s s o c i a t e d w i t h

l o w e r l i k e l i h o o d o f i n c i -

d e n t c o g n i t i v e i m p a i r -

m e n t i n p a r t l y a d j u s t e d

m o d e l ( O R ¼ 0 . 8 7 , 9 5 %

C I 0 . 7 6 – 1 . 0 0 ,

P ¼

0 . 0 4 6 ) .

T h i s r e l a t i o n s h i p w a s a t t e -

n u a t e d a f t e r i n c l u d i n g

d a t a f r o m c o g n i t i v e

a s s e s s m e n t s f o l l o w i n g

i n c i d e n t s t r o k e , b e c o m -

i n g n o s i g n i f i c a n t i n f u l l y

a d j u s t e d m o d e l s

( O R ¼

0 . 8 9 , 9 5 % C I

0 . 7 7 – 1 . 0 1 ,

P ¼

0 . 0 7 )

I n

t e r a c t i o n w i t h d i a b e t e s :

H i g h M e D i a d h e r e n c e


l o w e r r i s k o f i n c i d e n t

c o g n i t i v e i m p a i r m e n t i n

t h e n o n d i a b e t i c p o p u -

l a t i o n ( O R ¼

0 . 8 1 , 9 5 %

C I 0 . 7 0 – 0 . 9 4 ,

P ¼

0 . 0 0 7 ) a n d n o t i n

t h e d i a b e t i c p o p u l a t i o n

( O R ¼

1 . 2 7 , 9 5 %

C I ¼ 0 . 9 5 – 1 . 7 1 ,

P ¼

0 . 1 0 6 )





U p p s a l a L o n g i t u d i n a l

S t u d y , S w e d e n ,

O l s s o n e t a l . [ 4 0 ]

1 0 3 8 n o n d e m

e n t e d

m e n , a g e s

7 0 y e a r s

a n d o l d e r a t b a s e l i n e

1 2 y e a r s o n a v e r a g e

7 - d a y f o o d r e c o r d t o

c o m p u t e t h e M e D i

s c o r e ( 0 – 8 p o i n t s )

T h

r e e c a t e g o r i e s w e r e

c o n s i d e r e d :


( s c o r e s 0 – 2 )

M e d i u m a d h e r e n t s

( s c o r e s 3 – 5 )


( s c o r e 6 a n d o v e r )

I n c i d e n t A D ( n ¼

8 4 ) , i n c i -

d e n t a l l - t y p e d

e m e n t i a

( n ¼

1 4 3 ) a n d

i n c i d e n t

a l l - t y p e c o g n i t i v e i m p a i r -

m e n t ( n ¼

1 9 8

)

E n e r g y , e d u c a t i o n , A p o E ,

l i v i n g a l o n e , s m o k i n g ,

a n d p h y s i c a l a c t i v i t y

N


M e D i a d h e r e n c e ( þ 1

S D ) a n d r i s k o f A D

( H R ¼

1 . 0 0 , 9 5 % C I

0 . 7 5 – 1 . 3 3 ) o r a l l - t y p e

d e m e n t i a ( H R ¼

0 . 9 4 ,

9 5 % C I 0 . 7 5 – 1 . 1 8 ) , n o r

a l l - t y p e c o g n i t i v e i m p a i r -

m e n t ( O R ¼ 0 . 8 2 , 9 5 %

C I 0 . 6 5 – 1 . 0 5 ) i n f u l l y

a d j u s t e d m o d e l s

N


M e D i a d h e r e n c e c o n -

s i d e r e d a s c a t e g o r i c a l

v a r i a b l e a n d r i s k o f A D ,

a l l - t y p e d e m e n t i a o r

a l l - t y p e c o g n i t i v e

i m p a i r m e n t

S U . V I . M A X , F r a n c e ,

K e s s e - G u y o t

e t a l . [ 3 7 ]

3 0 8 3 p a r t i c i p

a n t s o f

t h e S U . V I . M

A X R C T ,

m e a n a g e ( S D ) 5 2 . 0

( 4 . 6 ) a t b a s e l i n e

( d i e t a r y a s s e s s m e n t )

1 3 y o n a v e r a g e

2 4

- h d i e t a r y r e c o r d , s i x

r e c o r d s p e r y e a r

C o g n i t i v e p e r f o r m a n c e s

a s s e s s e d o n c e b y e p i s o -

d i c m e m o r y ( 4 8 c u e d

r e c a l l t e s t ) , f o r w a r d a n d

b a c k w a r d d i g

i t s p a n ,

t r a i l m a k i n g t e s t , s e m a n -

t i c f l u e n c y t a s k , p h o n e -

m i c f l u e n c y t a

s k , a n d

u s e d t o c o m p u t e a c o m -

p o s i t e c o g n i t i v e s c o r e

A g e , s e x , e d u c a t i o n , f o l -

l o w - u p t i m e b e t w e e n

b a s e l i n e a n d c o g n i t i v e

e v a l u a t i o n , n u m b e r o f

2 4 - h d i e t a r y r e c o r d s ,

R C T t r e a t m e n t a r m ,

e n e r g y i n t a k e , B M I ,

o c c u p a t i o n a l s t a t u s ,

s m o k i n g , p h y s i c a l

a c t i v i t y , m e m o r y d i f f i c u l -

t i e s a t b a s e l i n e , d e p r e s s -

i v e s y m p t o m s , i n c i d e n c e

o f d i a b e t e s , h y p e r t e n -

s i o n , a n d c a r d i o v a s c u l a r

d i s e a s e d u r i n g f o l l o w - u p

N

o b e t t e r c o g n i t i v e p e r -

f o r m a n c e s ( c o m p o s i t e

c o g n i t i v e s c o r e ) w i t h

h i g h e r M e D i a d h e r e n c e

i n f u l l y a d j u s t e d m o d e l s

( P f o r t r e n d ¼

0 . 2 7 a n d

0 . 1 2 , r e s p e c t i v e l y )

( C o n t i n u e d )





T a b l e 1 ( C o n t i n u e

d )

S t u d y ,

l o c a t i o n ,





M



O u t c o m e s


M


M e D i s c o r e i n t h r e e

c a t e g o r i e s :


( s c o r e < 4 )


( s c o r e s 4 – 5 )


( s c o r e > 5 )

M S D P S i n t h r e e c a t e g o r i e s

( t e r t i l e s ) :


( s c o r e < 2 0 . 0 9 )


( s c o r e s 2 0 . 0 9 – 2 5 . 2 1 )


( s c o r e > 2 5 . 2 1 )

A

l o w e r M e D i a d h e r e n c e


p o o r e r b a c k w a r d d i g i t

s p a n p e r f o r m a n c e ( P f o r

t r e n d ¼ 0 . 0 3 ) a n d l o w e r

M S D P S w a s a s s o c i a t e d

w i t h p o o r e r p h o n e m i c

f l u e n c y p e r f o r m a n c e

( P f o r t r e n d ¼

0 . 0 4 8 )

S i g n i f i c a n t i n t e r a c t i o n w i t h

o c c u p a t i o n a l s t a t u s : m a n -

u a l l a b o r e r s w i t h p o o r e r

M e D i s c o r e h a d l o w e r

c o m p o s i t e c o g n i t i v e

s c o r e ( m e a n d i f f e r e n c e

5 . 4 1 , 9 5 % C I 9 . 1 8

t o 1 . 1 1 ,

P f o r

t r e n d ¼ 0 . 0 1 ) . N o s i m i l a r

s i g n i f i c a n t i n t e r a c t i o n

w a s d e t e c t e d w i t h

M S D P S

A D , A l z h e i m e r ’ s d i s e a s e ; A p o E , a p o l i p o p r o t e i n E ; C I , c o n f i d e n c e i n t e r v a l ; F F Q , F o o d F r e q u e

n c y Q u e s t i o n n a i r e ; H R , h a z a r d r a t i o ; M e D i , M e

d i t e r r a n e a n d i e t ; M S D P S , M e d i t e r r a n e a n - s t y l e d i e t a r y p a t t e r n s c o r e ; O R , o d d s

r a t i o ; R C T , r a n d o m i z e d c o n t r o l l e d t r i a l ; R E G A R D S , R e a s o n s f o r G e o g r a p h i c a n d R a c i a l D i f f e r e n c e s i n S t r o k e ; S D , s t a n d a r d d e v i a t i o n ; S E , s t a

n d a r d e r r o r ; S U . V I . M A X , S u p p l e m e n t a t i o n w i t h

V i t a m i n s a n d M i n e r a l

A n t i o x i d a n t s ; T I C S , t e l e p h o n e i n t e r v i e w f o r c

o g n i t i v e s t a t u s ; 3 M S , M o d i f i e d M i n i M e n t a l S t a t e E x a m i n a t i o n .





Main outcomes of this substudy were compositescores of global cognition and verbal memory. Aftermultivariate adjustment, there was no significantassociation between long-term MeDi adherence andcognitive change for 6 years. However, a modest butsignificant benefit of high MeDi adherence wasobserved on overall cognitive status, defined as

the average of the four repeated measures of cogni-tive function, at older ages. Despite some limita-tions, including a sample limited to women with arelatively high socioeconomic status and a low aver-age cognitive decline, which may have limited theability to detect associations with cognitive change,these results suggest a protective impact, althoughrelatively modest, of the long-term MeDi adherenceon cognitive status.

Cache County Study on Memory, Health,and Aging

The Cache County Study on Memory is a largepopulation-based prospective study of the pre-valence and incidence of dementia in elderlyresidents of Cache County, Utah, USA [36]. Among5092 participants, ages 65 years and older at base-line, 3580 participants without dementia completedthe baseline interview and a self-administered FoodFrequency Questionnaire. These data enabled us toassess the adherence to a MeDi and test its associ-ation with changes in Modified Mini-Mental StateExamination (3MS) performances, assessed fourtimes during 10.6 years on average. At baseline, afteradjustment for sociodemographic and clinical

characteristics, higher MeDi scores (quintiles 2–5),compared with quintile 1, were significantly associ-ated with higher 3MS performances. Regardingchanges in 3MS performances over time, they werenot statistically different across quintiles of MeDiadherence groups. These findings suggest that thebenefit of higher MeDi adherence observed at base-line would be maintained over time, but were notcumulative over a long-term period.

Reasons for Geographic and RacialDifferences in Stroke Study

Among 17 478 participants from the Reasons forGeographic and Racial Differences in Stroke study(REGARDS, conducted in the USA), MeDi adherencewas related to cognitive status [39]. Participants(ages 64.4 years on average at baseline) were fol-lowed up for 4 years on average and incident cog-nitive impairment was identified among 1248individuals. In a model adjusted for demographic,environmental, and vascular risk factors, no associ-ation was observed between baseline MeDi adher-ence and risk of incident cognitive impairmentover time. Interestingly, a statistically significant

interaction with diabetes was reported in therelationship between MeDi adherence and cognitiveimpairment. A higher adherence to the MeDi wasassociated with a 19% lower risk of incident cogni-tive impairment in the nondiabetic population(95% CI 30% to6%, P ¼0.007); in contrast, therewas no association among diabetic participants.

Findings from this very large population-basedcohort with relatively short follow-up were intrigu-ing and suggested that the prevention of cognitiveimpairment in population at higher risk of demen-tia, such as diabetic patients, appeared more chal-lenging than in healthy individuals.

Reports from Europe

Only two European studies have focused on theassociation between MeDi adherence and cognitivedecline or dementia in the last 18 months, asdescribed below.

Uppsala Longitudinal Study

In Sweden, a Mediterranean-like dietary pattern hasbeen computed from a 7-day food record, among1038 elderly men, participants of the Uppsala Longi-tudinal cohort, ages 71 years on average at baseline[40]. Among them, 84 incident cases of Alzheimer’sdisease, 143 incident cases of all-type dementia and198 incident cases of all-type cognitive impairmentwere identified during 12 years of follow-up onaverage (median follow-up 11.6 years). Overall, noassociation was reported between MeDi adherence,

considered as a continuous or categorical variable,and the development of Alzheimer’s disease or all-type dementia. A modest protective effect of a greaterMeDi adherence was observed against the develop-ment of all-type cognitive impairment, in a modeladjusted for energy intake, whereas this associationbecame no-significant in the fully adjusted model,including energy intake, education, genotype of apolipoprotein E ( APOE), living alone, smoking,and physical activity. In sensitivity analyses exclud-ing inadequate reporting of energy intake, a signifi-cant inverse association was observed between

MeDi adherence and all-type cognitive impairment(N ¼564men, among whom 105 incident cases of all-type cognitive impairment). Therefore, a major limitof this study is the highly selected group enrolled inthe sensitivity analysis that precludes the generaliz-ation of these positive findings.

Supplementation with Vitamins and Mineral Antioxidants Study

In France, the Supplementation with Vitamins andMineral Antioxidants (SU.VI.MAX) RCT was imple-mented among healthy men and women between





1994 and 2002 to evaluate the effect of daily supple-mentation with antioxidants and minerals on theincidence of cancer and ischemic heart disease [37].The baseline dietary survey was used to ascertainMeDi adherence. At the end of the RCT, someparticipants (N ¼3083, ages 65.4 years on average)completed a single neuropsychological evaluation

(on average 13 years after the initial enrollment inthe trial). Overall, no association between midlifeMeDi adherence and cognitive performance atthe end of follow-up was reported, except for someisolated tests. The authors also tested the hypothesisthat cognitive reserve markers, that is, educationand occupation, might modify the relationshipbetween the MeDi and cognition. Participants withmanual occupation and low MeDi adherence havelower composite cognitive performance, whereas nosignificant interaction between education and MeDiadherence with regard to cognitive function wasobserved. In this substudy, cognition was assessedat a single time point, so the association betweenMeDi adherence and cognitive decline could not beinvestigated. However, it suggested that some life-style characteristics may interfere on the relation-ship between MeDi adherence and cognitive health.

RANDOMIZED CONTROLLED TRIAL: MEDI

AS NUTRITIONAL INTERVENTION

To answer the issue of residual confounding inobservational studies, RCTs are the gold standard,but specially difficult to implement in nutritional

epidemiology and even more in the field of demen-tia, which requires a long period. Nevertheless,among participants of the PREDIMED RCT, 522from the Navarra center (74.6 years on average) wereenrolled in a substudy about cognition at the end of the nutritional intervention [47

&

]. Two cognitivetests [Mini Mental State Examination (MMSE) andClock Drawing Test (CDT)] were administered onceafter a mean follow-up of 6.5 years, which unfortu-nately prevented us from studying the cognitivedecline according to the arm of the intervention.In multivariate analyses, the mean cognitive

scores were higher for participants allocated to theMeDiþEVOO or MeDiþmixed nuts groups than forparticipants allocated to the arm ‘low-fat diet’ (i.e.,control diet). In a second report addressing the issueof diet–gene interactions, both MeDi allocationshave been combined as a single group of inter-vention, and genotypes of several susceptibilitygenes (i.e., APOE, CLU , CR1, PICALM ) associatedwith the risk of Alzheimer’s disease have been deter-mined [48

&

,49,50]. Overall, significant interactionsbetween MeDi and either APOE or CLU on MMSEperformance have been highlighted, whereas no

significant interaction between MeDi and eachgenetic polymorphism was observed on CDT per-formance. A beneficial effect of the MeDi inter-vention, compared with low-fat diet, on MMSEperformances was observed among subjects carryingthe T minor allele on CLU; which has been pre-viously associated with protective effect on risk of

Alzheimer’s disease. Regarding APOE polymor-phism, the MeDi intervention had a beneficial effecton MMSE for both non-APOE4 and APOE4 carriers,whereas mixed results were observed on CDT per-formances (i.e., a protective effect was only observedamong non-APOE4 carriers) [48

&

]. Altogether, theseresults showed that a nutritional intervention wasfeasible at the ‘dietary pattern level’, and not only at‘the single nutrient level’. Moreover, it underlinedthat the effect on cognition of an intervention withMeDi would be greater in participants with a favor-able genetic profile.

DISCUSSION

Despite promising results from meta-analyses thathighlighted a protective effect of a greater MeDiadherence on cognitive health, recent findings fromlongitudinal studies provided mixed results as withthose from secondary analyses of previous RCTs.Cumulative exposures to healthy diets over thelong-term might exert slow, cumulative beneficialeffects on the brain, as suggested by associationsbetween the MeDi and overall cognitive status inolder age found in large recent studies. Yet, several

studies from various populations in Europe and theUSA have also failed to evidence associations withcognitive change, which may suggest biologicaleffects at best modest. Nevertheless, these resultsshould be considered with caution as observationalstudies are subjected to bias. Indeed, some residualconfounding factors cannot be dismissed, especiallyas the MeDi is part of a healthier lifestyle in general,beyond dietary intake. Indeed, greater adherence toa MeDi is generally associated with higher educationand socioeconomic status. It is possible that theMeDi is more beneficial for brain health in low

socioeconomic populations with lower educationallevel and less ‘cognitive reserve’ (as indicated byFrench SU.VI.MAX results) [37]; this may partlyexplain stronger effects found in New York cohorts(low socioeconomic populations) [11] and modesteffects found in Harvard cohorts (with generallyhigher socioeconomic status) [33,34]. Moreover,the interaction of MeDi with endogenous (i.e.,genetic predisposition factor for dementia) orexogenous (i.e., chronic disease such as diabetes)factors leads the picture more complex thanexpected and underlines that the benefits of the





MeDi on cognitive health are only evident incertain subpopulations.

Several limits could also be attributed to thetools used to assess MeDi adherence, which limitedthe generalization of the results and prevented defi-nite conclusions, as previously reviewed [13

&

]. Amajor limitation of the original MeDi score [9] is

the use of thresholds based on medians of intake of each MeDi component, which are, per se, popu-lation-specific. Therefore, a MeDi score is, by defi-nition, population-specific and cannot be comparedwith a MeDi score computed in a different sample.This may have led to misclassifications, as low con-sumers from one cohort could be considered as highconsumers in another cohort for a particular foodgroup and vice versa [13

&

]. An alternate method of MeDi adherence assessment has been used in theFrench SU.VI.MAX study [37]. The major advantageof the Mediterranean-Style Dietary Pattern Score isthe weighting of the score by the selected foodgroups part of the typical MeDi, or not; althoughthe recent promising proposition of a new methodof computation of a MeDi score, derived from allavailable data from the most relevant observationalstudies, should still be tested and validated [18

&

].Finally, in a slowly evolving dementia syn-

drome, imposing a reasonable delay (i.e., at leastseveral

mediterranean diet and cognitive health: an update of available knowledge

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