ARTICLE
Auteur(s) : Pascale
Barberger-Gateau
Inserm, U593, University Victor Segalen Bordeaux 2, case 11, 146
rue Léo-Saignat,F-33076 Bordeaux cedex, France
As a consequence of population aging, the prevalence of dementia is
increasing all around the world [1]. The most frequent cause of
dementia is Alzheimer’s disease (AD), an irreversible condition in
our present state of knowledge [2]. The main risk factors of AD,
age and the epsilon4 allele of the gene of the apoliprotein E
(ApoE4), offer no possibility of prevention. In the absence of
curative treatment, the identification of environmental risk
factors of AD is therefore a research priority [3]. The role of
nutrition, a potentially modifiable factor, and particularly that
of dietary poly-unsaturated fatty acids (PUFA) arouses increasing
interest for the prevention of dementia and AD [4].Indeed, PUFA are
major components of neuron membranes and they are essential for
brain development. Long-chain PUFA (in particular arachidonic acid
C20:4(n-6), EPA C20:5(n-3) and DHA C22:6(n-3)) are synthesized
respectively from linoleic (LA) C18:2(n-6) and alpha-linolenic
(ALA) C18:3(n-3) essential fatty acids by elongase and desaturase
enzymes. However, the rate of conversion from ALA to DHA is very
low. Moreover, this enzymatic activity seems to decrease with aging
[5]. DHA status is then even more dependent on dietary supply [6].
In addition to their role in the composition and fluidity of neuron
membranes [7], the regulation of neurotransmitter release, and
their vascular properties [6, 8], several cellular mechanisms could
explain the effect of PUFA on cognition [9]. Firstly, the role of
PUFA in inflammation could explain their effect on brain aging.
Indeed, several studies have shown an association between
neuro-inflammation and neurodegenerative pathology [10].
Pro-inflammatory cytokines released by immune cells trigger the
expression of brain cytokine by microglia [11, 12]. During aging,
the increase of peripheral cytokines leads to an increase of brain
cytokines that could be responsible for the development of
cognitive disorders. Because n-3 PUFA are highly incorporated in
the brain and have potent anti-inflammatory effects, they could
counteract the development of neuro-inflammation and its
neuropsychological effects. Another innovative hypothesis suggests
an effect of PUFA through their impact on retinoid receptors and
the retinoid signalling pathway [9]. Indeed, PUFA are important
modulators of gene expression in the brain [13]. In particular, the
retinoid signalling pathway may be activated by some PUFA [14]
including DHA [15]. There is increasing evidence that
hypo-functioning of retinoid signalling is a key factor in
development of toxicity caused by the Abeta peptides which form
Alzheimer plaques [16].Epidemiological studies are necessary to
establish the relationship between dietary intake of various
sources and types of fat and risk of cognitive decline, dementia
and AD in humans. The purpose of this paper is to summarize and
up-date a previous review of epidemiological studies supporting a
link between dietary fat and brain aging published in the same
journal [17].
Data from observational epidemiological studies
Only prospective longitudinal studies (i.e. cohort studies) are
relevant in a disease whose main symptom is memory decline. The
epidemiological cohorts analysing the relationships between
nutrition and brain aging must record dietary and biological data
in large samples representative of the elderly population, with a
follow-up long enough to ensure the anteriority of dietary
behaviour relatively to cognitive decline assessed by repeated
neuropsychological testing and an active search for incident cases
of dementia. Very few studies presently meet these requirements in
the world.
Few longitudinal epidemiological studies have examined the
relationships between dietary fat and risk of dementia or cognitive
decline but most of their results converge to show a protective
effect of n-3 PUFA despite the great variability in dietary habits
(table 1). Fatty fish is very rich in
long-chain n-3 PUFA, in particular in DHA which is also a major
component of neuron membranes. The protective effect of fish
consumption on risk of dementia was first found in the Rotterdam
Study [18], but with a mean follow-up of only 2.1 years, thus the
participants might have modified their dietary behaviour because of
incipient cognitive impairment. Participants eating more than 18.5
g of fish per day (highest tertile of consumption) had a 60%
decreased risk of total dementia (p for trend 0.03) and a 70%
decreased risk of AD (p for trend 0.005). The same study evidenced
a considerably increased risk of all cause dementia (Odds Ratio
(OR) = 2.4, p for trend 0.02), and in particular vascular dementia
(OR = 3.0, p for trend 0.02), for subjects in the highest quartile
of total fat consumption. High saturated fat intake was also
associated with an increased risk of vascular dementia (OR = 2.9, p
for trend 0.01), but not AD, in that study. However, a second
analysis from the same study after a mean follow-up of 6 years
failed to find any association between dietary fat intake and risk
of dementia or its subtypes [19].
In the French Personnes Agées QUID (PAQUID) study, we showed an
inverse association between the frequency of fish consumption and
the risk of developing dementia in the 7 subsequent years [20].
Subjects who ate fish or seafood at least once a week had a
significant reduced risk (age- and sex-adjusted hazard ratio (HR) =
0.66 ; 95% confidence interval (CI) 0.47-0.93) of being
diagnosed as demented in the seven subsequent years. The risk of
developing specifically AD was also reduced, with borderline
significance (HR = 0.69, 95% CI 0.47-1.01).
A similar result was observed in the Chicago Health and Aging
Project (CHAP) study which also found a protective effect of
overall n-3 PUFA consumption against dementia [21], and a
protective effect of fish consumption against cognitive decline
[22]. Conversely, consumption of saturated fat and trans PUFA was
associated with increased risk of AD [23] and cognitive decline
[24] in that study. Recently, the Zutphen Elderly Study also
evidenced that fish consumption was associated with less subsequent
cognitive decline over 5 years in older men [25]. Moreover, a
dose-response relationship was observed between the combined intake
of EPA and DHA and cognitive decline in that study.
Three studies found interactions between dietary fat intake and
genetic characteristics for genes involved in the metabolism or
transportation of lipids such as the apolipoprotein E whose epsilon
4 allele is also a risk factor for AD. The Washington Heights
Inwood Columbia Aging Project (WHICAP) study found no association
between PUFA intake and risk of AD, but this study showed a
deleterious effect of total energy intake and total fat intake in
participants with the apoE4 allele [26]. In the Cardiovascular
Health Cognition Study (CHCS), consumption of at least four
servings of fatty fish par week was associated with a significantly
reduced risk of dementia only in ApoE4 non-carriers in fully
adjusted models [27]. There was no association with consumption of
lean fried fish. In the French Three-City (3C) study, weekly
consumption of fish was also associated with a reduced risk of
incident AD and all cause dementia over 4 years of follow-up but
only among ApoE4 non-carriers for the latter [28]. Regular use of
n-3 PUFA rich oils (rapeseed or nut oil) was also associated with a
significantly decreased risk for all cause dementia (HR = 0.41, 95%
CI 0.17-0.995) which was of borderline significance after
adjustment for the ApoE genotype. Regular consumption of n-6 rich
oils (sunflower or grape seed oil) not compensated by consumption
of n-3 rich oils nor fish was associated with a considerably
increased risk of dementia but only among ApoE4 non-carriers (RR =
2.12, 95% CI: 1.30-3.46) [28]. Our results therefore support a
protective effect of both sources of precursor (vegetable oils) and
long-chain (fish) PUFA against dementia.
In the 3C study, we also showed that regular fish consumers had
better general cognitive performances, a better perceived health
status and less depressive symptoms [29]. Similarly, the Doetinchem
Cohort Study evidenced a protective effect of fish and long-chain
n-3 PUFA (EPA and DHA) consumption on cognitive performance at
middle age [30]. Although these are cross-sectional analyses, they
are congruent with longitudinal analyses and they also support the
hypothesis of an impact of PUFA on well-being through their effect
on neuro-inflammation [31].
Biological data give strong support to the results obtained with
dietary data. The French Epidémiologie du Vieillissement Artériel
(EVA) study found a significant increase of the risk of cognitive
decline with increasing level of n-6 PUFA in erythrocyte membranes
[32]. Conversely, the level of total n-3 PUFA, and more
specifically that of EPA and DHA, was inversely associated with
cognitive decline in that study. In the Framingham Heart Study,
subjects in the top quartile of plasma DHA level had a
significantly reduced risk of developing dementia [33]. The mean
dietary intake of these subjects was estimated to be equivalent to
180 mg DHA per day or three servings of fish per week in a
sub-sample. Plasma fatty acids were also associated with cognitive
decline after age 60 in the Atherosclerosis Risk in Communities
Study but in an unexpected way [34]. In that study, total PUFA,
total n-6 PUFA and linoleic acid were all inversely related to
cognitive decline, whereas palmitic acid (a saturated fatty acid)
was positively associated with the risk of cognitive decline. Total
n-3 PUFA in general and EPA+DHA in particular had no significant
effect on global cognitive decline. However, total EPA+DHA was
associated with less decline in verbal fluency in particular among
hypertensive patients and among ApoE4 non-carriers.
Despite adjustment for many covariates in multivariate analyses,
we cannot rule out residual confounding in observational studies.
In the PAQUID study, the protective effect of fish consumption was
partly explained by the higher educational level of regular fish
consumers [20]. In the 3C study, regular fish consumers were more
educated and had a higher income [29]. They also had a healthier
diet including a higher consumption of fruits and vegetables.
Paradoxically, they suffered more often from hypertension and past
stroke. All these factors have previously been found to be
associated with risk of dementia, either in a protective or a
deleterious way [35]. They could therefore act as confounders in
the relationship between fish consumption and dementia. Moreover,
measurement errors may hamper the validity of the results obtained
with dietary data. Randomized controlled trials (RCT) conducted
with supplements are the only means to definitely rule out such
confounding effects and identify the specific effect of a given
nutrient.
Table 1 Main longitudinal epidemiological studies of
the association between dietary fat intake and risk of dementia or
cognitive decline.
|
Study (country)
|
N
|
Age (years)
|
Dietary factors
|
Outcomes
|
Results (multivariate analyses)
|
- Rotterdam Study
- (The Netherlands)
- [18]
- [19]
|
5434
|
≥ 55
|
- Fish
- Total fat
- Fatty acids
|
- All cause dementia
- AD
- Vascular dementia
|
- Protective effect of fish consumption against dementia and
AD
- No association with total fat nor specific fatty acids
|
|
1416
|
≥ 68
|
Fish
|
|
Protective effect of fish consumption against dementia, borderline
significance for AD
|
|
815
|
≥ 65
|
|
AD
|
- Protective effect of consumption of fish, total n-3 PUFA and
DHA
- Increased risk with saturated fat and trans-unsaturated fat
intake
|
|
2560
|
≥ 65
|
|
Cognitive decline
|
- Deleterious effect of saturated fat and trans-unsaturated fat,
protective effect of monounsaturated fat and a high ratio of
polyunsaturated to saturated fat intake
- Protective effect of fish consumption
|
|
980
|
≥ 65
|
|
AD
|
Increased risk with total energy and total fat intake among ApoE4
carriers
|
|
2233
|
≥ 65
|
Fatty and lean fried fish
|
|
Protective effect of fatty fish against dementia among ApoE4
non-carriers
|
|
8085
|
≥ 65
|
|
|
- Protective effect of regular consumption of n-3 PUFA rich oils
against dementia
- Protective effect of regular fish consumption against AD, and
all cause dementia among ApoE4 non-carriers
|
- Zutphen Study
- (The Netherlands)
- [25]
|
210
|
70-89
|
|
Cognitive decline
|
Protective effect of consumption of fish, EPA and DHA
|
Data from intervention studies
In spite of increasing evidence from observational studies of a
link between dietary fat intake and risk of dementia or cognitive
decline, no RCT evaluating the effect of n-3 PUFA in the primary
prevention of dementia in humans has been published [36]. An
experiment which showed a significant decrease in the number and
burden of amyloid plaques in the brain of an aged Alzheimer mouse
model fed a high DHA diet raises considerable hope for its use as
an adjuvant treatment of dementia or AD [37]. For ten years, there
have been only two RCT assessing the efficacy of n-3 PUFA in
demented patients [38, 39]. A single blind RCT showed a positive
effect of joint PUFA (with a n-6/n-3 ratio = 4.5) and vitamin E
supplementation on memory, mood and appetite of 100 Alzheimer
patients as reported by their caregivers [38]. However, this small
trial suffers from several methodological flaws. Another RCT was
conducted in elderly Japanese suffering from dementia with
thrombotic cerebrovascular disease [39]. The 10 patients in the
intervention group received 720 mg DHA daily whereas the 10
participants in the control group received usual care for one year.
The intervention group showed significant improvements on the
Dementia Rating Scale and Mini Mental status Examination (MMSE).
Although promising, this trial relies on a very small sample
affected by a very specific cause of dementia.
Recently, the OmegAD intervention trial was the first published
large scale RCT with n-3 PUFA in 204 patients with mild to moderate
AD (MMSE between 15 and 30) [40]. In addition to acetylcholine
esterase inhibitors, the participants received four 1-g capsules
daily, each containing either a combination of 430 mg of DHA and
150 mg of EPA (intervention group) or an isocaloric placebo oil (1
g of corn oil, including 0.6 g of linoleic acid) for 6 months,
followed by 6 months of open treatment with n-3 PUFA fatty acid
supplementation in all patients. There was no statistically
significant difference for cognitive decline over 12 months between
the two groups. However, in the sub-group of 32 patients with very
mild AD (scoring above 27 on the MMSE at baseline), there was a
significant effect of treatment on cognitive decline. Although this
post-hoc analysis should be taken with caution, it suggests a
protective effect of long-chain n-3 PUFA at the early phase of
dementia.
Conclusion
These results considered all together suggest a protective effect
of long-chain n-3 PUFA against cognitive decline and dementia.
However, the complex mechanisms of action of PUFA at the different
stages of brain aging and their interaction with the apoE genotype
still have to be elucidated. It is necessary to determine the
specific role of the various long-chain PUFA, to define the optimal
n-6/n-3 ratio for the prevention of cognitive decline, to study
interactions with other nutrients, in particular anti-oxidants, and
to characterise the persons who would be more susceptible to
benefit from a prevention by nutrition. This requires a coordinated
research program, including epidemiologic studies to complete
observational data in an aged general population, and fundamental
research to identify the mechanisms involved. In a recent review, a
task force of the International Academy on Nutrition and Aging
stressed the need to develop further prospective studies of
adequate duration, including subjects whose diet is monitored at a
sufficiently early stage or at least before the onset of disease or
cognitive decline [41]. The COGINUT (COGnition, anti-oxidants, and
fatty acids: Interdisciplinary approach of the role of NUTrition in
brain aging) research program is a collaborative project organised
around the 3C epidemiological cohort and funded by the French
National Agency for Research
(http://www.inra.fr/layout/set/print/les_partenariats/programmes_anr/alimentation_nutrition_humaine/appel_a_projets_2006/resultats_aap_2006).
COGINUT involves a consortium of epidemiological and fundamental
research teams, a technical centre (Department of Nutrition of the
ITERG, Technical Institute for Fat) and the Lesieur company
(http://www.prodinnov.fr/projets_collaboration_industrielle.php).
The general aim of the COGINUT project is to analyze the
relationships between nutritional status and pathological brain
aging (dementia, cognitive decline, mood disorders) in older
persons, with a particular interest in the joint role of
anti-oxidants and PUFA. We shall analyze more specifically the
impact of PUFA on inflammation and on the retinoid signalling
pathway. This project is a preliminary step before the
implementation of nutritional interventions in elderly persons at
high risk of pathological brain aging because of their nutritional,
medical, psychosocial or genetic characteristics. These
interventions could take the form of nutritional recommendations,
supplements or functional food.
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