Omega-3 na prevenção e tratamento de declinio da cognição e demencia

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Are omega-3 fatty acids options
 for prevention and treatment of
cognitive decline and dementia?
Tommy Cederholma and Jan Palmbladb
aClinical Nutrition and Metabolism, Department of
Public Health and Caring Sciences, Uppsala University,
Uppsala and bDepartment of Medicine, Karolinska
Institutet, Karolinska University Hospital Huddinge,
Stockholm, Sweden
Correspondence to Tommy Cederholm, Clinical
Nutrition and Metabolism, Department of Public Health
and Caring Sciences, Dag Hammarskjöldsväg 14B,
Uppsala Science Park, 751 85 Uppsala, Sweden
Tel: +46 18 611 7970; fax: +46 18 611 7976;
e-mail: tommy.cederholm@pubcare.uu.se
Current Opinion in Clinical Nutrition and
Metabolic Care 2010, 13:150–155
Purpose of review
To report recent data on the potential role of omega-3 fatty acids (n-3 FA) found in oily
fish, especially docosahexaenoic acid (DHA), to prevent and treat cognitive decline and
Alzheimer’s disease.
Recent findings
Observational studies still provide conflicting results, in which the majority indicate
beneficial effects on cognition, both when assessed as a continuous variable or as
incident dementia, mainly Alzheimer’s disease. Experimental studies have demonstrated
potentially ameliorating effects of eicosapentaenoic acid (EPA) and DHA on amyloid
fragment formation, signal transduction including upregulation of the apolipoprotein
receptor SorLA, as well as on angiogenesis. The role of EPA and DHA metabolites on
Alzheimer’s disease pathology is under investigation. Recently, three randomized
intervention studies, with duration up to 6 months have been reported. In contrast to a
small study from Taiwan, no positive overall effects were reported from the Swedish
OmegAD Study or from a Dutch study, although post hoc analyses indicate that
selected individuals with mild forms of Alzheimer’s disease or cognitive decline may
respond to treatment.
Summary
No firm conclusions can be drawn. Based on epidemiological data, fish including oily
fish could be advised as part of a balanced diet for public health purpose, although the
evidence for better cognition is only fairly consistent. It is unlikely that n-3 FA will emerge
as a treatment option in general for improving cognitive function in patients with
Alzheimer’s disease. n-3 FA, especially DHA, may turn out as an adjuvant therapy in
selected cases. Further long-term intervention studies on individuals with mild cognitive
reductions are awaited.
Keywords
Alzheimer’s disease, dementia, docosahexaenoic acid, omega-3 fatty acids
Curr Opin Clin Nutr Metab Care 13:150–155
� 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins
1363-1950
Introduction
Next to subcutaneous fat the brain is the richest fat organ
of the body. The long-chained omega-3 fatty acids (n-3
FA) eicosapentaenoic acid (EPA) and docosahexaenoic
acid (DHA) are strictly not essential FAs but mainly
provided by oily fish. EPA and especially DHA are
concentrated in the brain. Early findings of reduced
levels of the n-3 FAs in the brain and in the blood of
individuals with Alzheimer’s disease indicated specific
functional roles for these substances. Longitudinal epi-
demiological studies during the past decade came up with
somewhat diverging results, but the majority of studies
indicated a preventive effect for cognitive decline by a
high intake of fish, either determined by dietary recalls or
food frequency questionnaires (FFQ), or by high blood
levels of DHA or EPA [1�,2,3]. Published experimental
opyright © Lippincott Williams & Wilkins. Unautho
1363-1950 � 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins
studies were more consistently supporting the hypothesis
that increased intake of n-3 FA exerted positive cognitive
effects when provided in animal models [4]. Up until
2006 only a few small treatment studies had been pub-
lished, reporting mixed results on cognition and quality
of life in patients with Alzheimer’s disease [5–7]. The
OmegAD Study was the first in 2006 to report a larger
double-blind randomized placebo controlled inter-
vention effort in 204 patients with mild-to-moderate
Alzheimer’s disease, that is, Mini Mental State Examin-
ation (MMSE) more than 15 points, given a DHA-
enriched supplementation (1.7 g DHA and 0.4 g EPA)
or placebo for 6 months, followed by open treatment of
all participants for another 6 months [8]. The primary
hypothesis of reduced cognitive decline by DHA-
enriched treatment was not confirmed, but subgroup
analyses of the study participants with the mildest forms
rized reproduction of this article is prohibited.
DOI:10.1097/MCO.0b013e328335c40b
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Omega-3 fatty acids and cognition Cederholm and Palmblad 151
of Alzheimer’s disease, that is, MMSE more than 27,
revealed a significant decrease in declination rate. More-
over, a corresponding reduction was found in the placebo-
treated participants with MMSE more than 27, when
they received the active treatment for the subsequent
6 months.
This area of research has been extensive during the past
years and has yielded a great public interest and expec-
tations that increased n-3 FA intake may decrease the risk
of Alzheimer’s disease. The present review will describe
the recent literature on epidemiologic, experimental and
treatment efforts to establish firm knowledge in the field.
Epidemiological observational studies
Previous studies indicate that results may differ due to
design and methods used, that is, whether the obser-
vations are cross-sectional or longitudinal, the n-3 FA
levels are assessed by dietary recalls or blood analyses or
if cognition or the change of cognition is assessed as a
continuous variable or as incident dementia [9]. Further-
more, carrying the epsilon 4 genotype of apolipoprotein E
(APOE) or not appears to influence the potential role of
n-3 FA. In the present article, 13 recent observational
studies, seven using biochemical indicators and six using
dietary recalls for assessment of n-3 FA levels will be
presented.
Biochemical indicators
Among 1214 nondemented old persons in southern
France 65 developed dementia in 4 years. Low plasma
n-3 FA concentrations were related to incident dementia,
and reduced EPA levels in particular remained indepen-
dently associated even in multivariate models [10�].
Corresponding findings were not observed in a Canadian
cohort of 663 nondemented older adults studied between
1991 and 2002, where erythrocyte membrane levels
of DHA and EPA were related to incident dementia in
149 cases [11]. High plasma levels of n-3 FA were related
to lesser decline in some but not all cognitive domains
among 404 older Dutch persons during 3 years [12],
and similarly in 2251 50–65-year-old white Americans
followed for 9 years [13]. A smaller Scottish study on
120 volunteers registered cognitive changes from 64 to
68 years of age and observed beneficial outcomes by
higher erythrocyte total n-3 FA and DHA levels. Inter-
estingly, this was only noticed in the absence of the
APOEepsilon4 allele [14]. Two recent cross-sectional
studies also support the notion that low blood levels of
n-3 FAs are associated with worse cognitive status. First, a
north-west American study assessed erythrocyte mem-
brane DHA and MMSE in a smaller group of patients
with Alzheimer’s disease [15]. Secondly, a report from the
Italian inChianti study displayed low plasma n-3 FA
levels, particularly of a-linolenic acid, in those, out of
opyright © Lippincott Williams & Wilkins. Unauth
935, community-dwelling older persons who were diag-
nosed with dementia [16].
Fish intake
Biochemical markers of n-3 intake may be modified by
endogenous adaptations, whereas dietary assessments may
be biased by under or over-reporting. However, encoura-
gingly a recent report showed decent significant corre-
lations (r�0.5) between DHA and EPA intake according to
FFQ, and plasma phospholipidconcentrations in 273 older
Boston community dwellers with various cognitive capa-
cities [17]. Turning back to southern France, dietary recalls
among more than 8000 nondemented adults of above
65 years of age indicated that weekly consumption of
fish was associated with reduced 4 year risk of incident
Alzheimer’s disease. This relation was, however, only
found in those without the APOEepsilon4 genotype
[18]. From the Rotterdam cohort of more than 5000
participants of above 55 years of age who gave reported
dietary information the third follow-up has recently been
reported [19�]. After an average of 9.6 years when 465
participants had developed dementia, the total fish intake
as well as of the various n-3 FAs was not related to the risk
of incident dementia. Thus, this report corroborates the
negative findings from the 6-year follow-up [20], and
disaffirms the positive 2-year follow-up data [21]. In con-
trast, another Dutch study of a smaller cohort of 210 older
individuals indicated that there was a linear relation
between intake of EPA and DHA and reduced cognitive
decline during a 5-year period, that is, an average differ-
ence of 380 mg n-3 FA/day was related to an average of
1.1 points difference in cognitive decline [22]. There are
several recent cross-sectional studies on the relation
between fish consumption and cognitive status. One is
based on 15 000 older adults from Latin America, China
and India, in which face-to-face interviews on dietary
habits revealed adjusted inverse dose–dependant relation
between fish consumption and risk of dementia at all sites
except for India. In contrast, meat consumption was posi-
tively related to dementia [23]. Baseline cross-sectional
data from the Opal Study in the UK, that is, a randomized
intervention study on 867 older people between 70 and
79 years with MMSE more than 24, revealed unadjusted
associations between reported fish intake and verbal learn-
ing. The associations did not remain after adjustment
for education and psychological health [24]. Finally, a
Norwegian study on 2031 individuals aged 70–74 years
showed a dose–dependant association between seafood
intake and cognition, with the maximum effect at a daily
fish intake of 75 g. Moreover, both lean and fatty fish were
beneficial [25].
Intervention studies
Commonly, observations from epidemiological studies
need to be confirmed by randomized intervention
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152 Lipid metabolism and therapy
Figure 1 Appetite and weight changes for 174 Alzheimer’s disease patients during the OmegAD trial
0 6 12
4.0
4.4
4.8
5.2
5.6
6.0
6.4
0 6 12
66
67
68
69
70
71
72
73
74
75
Months
Appetite,
score
Body
weight, kg
In this RCT patients were randomized to either daily substitution with a DHA rich n-3 FA fish oil supplementation ( ) or an isocaloric placebo
preparation ( ) for the first 6 months. During the next 6 months both groups received the n-3 FA preparation. Note, that when the placebo group
switched to the n-3 oil, weight and appetite gains became similar to those of the n-3 group. Adapted with permission [29].
studies, whereas experimental studies are needed to
understand the mechanisms for the specific effects, in
order to provide an evidence-based foundation for recom-
mendations. Food or nutrient intervention studies may
be cumbersome to perform and to interpret according to
the regular RCT scheme for pharmaceutical substances.
One limitation may be that the exposure time for the
specific nutrient may need to be very long before effects
appear. Nevertheless, it is of utmost importance that well
designed n-3 FA randomized controlled trials (RCTs)
are executed.
Since the first OmegAD Study report in 2006 [8], reports
have come out from a Dutch double-blind placebo con-
trolled trial, including 302 healthy participants aged over
65 years and with MMSE more than 21. They were
randomized to receive daily 1.8 g EPA and DHA, 0.4 g
EPA and DHA or placebo for 26 weeks. No overall effects
on cognition were observed in any of the treatment
groups [26��]. This was somewhat contrasting to the post
hoc findings in the OmegAD Study of positive effects of
n-3 FA supplementation in those with the mildest forms
of Alzheimer’s disease. However, the Dutch researchers
also found positive effects in post hoc analyses on the
cognitive domain of attention, mainly in men and in
carriers of APOEepsilon4. The findings of the Swedish
and Dutch studies may thus indicate that there are
subgroups of individuals with high risk of developing
opyright © Lippincott Williams & Wilkins. Unautho
Alzheimer’s disease that may respond to n-3 FA treat-
ment. Still, it cannot be ruled out that the post hoc
findings in both studies are by chance. Another four
studies have so far come out from the OmegAD Study.
One reported no effect on Neuropsychiatric Inventory,
Montgomery Åsbergs Depression scale, Care Givers
Burden or activities of daily living [27], but post hoc
analyses revealed possible helpful effects on depressive
symptoms in non-APOEepsilon4 carriers and on agitation
symptoms in APOEepsilon4 carriers. Chance findings
cannot be ruled out. A subgroup of the 174 treated
Alzheimer’s disease patients were analyzed according
to possible effects on neuroinflammation determined
by cytokine concentrations in cerebrospinal fluid, but
no effects were noticed [28]. Interestingly, the patients
that received active n-3 FA treatment increased their
weight, in contrast to the expected finding of weight loss
(Fig. 1). This effect was related to improved appetite
[29]. More recently, reduced cytokine release from
mononuclear cells ex vivo from participants in the
OmegAD Study treated with n-3 FA has been reported
[30]. A 24-week randomized study from Taiwan on 46
participants with mild-to-moderate Alzheimer’s disease
and mild cognitive impairment, respectively, treated with
1.8 g/day of n-3 FAs, displayed positive effects assessed
by clinicians’ interview-based impression of change scale.
Moreover, higher levels of EPA in erythrocyte mem-
branes corresponded to better cognitive outcome [31].
rized reproduction of this article is prohibited.
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Omega-3 fatty acids and cognition Cederholm and Palmblad 153
Experimental studies
After the initial reports of the brain disorder in transgenic
animal models of Alzheimer’s disease, a number of inter-
esting findings have been reported in relation to n-3 FAs.
They encompass areas such as amyloid plaque develop-
ment (and regression) [4], amyloid fibrillation, signal
transduction and angiogenesis. Another approach has
focused on the unique FA composition of the brain, so
rich in DHA (and arachidonic acid), which points to the
possibility that DHA metabolites may play a role for
apoptosis and protection of neuronal cells [32��].
Docosahexaenoic acid metabolites
Although potent anti-inflammatory and anti-apoptotic
metabolites, for example, (neuro)protectins and resolvins,
are formed from EPA and DHA in various organs including
the brain, for example after hypoxic injury, little new
information has been reported on their involvement and
role(s) in neurodegenerative disorders during the past year.
Two new DHA derivatives have recently been reported,
maresins [33�] and cyclopentenone neuroprostanes [34].
Both may contribute to the anti-inflammatory actions of
DHA. Thus, the previously reported actions of (neuro)-
protectin (NPD1) and DHA as inhibitors of Ab peptide
generation and shedding from brain cells (mediated via
stimulation of a-secretase activities [35�] remain to be
explored further in order to enhance our understanding
of the relationship to Alzheimer’s disease. A related obser-
vation is that DHA confers robust neuroprotection in a rat
model of focal cerebral ischemia [36].
Amyloid peptide generation
After the first report that DHA stabilizes soluble Ab pro-
tofibrils andsustainsAb-inducedneurotoxicity invitro[37],
an interest arose in understanding the direct FA-protein
interactions in relation to Alzheimer’s disease mechanisms.
Recently, DHA administration was reported to stimulate
nonamyloidogenic amyloid precursor protein processing
and reduced levels of Ab, providing a mechanism for the
reported beneficial effects of DHA in vivo [38].
A number of recent publications bring this issue forward,
showing that DHA restrains generation and fibrillation of
toxic Ab fragments (for example [39,40]) as well as that
DHA promotes neuronal differentiation by regulating
basic helix-loop-helix transcription factors and cell cycle
in neural stem cells [41�]. In addition, this research group
presents evidence that EPA, by acting as a precursor for
DHA, ameliorates learning deficits in rats infused with
Ab1-40 and that these effects are modulated by the
expression of proteins involved in neuronal plasticity
[42]. A related finding is that giving uridine plus DHA
triggers a neuronal program that controls synaptogenesis
by accelerating phosphatide and synaptic protein syn-
thesis [43].
opyright © Lippincott Williams & Wilkins. Unauth
In conclusion, results suggest that the proposed protec-
tive role of DHA in Alzheimer’s disease pathogenesis
might be mediated by altered amyloid precursor protein
processing and Ab production.
Signal transduction mechanisms
One new report concerns the ability of DHA to increase
the activity of a lipid regulating receptor. SorLA/LR11
belongs to the ApoE/low-density lipoprotein receptor
family, functioning as a sorting and trafficking protein,
eventually leading to reduction of Ab production. It has
been reported to be deficient in late-onset Alzheimer’s
disease. Ma et al. [44] reported that DHA increased the
SorLA protein levels in primary rat and human neurons
and in aged transgenic Alzheimer’s disease mice. The
same research group also reported that DHA reduced
phosphorylation of tau in vitro, suggesting that DHA
abrogates the generation of Alzheimer’s disease-related
proteins [45]. Reduced SorLA levels in CSF of patients
with Alzheimer’s disease may have potential as a diag-
nostic biomarker for patients with SorLA deficits that
promote Ab production or as an index of therapeutic
response in late-onset Alzheimer’s disease [46�].
Angiogenesis, that is, outgrowth of new blood vessels from
existing ones, occurs as a response to hypoxia and inflam-
mation during tissue remodeling. Although these pro-
cesses clearly exist in the Alzheimer’s disease brain,
the role of angiogenesis in Alzheimer’s disease remains
elusive. However, some new findings emphasize a role
for angiogenesis in this disorder. Angiogenesis may be
increased and related to Ab peptides, apparently as
an early phenomenon in many parts of brains from
Alzheimer’s disease patients and from transgenic mice
[47–49]. Of note, the brain of the Alzheimer’s disease
mice model displays an abnormal 3D structure with abrupt
ending of blood vessels close to amyloid plaques [50��].
This highly unusual vascular (mal)formation has not yet
been documented in the human Alzheimer’s disease brain.
Since other reports suggest that n-3 FAs or their meta-
bolites modulate angiogenesis [51] further studies of this
phenomenon might be of interest in order to explain
beneficial effects of n-3 FA in neurodegenerative diseases.
Conclusion
The present review indicates that the role of n-3 FAs in
the prevention and treatment of cognitive decline,
dementia and Alzheimer’s disease is still not resolved
although a number of observational and experimental
studies together with three intervention studies in
humans have been published during the past years.
Several factors combined indicate that especially DHA
plays a role for cognitive performance, and that fish or
DHA intake may be a preventive option at the population
level and may emerge as an adjuvant treatment for selected
orized reproduction of this article is prohibited.
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154 Lipid metabolism and therapy
individuals early in the Alzheimer’s disease trajectory.
Examples of such factors are the abundance and concen-
tration of n-3 FAs in the brain, the well known deleterious
effects on cognition by genetic n-3 FA handling defects, for
example,MbZellweger, themajority of longitudinalobser-
vational studies supporting beneficial effects of either
increased fish intake or high blood levels of n-3 FAs,
experimental animal studies showing positive cognitive
effects by n-3 FA, mainly DHA supplementation, the
identification of (neuro)protectin D1 (NPD1) from
DHA, the increased understanding of DHA effects on
amyloid precursor protein handling and amyloid depo-
sition, and some findings in, so far short term, human
interventionstudies.However, itmaybethat theAPOEep-
silon4 genotype is a too strong risk factor for n-3 FA
supplementation to be able to influence the disease course.
It may also surface that, as for many nutrients, the weak
beneficial effects will need decades of exposure to emerge.
In that case, RCTs will have difficulties to provide proof,
and we may have to rely on good longitudinal observational
studies.
We cannot overrule the possibility that the epidemiolo-
gical associative findings are mere artifacts due to a
reduced fish intake as a result of the cognitive decline
early in the Alzheimer’s disease process. Fish, and oily
fish, does not only contain n-3 FA. Other nutrients such as
vitamin D may emerge as the factor responsible for
potential positive effects by fish.
The research field is far from having reached satiation.
We are eagerly awaiting the results from further inter-
vention studies. There are at least two ongoing studies on
n-3 FA treatment. The British Older People And n-3
Long-chain fatty acids (OPAL, www.controlled-trials.-
com/mrct/trial/485767/OPAL) study randomly supple-
ment more than 800 nondemented adults (MMSE
>24) between 70 and 79 years for 24 months. The French
Multidomain Alzheimer Preventive Trial (MAPT) plans
to enroll 1200 frail older adults to be randomly allocated
to a combined nutritional (n-3 FA), functional and cog-
nitive treatment for 3 years.
Acknowledgement
The OmegAD Study, for which T.C. and J.P. were principal
investigators and initiators, received financial support from Pronova
AS, Norway who provided the n-3 FA supplementation.
References and recommended reading
Papers of particular interest, published within the annual period of review, have
been highlighted as:
� of special interest
�� of outstanding interest
Additional references related to this topic can also be found in the Current
World Literature section in this issue (p. 216).
1
�
Cole G, Ma Q, Frautschy S. Omega-3 fatty acids and dementia. Prostaglan-
dins Leukot Essent Fatty Acids 2009; 81:213–221.
An excellent review.
opyright © Lippincott Williams & Wilkins. Unautho
2 Riediger N, Othman R, Suh M, Moghadasian M. A systematic review of the
roles of n-3 fatty acids in health and disease. J Am Diet Assoc 2009;
109:668–679.
3 Morris M. The role of nutrition in Alzheimer’s disease: epidemiological evi-
dence. Eur J Neurology 2009; 16:S1–S7.
4 Calon F, Cole G. Neuroprotective action of omega-3 polyunsaturated fatty
acids against neurodegenerative diseases: evidence from animal studies.
Prostaglandins Leukot Essent Fatty Acids 2007; 77:287–293.
5 Yehuda S, Rabinovtz S, Carasso RL, Mostofsky DI. Essential fatty acids
preparation (SR-3) improves Alzheimer’s patients quality of life. Int J Neurosci
1996; 87:141–149.
6 Boston PF, Bennett A, Horrobin DF, Bennett CN. Ethyl-EPA in Alzheimer’s
disease: a pilot study. Prostaglandins Leukot Essent Fatty Acids 2004;
71:341–346.
7 Kotani S, Sakaguchi E, Warashina S, et al. Dietary supplementation of
arachidonic and docosahexaenoic acids improves cognitive dysfunction.
Neurosci Res 2006; 56:159–164.
8 Freund Levi Y, Eriksdotter-Jönhagen M, Cederholm T, et al. Omega-3 fatty
acid treatment of 174 patients with mild to moderate Alzheimer’sdisease
(OmegAD): a randomized double-blind trial. Arch Neurol 2006; 63:1402–
1408.
9 Fotuhi M, Mohassel P, Yaffe K. Fish consumption, long-chain omega-3 fatty
acids and risk of cognitive decline or Alzheimer disease: a complex associa-
tion. Nat Clin Pract Neurol 2009; 5:140–152.
10
�
Samieri C, Féart C, Letenneur L, et al. Low plasma eicosapentaenoic acid and
depressive symptomatology are independent predictors of dementia risk. Am
J Clin Nutr 2008; 88:714–721.
An important prospective epidemiologic study using biochemical indicators for n-3
FA status.
11 Kröger E, Verreault R, Carmichael P-H, et al. Omega-3 fatty acids and risk of
dementia: the Canadian Study of Health and Aging. Am J Clin Nutr 2009;
90:184–192.
12 Dullemeijer C, Durga J, Brouwer I, et al. N-3 fatty acid proportions in plasma
andcognitiveperformance inolderadults.AmJClinNutr2007;86:1479–1485.
13 Beydoun MA, Kaufman JS, Satia JA, et al. Plasma n-3 fatty acids and the risk of
cognitive decline in older adults: the Atherosclerosis Risk in Communities
Study. Am J Clin Nutr 2007; 85:1103–1111.
14 Whalley LJ, Deary IJ, Starr JM, et al. N-3 Fatty acid erythrocyte membrane
content, APOE varepsilon4, and cognitive variation: an observational follow-
up study in late adulthood. Am J Clin Nutr 2008; 87:449–454.
15 Wang W, Shinto L, Connor WE, Quinn JF. Nutritional biomarkers in Alzhei-
mer’s disease: the association between carotenoids, n-3 fatty acids, and
dementia severity. J Alzheimers Dis 2008; 13:31–38.
16 Cherubini A, Andres-Lacueva C, Martin A, et al. Low plasma N-3 fatty acids
and dementia in older persons: the InCHIANTI study. J Gerontol A Biol Sci
Med Sci 2007; 62:1120–1126.
17 Arsenault LN, Matthan N, Scott TM, et al. Validity of estimated dietary
eicosapentaenoic acid and docosahexaenoic acid intakes determined by
interviewer-administered food frequency questionnaire among older adults
with mild-to-moderate cognitive impairment or dementia. Am J Epidemiol
2009; 170:95–103.
18 Barberger-Gateau P, Raffaitin C, Letenneur L, et al. Dietary patterns and risk
of dementia: the Three-City cohort study. Neurology 2007; 69:1921–1930.
19
�
Devore EE, Grodstein F, van Rooij FJ, et al. Dietary intake of fish and omega-3
fatty acids in relation to long-term dementia risk. Am J Clin Nutr 2009;
90:170–176.
The third longitudinal report from the Rotterdam study.
20 Engelhart MJ, Geerlings MI, Ruitenberg A, et al. Diet and risk of dementia:
does fat matter?: the Rotterdam study. Neurology 2002; 59:1915–1921.
21 Kalmijn S, Launer LJ, Ott A, et al. Dietary fat intake and the risk of incident
dementia in the Rotterdam Study. Ann Neurol 1997; 42:776–782.
22 van Gelder BM, Tijhuis M, Kalmijn S, Kromhout D. Fish consumption, n-3 fatty
acids, and subsequent 5-y cognitive decline in elderly men: the Zutphen
Elderly study. Am J Clin Nutr 2007; 85:1142–1147.
23 Albanese E, Dangour A, Uauy R, et al. Dietary fish and meat intake and
dementia in Latin America, China, and India: a 10/66 Dementia Research
Group population-based study. Am J Clin Nutr 2009; 90:392–400.
24 Dangour AD, Allen E, Elbourne D, et al. Fish consumption and cognitive
function among older people in the UK: baseline data from the OPAL study.
J Nutr Health Aging 2009; 13:198–202.
25 Nurk E, Drevon CA, Refsum H, et al. Cognitive performance among the elderly
and dietary fish intake: the Hordaland Health study. Am J Clin Nutr 2007;
86:1470–1478.
rized reproduction of this article is prohibited.
http://www.controlled-trials.com/mrct/trial/485767/OPAL
http://www.controlled-trials.com/mrct/trial/485767/OPAL
C
Omega-3 fatty acids and cognition Cederholm and Palmblad 155
26
��
van de Rest O, Geleijnse JM, Kok FJ, et al. Effect of fish oil on cognitive
performance in older subjects. A randomized, controlled trial. Neurology
2008; 71:430–438.
An impressive large intervention study on healthy older Dutch adults.
27 Freund-Levi Y, Basun H, Cederholm T, et al. Omega-3 supplementation in
mild to moderate Alzheimer’s disease: effects on neuropsychiatric symptoms.
Int J Geriatr Psychiatry 2008; 23:161–169.
28 Freund-Levi Y, Hjorth E, Lindberg C, et al. Effects of omega-3 fatty acid
on inflammatory markers in CSF and plasma in Alzheimer’s disease. The
OmegAD study. Dement Geriatr Cogn Disord 2009; 27:481–490.
29 Faxén Irving G, Freund-Levi Y, Eriksdotter-Jönhagen M, et al. N-3 fatty acid
supplementation effects on weight and appetite in patients with Alzheimer’s
disease: the OmegAD Study. J Amer Ger Soc 2009; 57:11–17.
30 Vedin I, Cederholm T, Freund Levi Y, et al. Effects of DHA rich n-3 fatty acid
supplementation on cytokine release from blood mononuclear leukocytes. The
OmegAD study. Am J Clin Nutr 2008; 87:1616–1622.
31 Chiu CC, Su KP, Cheng TC, et al. The effects of omega-3 fatty acids
monotherapy in Alzheimer’s disease and mild cognitive impairment: a pre-
liminary randomized double-blind placebo-controlled study. Prog Neuropsy-
chopharmacol Biol Psychiatry 2008; 32:1538–1544.
32
��
Serhan CN, Chiang N, Van Dyke TE. Resolving inflammation: dual anti-
inflammatory and pro-resolution lipid mediators. Nat Rev Immunol 2008;
8:349–361.
Excellent review of the novel EPA and DHA derived anti-inflammatory mediators
that might be of significance also for neurodegenerative disorders
33
�
Serhan CN, Yang R, Martinod K, et al. Maresins: novel macrophage mediators
with potent antiinflammatory and proresolving actions. J Exp Med 2009;
206:15–23.
This is the first description of a novel metabolite of n-3 FA that might be of
significance for anti-inflammatory processes.
34 Musiek ES, Brooks JD, Joo M, et al. Electrophilic cyclopentenone neuropros-
tanes are anti-inflammatory mediators formed from the peroxidation of the
omega-3 polyunsaturated fatty acid docosahexaenoic acid. J Biol Chem
2008; 283:19927–19935.
35
�
Lukiw WJ, Bazan NG. Docosahexaenoic acid and the aging brain. J Nutr
2008; 138:2510–2514.
Summarizes recent knowledge on DHA and Alzheimer’s disease.
36 Belayev L, Khoutorova L, Atkins KD, Bazan NG. Robust docosahexaenoic
acid-mediated neuroprotection in a rat model of transient, focal cerebral
ischemia. Stroke 2009; 40:3121–3126.
37 Johansson AS, Garlind A, Berglind-Dehlin F, et al. Docosahexaenoic acid
stabilizes soluble amyloid-beta protofibrils and sustains amyloid-beta-induced
neurotoxicity in vitro. FEBS J 2007; 274:990–1000.
38 Sahlin C, Pettersson FE, Nilsson LN, et al. Docosahexaenoic acid stimulates
nonamyloidogenic APP processing resulting in reduced Abeta levels in
cellular models of Alzheimer’s disease. Eur J Neurosci 2007; 26:882–889.
opyright © Lippincott Williams & Wilkins. Unauth
39 Hossain S, Hashimoto M, Katakura M, et al. Mechanism of docosahexaenoic
acid-induced inhibition of in vitro Abeta1-42 fibrillation and Abeta1-42-
induced toxicity in SH-S5Y5 cells. J Neurochem 2009; 111:568–579.
40 Hashimoto M, Shahdat HM, Katakura M, et al. Effects of docosahexaenoic
acid on in vitro amyloid beta peptide 25-35 fibrillation. Biochim Biophys Acta
2009; 1791:289–296.
41
�
Katakura M, Hashimoto M, Shahdat HM, et al. Docosahexaenoic acid pro-
motes neuronal differentiation by regulating basic helix-loop-helix transcription
factors and cell cycle in neural stem cells. Neuroscience 2009; 160:651–
660.
Adds to our knowledge of effects of DHA on brain cells.
42 Hashimoto M, Hossain S, Tanabe Y, et al. The protective effect of dietary
eicosapentaenoic acid against impairment of spatial cognition learning ability
in rats infused with amyloid beta(1-40). J Nutr Biochem 2008; 20:965–
973.
43 Wurtman RJ, Cansev M, Ulus IH. Synapse formation is enhanced by oral
administration of uridine and DHA, the circulating precursors of brain phos-
phatides. J Nutr Health Aging 2009; 13:189–197.
44 Ma QL, Teter B, Ubeda OJ, et al. Omega-3 fatty acid docosahexaenoic acid
increases SorLA/LR11, a sorting protein with reduced expression in sporadic
Alzheimer’s disease (AD): relevance to AD prevention. J Neurosci 2007;
27:14299–14307.
45 Ma QL, Yang F, Rosario ER,et al. Beta-amyloid oligomers induce phosphor-
ylation of tau and inactivation of insulin receptor substrate via c-Jun N-terminal
kinase signaling: suppression by omega-3 fatty acids and curcumin. J Neuro-
sci 2009; 29:9078–9089.
46
�
Ma QL, Galasko DR, Ringman JM, et al. Reduction of SorLA/LR11, a sorting
protein limiting beta-amyloid production, in Alzheimer disease cerebrospinal
fluid. Arch Neurol 2009; 66:448–457.
This study describes a new marker in cerebrospinal fluid for Alzheimer’s
disease.
47 Desai BS, Schneider JA, Li JL, et al. Evidence of angiogenic vessels in
Alzheimer’s disease. J Neurol Transm 2009; 116:587–597.
48 Patel NS, Quadros A, Brem S, et al. Potent antiangiogenic motifs within the
Alzheimer beta-amyloid peptide. Amyloid 2008; 15:5–19.
49 Boscolo E, Folin M, Nico B, et al. Beta amyloid angiogenic activity in vitro and
in vivo. Int J Mol Med 2007; 19:581–587.
50
��
Meyer EP, Ulmann-Schuler A, Staufenbiel M, Krucker T. Altered morphology
and 3D architecture of brain vasculature in a mouse model for Alzheimer’s
disease. Proc Natl Acad Sci U S A 2008; 105:3587–3592.
This study describes a unique feature of blood vessels in the Alzheimer’s disease
brain that might be a signature for the Alzheimer’s disease process
51 Jin Y, Arita M, Zhang Q, et al. Antiangiogenesis effect of the novel anti-
inflammatory and pro-resolving lipid mediators. Invest Ophthalmol Vis Sci
2009; 50:4743–4752.
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	Are omega-3 fatty acids options for prevention and treatment of cognitive decline and™dementia?
	Introduction
	Epidemiological observational studies
	Biochemical indicators
	Fish intake
	Intervention studies
	Experimental studies
	Docosahexaenoic acid metabolites
	Amyloid peptide generation
	Signal transduction mechanisms
	Conclusion
	Acknowledgement
	References and recommended reading