Nutritional Neuroscience

An International Journal on Nutrition, Diet and Nervous System

ISSN: 1028-415X (Print) 1476-8305 (Online) Journal homepage: http://www.tandfonline.com/loi/ynns20

Omega-3 fatty acids' supplementation in

Alzheimer's disease: A systematic review

Scheine Canhada, Kamila Castro, Ingrid Schweigert Perry & Vivian Cristine
Luft

To cite this article: Scheine Canhada, Kamila Castro, Ingrid Schweigert Perry & Vivian Cristine
Luft (2017): Omega-3 fatty acids' supplementation in Alzheimer's disease: A systematic review,
Nutritional Neuroscience, DOI: 10.1080/1028415X.2017.1321813

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Download by: [The UC San Diego Library] Date: 30 May 2017, At: 17:53
Omega-3 fatty acids’ supplementation in
Alzheimer’s disease: A systematic review
Scheine Canhada 1 , Kamila Castro2,3, Ingrid Schweigert Perry 3,4, Vivian Cristine
Luft1,3
1
Postgraduate Program in Epidemiology, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil,
2
Postgraduate Program in Child and Adolescent Health, Universidade Federal do Rio Grande do Sul, Porto
Alegre, Brazil, 3Food and Nutrition Research Centre (CESAN), Hospital de Clínicas de Porto Alegre,
Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil, 4Postgraduate Program in Collective Health,
Academic Unit of Health Sciences, Universidade do Extremo Sul Catarinense, Criciúma, Brazil

Introduction: Alzheimer’s disease (AD) is a neurodegeneration disorder characterized by progressive

impairments of memory, language, reasoning, and other cognitive functions. Evidence suggests that
omega-3 fatty acids may act as a possible protection factor in AD.
Objective: To evaluate the results available in the literature involving omega-3 fatty acids supplementation
and its effect on cognitive function in AD patients.
Methods: A systematic review of MEDLINE (from PubMed), Excerpta Medica Database, and Cochrane
Library databases was conducted according to Preferred Reporting Items for Systematic Reviews and
Meta-Analyses guidelines. Inclusion criteria consisted in original intervention studies, controlled by
placebo, that assessed the impact of supplementation or dietary intake of omega-3 fatty acids on
cognitive function, in humans with AD, without limitation for prime date of publication.
Results: Initial search resulted in 361 articles. Seven studies fully met the inclusion criteria. Most studies did
not find statistically significant results for the omega-3 fatty acids supplementation compared to placebo, and
those who show some benefit do it only in a few cognitive assessment scales. However, the effects of omega-
3 fatty acids appear to be most effectively demonstrated in patients with very mild AD.
Conclusion: The effects of omega-3 fatty acids supplementation in mild AD corroborate epidemiological
observational studies showing that omega-3 fatty acids may be beneficial in disease onset, when there is
slight impairment of brain function. Although some studies have shown changes in scales of cognitive
function in more severe cases, they are not enough to support omega-3 fatty acids supplementation in the
treatment of AD.
Keywords: Omega-3 fatty acids, Eicosapentaenoic acid, Docosahexaenoic acid, Alzheimer’s disease, Cognition, Neuroinflammation

Introduction components may interfere directly in disease’s patho-

Alzheimer’s disease (AD) is a neurodegeneration dis-
order, with slow and continuous progression, character-
ized by progressive impairments of memory, language,
reasoning, and other cognitive functions.1 AD results
from nervous cell damage which is associated with the
accumulation of insoluble forms of amyloid-β (Aβ) in
plaques and aggregation of the microtubule protein
tau in neurofibrillary tangles.1 AD prevalence is esti-
mated to quadruplicate until 2050.2
There is a growing interest in lifestyle and dietary
components as possible protection factors for AD,
including omega-3 fatty acids.3–8 Some dietary
Correspondence to: Scheine Canhada, Postgraduate Program in
Epidemiology, School of Medicine, Federal University of Rio Grande do
Sul, Ramiro Barcelos, 2400, Santa Cecília, Porto Alegre, RS, Brazil.
Email: scheinelc@gmail.com
logic hallmarks – like Aβ’s excessive production or
deposition and neurodegeneration, – although mech-
anisms still remain uncertain.9
Evidence suggests that omega-3 fatty acids’ modu-
late numerous molecular and cellular processes,
which include brain and visual development, inflam-
matory reactions, thrombosis, and carcinogenesis.10
Omega-3 fatty acids are considered essential for the
human body because we are unable to produce them,
so they must be obtained from dietary sources.11,12
Among them, alpha-linolenic acid is present in flax-
seed and canola oils, and eicosapentaenoic acid
(EPA) and docosahexaenoic acid (DHA) are found
in fatty fish such as salmon, trout, and tuna, and in
fish-oil supplements.12 Observational studies have
suggested that omega-3 fatty acids and its food

© 2017 Informa UK Limited, trading as Taylor & Francis Group

DOI 10.1080/1028415X.2017.1321813 Nutritional Neuroscience 2017 1
Canhada et al. Omega-3 fatty acids’ supplementation in Alzheimer’s disease
sources are associated with lower incidences of AD
and dementias in general.4,6–8 However, omega-3
fatty acids’ role in AD treatment, when the disease
already exists, is still controversial in the literature.
The present study systematically reviews the effects
of interventions using omega-3 fatty acids’ supplemen-
tation on cognitive function in individuals with AD.
Methods
This is a systematic review of articles found in
MEDLINE (US National Library of Medicine and
National Institute of Health) – using PubMed –,
Cochrane Library, and EMBASE (Excerpta Medica
Database). Furthermore, the reference lists of the
selected relevant papers were screened by hand for
potentially additional papers in the subject. The
search strategy combined the terms “Fatty Acids,
Omega-3”[Mesh] AND “Alzheimer Disease”[Mesh].
Guidelines established from Preferred Reporting
Items for Systematic Reviews and Meta-Analyses
(PRISMA) were followed.13
Inclusion criteria consisted in original intervention
studies, controlled by placebo, that assessed omega-3
fatty acids’ impact on cognitive function markers, in
humans with AD, published in any language until
March 2017, without limitation for the initial date of
publication. Non-original articles, such as reviews,
editorials, and letters, were excluded, as well as
studies in animals or in vitro. We searched for interven-
tions using omega-3 fatty acids as supplementation (in
capsules, or in any other form than in food itself ) or as
increased dietary intake (throughout its food sources,
such as fish or fish oils).
We first applied eligibility criteria in titles’ analysis,
followed by abstracts’ analysis and full texts’ reading.
Search, selection, and information extraction were per-
formed independently by two reviewers. In order to
favor reliability, data were collected independently in
a table including first author, year, journal, study
design, population characteristics, initial and final
sample size, type and dosage of supplementation,
exposure period, outcome measures, and results. A
third investigator solved eventual disagreements.
One of the researchers evaluated bias risk for each
study included in this review, after data extraction,
through the application of a tool available on
Cochrane Handbook for Systematic Reviews of
Interventions and with the support of the software
Review Manager. This information was reported in
the discussion section, regarding validity of effects
found for each study.
Results from the original papers are presented
comparing scores of cognitive function derived from
questionnaires, between intervention and placebo
groups, as in P values and, when statistically significant
(P < 0.05), additionally as means and its standard
2 Nutritional Neuroscience 2017
deviation or confidence interval. Results are not
described when not available in the original articles.
Results
The search strategy resulted in a total of 361 articles.
After eligibility analyses, a total of seven papers ful-
filled all criteria. The selection process is shown in
Figure 1. Publication year varied from 2006 to 2015.
All articles were available in English.
The questionnaires that were used in these studies
were Alzheimer’s Disease Assessment Scale –
Cognitive section (ADAS-cog), Clinicians Global
Impression of Change (CIBIC-plus), Mini-Mental
State Examination (MMSE), Hamilton Depression
Scale (HDRS), Montgomery Asberg Depression
Rating Scale (MADRS), Clinical Dementia Rating
Scale (CDR), Alzheimer’s Disease Cooperative
Study – Activities of Daily Living (ADCS-ADL),
Alzheimer’s Disease Cooperative Study – Instrumental
Activities of Daily Living (ADCS-IADL), Caregivers
Burden Scale (CGB), Disability Assessment for
Dementia Scale (DAD), Neuropsychiatric Inventory
(NPI), Neuropsychological Test Battery (NTB), and
Bristol’s Activities of Daily Living Scale (BADLS).
The most frequent questionnaires were ADAS-cog
and MMSE, both present in four studies.14–17 The
main scales are summarized in Table 1.
Sample size varied from 19 to 402 men and women,
summing a total of 429 individuals randomized for
omega-3 fatty acids’ intervention and 366 for
placebo. Patients were 55–90 years old and presented
mild and moderate AD, according to MMSE ques-
tionnaire, used in all seven studies, and additionally
CDR questionnaire, used in one study. Information
about these studies are shown in Table 2.
In six studies, omega-3 fatty acids’ supplementation
combined both DHA and EPA14–16,24–26 and one
study supplemented only DHA.17 Placebo groups
received olive oil capsules, soy oil, corn oil, and/or
an isocaloric product. In four studies, both groups,
intervention and placebo, received other nutrients
additionally, such as tocopherols and hydro-
quinones.14,16,24–26 None of the studies supplemented
omega-3 fatty acids by increasing intake of its food
sources. The intervention period varied from 4
months to 18 months.
Concomitant pharmacological treatment for AD
was not allowed in some studies.16,24 In studies that
allowed the adjuvant treatment with medi-
cines,14,15,17,25,26 the stable use for 3 or 4 months
prior to the beginning of intervention was required.
The first randomized clinical trial controlled by
placebo that evaluated omega-3 fatty acids’ impact
in AD was published in 2006. Freund-Levi et al. 14
assessed omega-3 fatty acids’ supplementation in 204
subjects with mild-to-moderate AD (mean age: 74 ±
 Canhada et al. Omega-3 fatty acids’ supplementation in Alzheimer’s disease

Figure 1 Flow diagram of the systematic review of the impact of omega-3 fatty acids’ supplementation on cognitive function in
AD patients.

9 years). The intervention group received omega-3
fatty acids in the dosages of 1720 mg DHA and
600 mg EPA and the placebo group received
4000 mg of corn oil (containing 2400 mg of linoleic
acid) for 6 months, followed by more 6 months of
omega-3 fatty acids’ supplementation for both
groups. Medication for AD treatment was allowed. As
a result, there was no significant statistical difference
at 6 months and 12 months between groups in
ADAS-cog (P > 0.05), MMSE (P > 0.05) e CDR
(P > 0.05). In a subgroup with very mild AD
(MMSE > 27 and CDR 0.5–1), there was a significant
difference in MMSE between intervention and placebo
in the first 6 months (placebo group had a decline of
−2.6 points and intervention group had −0.5 points;
P = 0.01).
In a second paper published in 2008, Freund-Levi
et al. 25, using the exact same sample from 2006,
assessed other questionnaires. No significant statistical
difference was found at 6 months and 12 months

Table 1 Summary of main scales used for cognitive assessment in AD.

Main scales Description

ADAS-cog18 Is a sensitive and reliable method for the assessment of cognitive function in dementias. It consists of a
psychometric scale of 11 items, and scores range from 0 (no impairment) to 70 (very severe impairment).
It is considered to have a good sensitivity to evaluate changes over time
ADCS-ADL; ADCS- It measures the functional ability to perform activities of daily life. ADL assess basic living skills such as
IADL19 bathing and eating, whereas IADL measure more complex tasks such as using the telephone or
preparing meals. A higher ADL or IADL score indicates a worsening functionality. Scores range from 0 to
27 for ADL and 0 to 14 for IADL
CDR20 It is a global measure that assesses memory, orientation, judgment, and other features. Is based on
caregiver interview. Classifies dementia into questionable, mild, moderate, and severe
CIBIC-plus21 It is a global measure capable of detecting changes in cognition, functionality, and behavior, thus
assessing dementia’s severity and progression. Requires separate interviews with patients and
caregivers. It is a 7-point Likert-type scale, in which 1 represents markedly improved; 4, no change; and
7, markedly worse
MMSE22 Evaluates cognitive function in the areas of orientation, memory, attention, calculation, language, and visual
construction. It is widely translated and used in clinical practice. Patients score between 0 and 30 points,
and cutoffs of 23/24 have typically been used to show significant cognitive impairment
NTB23 This scale assesses changes in cognitive function and is seen as a promising method for mild AD. NTB has
shown to be able to detect changes in memory performance

Nutritional Neuroscience 2017 3

4
Nutritional Neuroscience
Table 2 Clinical trials assessing the impact of omega-3 fatty acid’s supplementation on cognitive function in Alzheimer’s disease patients.
Authors Sample
Freund-Levi Initial sample: 204
2017
et al.14 Final sample: 174 patients completed the protocol (85%)
Recruitment: patients from a specialist memory clinic
Local: Stockholm, Sweden
Inclusion criteria: AD (DSM-IV); MMSE- 15 score between 15
and 30 points; patient living in his or her own home;
Treatment with a stable dose of acetylcholine esterase
inhibitors for at least 3 months; and plan to continue
acetylcholine esterase inhibitors for the duration of the study
Exclusion criteria: treatment with nonsteroidal anti-
inflammatory agents (low-dose acetylsalicylic acid was
accepted), w3 preparations, or anticoagulants; alcohol
abuse; concomitant serious disease; did not have a caregiver
Chiu et al. 16 Initial sample: 46
Final sample: 29 completed the protocol (63.04%)
Recruitment: newspaper advertisements
Local: Tapei, Taiwan
Inclusion criteria: AD (DSM-IV), mild-or-moderate severity
(MMSE score between 10 and 26, and a CDR score of 1 or
2), or amnesic MCI, age range between 55 and 90 years old
Exclusion criteria: inadequate motor or sensory capacity;
ischemic lesion on brain computed tomography (CT); a
modified Hachinski Ischemic Scale scoreN4; a 17-item HDRS
(Hamilton, 1960) scoreN13; abnormal levels of folic acid,
vitamin B12, or thyroid function; severe comorbidity (another
neurodegenerative diseases, chronic debilitating neurological
illness, brain trauma, tumors, severe pulmonary, renal, liver
disease, cardiac disease, or autoimmune disease, or
conditions expected to cause death within 1 year, alcoholism,
schizophrenia, and bipolar disorder, receiving cholinesterase
agents during the screen or taking NSAID on a long-term
basis)
Methods
Design: randomized, double-blind, placebo-controlled study
Follow-up: 6 months of placebo-controlled intervention,
followed by 6 months of treatment for both groups
Group w3/w3: 1720 mg DHA + 600 mg EPA, daily (from w3
fatty acid concentrate in triglyceride form)
Group placebo/w3: isocaloric placebo oil (4000 mg of corn
oil) daily for 6 months, followed by 6 months of treatment with
w3 fatty acid supplementation
Both groups received 24 mg of vitamin E (tocopherol) added
in their capsules
Assessments: Baseline, 6 and 12 months: global function
(CDR), cognitive function (MMSE), and the modified cognitive
portion (ADAS-COG)
Design: randomized, double-blind, placebo-controlled study
Follow-up: 24 weeks
Group w3: 1080 mg EPA + 720 mg DHA, daily (the source of
the omega-3 fatty acids was menhaden fish body oil
concentrate)
Group placebo: olive oil esters (dosage not informed)
Both groups receive antioxidants in their capsules (1.2 mg of
hydroquinone and 12 mg of tocopherols, daily)
Assessments: baseline and at weeks 6, 12, 18, and 24:
cognitive portion of the ADAS (ADAS-cog), CIBIC-plus scale,
and HDRS
Baseline, weeks 12, 18, and 24: Erythrocyte membrane fatty
acid compositions
Baseline and week 24: plasma fatty acids
Canhada et al.
Omega-3 fatty acids’ supplementation in Alzheimer’s disease
Results
Group w3/w3: 89 individuals, 72.6±9.0 years, 57%
women,
Group placebo/w3: 85 individuals, 72.9±8.6 years, 46%
women
Outcomes: MMSE, ADAS-cog, and CDR: There was no
statistically significant difference during 6 and 12 months
between groups on the ADAS-cog (P > 0.05), MMSE
(P > 0.05), or CDR (P > 0.05).
In a subgroup analyses (n = 32), with subjects with very
mild cognitive dysfunction (MMSE > 27 e CDR 0.5–1), a
significant (−0.5 points vs. −2.6 points; P = 0.01)
reduction in decline rate was observed in the omega-3
fatty acids’ group when compared with placebo between
baseline and 6 months.
Group 1 (omega-3 fatty acids): 20 individuals, 74.0 years
(70.1–77.8), 8 AD and 12 with MCI, 65% women (at
baseline)
Group 2 (placebo): 15 individuals, 76.5 (71.8–81.1), 9 AD
and 6 with MCI, 46.7% women (at baseline)
Outcomes: ADAS, MMSE, HDRS: there were no
differences between groups (P > 0.05, P = 0.87 and,
P = 0.76, respectively).
In subgroup analyses, the omega-3 fatty acids’ fatty acids
group showed significant improvement in ADAS-cog
compared to the placebo group in participants with mild
cognitive impairment (−3.23 ± 3.82 vs. −0.37 ± 1.4,
P = 0.03), which was not observed in those with AD.
There was a relative improvement in the CIBIC-plus score
in omega-3 fatty acids’ fatty acid group of −0.35 (−0.61 to
−0.09, P = 0.008) compared to placebo group every 6
weeks
Continued
 Table 2 Continued
Authors Sample
Quinn Initial sample: 402
et al. 17 Final sample: 295 completed the protocol (73.4%)
Recruitment: Fifty-one US clinical research sites of the
Alzheimer’s Disease Cooperative Study
Local: US
Inclusion criteria: probable AD if MMSE score was between
14 and 26, they were medically stable, they consumed on
average no more than 200 mg/d of DHA, and they were not
taking DHA or omega-3 fatty acids’ fatty acid supplements
Exclusion criteria: taking drugs with central anticholinergic
effects or sedatives or receiving any investigational treatment
for AD. Stable use (>3 months) of cholinesterase inhibitors or
mean time was permitted
Scheltens Initial sample: 259
et al. 24 Final sample: 238 completed the protocol (92%)
Recruitment: from 27 AD Center
Local: The Netherlands, Germany, Belgium, Spain, Italy, and
France
Inclusion criteria: age ≥50 years, AD (NINCDS-ADRDA),
MMSE score of ≥20, recent MRI or computed tomography
(CT) scan with no evidence of any other potential causes of
dementia
Exclusion criteria: other neurological diseases; a Geriatric
Depression Scale (15-item) score of >6; use of a
cholinesterase inhibitor or NMDA-receptor antagonist within 3
months prior to baseline; use of omega-3 fatty acids
containing supplements or regular consumption of oily fish
(>twice/week) within 2 months prior to baseline; use of
atropine, scopolamine, tolterodine, hyoscyamine, biperiden,
benztropine, trihexyphenidyl, oxybutynin, antipsychotics,
vitamins B, C, and/or E (>200% of the recommended daily
intake), consumption of high-energy and/or high-protein
Nutritional Neuroscience
nutritional supplements, a change in dose of lipid-lowering
medications, antidepressants, antihypertensives, or the use of
other investigational products within 1 month prior to
baseline; excessive alcohol intake or drug abuse; nursing
home institutionalization; or investigator’s uncertainty
regarding the willingness or ability of the patient to comply
with the protocol
2017
5
Methods
Design: randomized, double-blind, placebo-controlled trial
Follow-up: 18 months
Group DHA: 2000 mg of DHA daily (algal-derived)
Group placebo: corn or soy oil (dosage not informed)
Assessments: baseline, 6 months, 12 months: cognitive
subscale (ADAS-cog) and CDR sum of boxes. Brain atrophy
[volumetric magnetic resonance imaging (MRI)] in a
subsample of participants (n = 102). ADCS-ADL, NPI, and the
Quality of Life AD scale.
Baseline and 18 months: MMSE
Design: randomized, controlled, double-blind, parallel-group,
multi-country trial
Follow-up: 24 weeks
Group active: 1200 mg DHA + 300 mg EPA + phospholipids,
choline, UMP, vitamin B12, B6, and folate, vitamins C and E,
and selenium from Souvenaid®
Group control: isocaloric control product
Both study products were available as a 125 ml drink with an
identical taste and appearance, taken once daily
Assessments: baseline, 12, and 24 weeks: memory function
domain score (NTB); executive function (WMS-r Digit Span,
Trail Making Tests parts A and B), category Fluency
(Controlled Oral Word Association Test), functional ability
(DAD)
Nutritional blood parameters (plasma vitamin E, erythrocyte
DHA and EPA, and homocysteine), and EEG to assess eyes-
closed resting-state oscillatory brain activity and functional
brain connectivity in a subset of patients
Results
Group DHA: 238 individuals, 76 (9.3) years, 47.1% female
sex (at baseline)
Group placebo: 164 individuals, 76 (7.8) years, 59.8
female sex (at baseline)
Outcomes: There was no statistically significant difference
between groups on the ADAS-cog (P = 0.41), CDR
(P = 0.68), ADCS-ADL (P = 0.38), NPI (P = 0.11), or MMSE
(P = 0.88) on the 18-month follow-up.
Brain atrophy decline difference was not statistically
significant between groups during 18 months (P = 0.79)
Active: 130 individuals, 74.4 (6.9) years, 52.3% male (at
baseline)
Control: 129 individuals, 73.2 (8.4) years, 49.6% male (at
baseline)
Outcomes: NTB memory domain: Z-score was
significantly increased in the active vs. the control group
over the 24-week intervention period (P = 0.023; Cohen’s
Canhada et al.
d = 0.21; 95% confidence interval [−0.06]–[0.49]); a trend
for an effect was observed on the NTB total composite z-
score (P = 0·053); no statistically significant difference
between groups was found on the NTB executive
function domain (P = 0.686)
Omega-3 fatty acids’ supplementation in Alzheimer’s disease
EEG measures of functional connectivity in the delta band
were significantly different between study groups during
24 weeks in favor of the active group (P = 0.011)
Continued
6
Nutritional Neuroscience
Table 2 Continued
Authors Sample
Shinto Initial sample: 39
et al. 15 Final sample: 34 completed the protocol (87%)
Recruitment: -
Local: US
Inclusion criteria: age ≥55 years, AD (NINCDS/ADRDA),
MMSE score 15–26, CDR 0.5 to 1.0, not depressed (CESD
2017
<4.0), general health status that would not interfere with
patient’s ability to participate and complete the study, and
caregiver/informant able to accompany participant to study
visits
Exclusion criteria: non-AD dementia, residence in a long-term
care facility at screening visit, history of stroke, health
conditions such as cancer (prostate cancer gleason grade
<3 and non-metastatic cancers were acceptable), liver
disease, history of ventricular fibrillation or ventricular
tachycardia, major psychiatric disorder, major central nervous
system diseases, taking lipid-lowering medication,
hyperlipidemic, fish oil or cod liver oil supplementation within
30 days of enrollment, greater than one 6 ounce serving per
week of fish or seafood within 30 days of enrollment, lipoic
acid supplementation within 30 days of enrollment, taking
systemic corticosteroids, neuroleptics, antiparkinsonian
agents, and narcotic analgesics. The following medications
and supplements were allowed if stable for 4 months prior to
study enrollment, acetylcholinesterase inhibitors, memantine,
vitamin E, and ginkgo biloba
Freud-Levi Initial sample: 204
et al. 25 Final sample: 174 completed the protocol (85%)
Recruitment: patients from a specialist memory clinic
Local: Stockholm, Sweden
Inclusion criteria: AD (DSM-IV), MMSE score inclusive of 15
and 30, living in their own homes;
Treatment with a stable dose of acetylcholine esterase
inhibitors for at least 3 months before the study start
Exclusion criteria: use of NSAID (low-dose acetylsalicylic acid
was accepted), ω3 preparations, anticoagulation agents;
alcohol abuse; concomitant serious disease; or did not have
a caregiver
Exclusion criteria: treatment with nonsteroidal anti-
inflammatory agents (low-dose acetylsalicylic acid was
accepted), w3 preparations, or anticoagulants; alcohol
abuse; concomitant serious disease; did not have a caregiver
Methods
Design: 3-arm, parallel group, randomized, double-blind,
placebo-controlled pilot clinical trial
Follow-up: 12 months
Group w3: omega-3 fatty acids’ fish oil concentrate containing
a daily dose of 675 mg DHA and 975 mg EPA
Group w3/LA: omega-3 fatty acids’ (fish oil concentrate
containing a daily dose of 675 mg DHA and 975 mg EPA) plus
LA (600 mg/day)
Group placebo: soy oil
Assessments: Baseline to 12 months: cognitive subscale
(ADAS-cog), cognitive function (MMSE), Activities of Daily
Living/Instrumental Activities of Daily Living (ADL/IADL)
Design: randomized, double-blind placebo-controlled clinical
trial
Follow-up: 12 months
Group w3: 430 mg DHA and 150 mg EPA in four capsules
daily
Group placebo: isocaloric placebo oil (containing 1 g of corn
oil, including 0.6 g of linoleic acid) for 6 months, followed by 6
months’ open treatment with omega-3 fatty acids for all
patients
4 mg vitamin E (tocopherol) was added to each EPAX1050TG
and placebo capsule
Assessments: Baseline, 6 and 12 months: Neuropsychiatric
symptoms (NPI); Depressive symptoms (MADRS); Burden of
the caregiver was evaluated using three items from CGB.
Activities of daily living were rated (DAD)
Canhada et al.
Omega-3 fatty acids’ supplementation in Alzheimer’s disease
Results
Placebo: 13 individuals, 75.2 (10.8) years, 54% female (at
baseline)
Omega-3 fatty acids: 13 individuals, 75.9 (8.1) years, 39%
female (at baseline)
Omega-3 fatty acids + LA: 13 individuals, 76.7 (10.6)
years, 39% female (at baseline)
Outcomes: ADAS-cog: The ω-3 + LA and ω-3 were not
significantly different than the placebo group (P = 0.98,
P = 0.86)
ADL: The ω-3 + LA and ω-3 were not significantly different
than the placebo group (P = 0.15, P = 0.82).
MMSE: The mean change over 12 months between
placebo group and intervention group with ω-3 was not
statistically significant (−4.6 points (±1.4) for the placebo
group vs. −4.3 points (±1.3) for the ω-3 group; P = 0.80);
but there was a significant difference between placebo
and ω-3+LA (−4.6 points (±1.4) for placebo vs. −1.0
points (±0.7) for ω-3+LA; P < 0.01), suggesting that the
combination therapy decreased the rate of decline in
MMSE over 12 months
IADL: The mean change over 12 months between
placebo group and ω-3 group was statistically significant
(4.2 points (±0.9) vs. 0.7 points (±1.0); P < 0.01) and
between placebo and ω-3+LA (4.2 points (±0.9) vs. 0.9
points (±1.1); P = 0.01)
Group w3/w3: 89 individuals, 72.6 ± 9.0 years. 57%
women
Group placebo/w3: 85 individuals, 46% women,
72.9 ± 8.6 years
Outcomes: NPI: no significant difference over 6 and 12
months was observed between the w3/w3 and the
placebo/w3 groups (P = 0.52)
No significant differences in depressive symptoms
occurred in either the v3/v3 or the placebo/v3 groups at
0–6 and 6–12 months, whether assessed using the
depressive domain of NPI (P = 0.84) or by MADRS
(P = 0.49)
No significant differences in DAD score change or in the
three items of care givers burden (CGB) between the v3/
v3 and placebo/v3 at 0 and 6 months were found
Continued
 Canhada et al. Omega-3 fatty acids’ supplementation in Alzheimer’s disease

between intervention and placebo in NPI (P = 0.52),

Outcomes: There was no statistically significant difference

53.8% female sex (at baseline – except for the number of

(P = 0.576), BADLS (P = 0.595) in the 4 months of follow-

between groups on the MMSES7 (P = 0.711), MMSEWB
MADRS (P = 0.49), DAD (P > 0.05) e CGB (P >

Group omega-3 fatty acids: Eight individuals, 71.1 (4.8)

years, 56.8% female sex (at baseline – except for the
number of individuals, data refer to 37 CNID and AD

Group placebo: Eleven individuals, 71.1 (9.5) years,

0.05).

individuals, data refer to 39 CNID and AD patients)

Chiu et al. 16 studied 46 subjects with mild-to-mod-
erate AD or mild cognitive impairment (mean age:
55–90 years). During 24 weeks, intervention group
received omega-3 fatty acids in the form of 1080 mg
Results

of EPA and 720 mg of DHA, while placebo group

received olive oil. Medication for AD treatment was
not allowed. There was no significant statistical differ-
ence in ADAS-cog (P > 0.05), MMSE (P = 0.87), and
HDRS (P = 0.76) between the two groups in 24 weeks.
A significant improvement was observed in CIBIC-
plus in the intervention group of −0.35 (IC95%
patients)

−0.61 a −0.09, P = 0.008) every 6 weeks compared

to placebo group. In a subgroup analysis, participants
up

with mild cognitive impairment, but not with AD,

showed a significant additional delay in ADAS-cog
Both groups also received 20 mg mixed tocopherols, daily, in
Group omega-3 fatty acids: 625 mg DHA and 600 mg EPA,

Assessments: Baseline, 1 and 4 months: cognitive function

decline compared to placebo group (−3.23 ± 3.82 vs.

(MMSE: MMSES7 and MMSEWB), activities of daily living

−0.37 ± 1.4, P = 0.03).

Quinn et al. 17 assessed 402 subjects with mild-to-
moderate AD (age: 76 ± 8.7 years). The intervention
Group placebo: olive oil (dosage not informed)
Design: randomized, double-blind, placebo-

group received 2000 mg of DHA and the placebo

group received corn or soy oil for 18 months.
Methods

Medication for AD treatment was allowed. A sub-

sample received magnetic resonance imaging (MRI)
assessments. There was no significant effect from the
intervention in cognitive decline rhythm in ADAS-
cog (P = 0.41), CDR (P = 0.68), ADCS-ADL (P =
Follow-up: 4 months

(BADLS) and others

0.38), NPI (P = 0.11), or in MMSE (P = 0.88).

controlled study

their capsules

There was also no change in cerebral volume at 18

months of trial (P = 0.79).
Scheltens et al. 24 assessed 259 subjects with mild AD
daily

(age of 55 years or higher). The intervention group

received 1200 mg of DHA and 300 mg of EPA with
needs that would prevent the study’s requirements from being
of other psychiatric or neurological conditions; current drug or
minimum of 3 months prior to entering the study; MMSE score
have been on a stable dose of a cholinesterase inhibitor for a

Exclusion criteria: if another dementia was suspected; history

Inclusion criteria: AD (diagnosis based on NINCDS-ADRDA);
Final sample: 19 completed the protocol (100%). There were

the addition of other nutrients in the form of the

accompany them to research visits and who lived with them
alcohol addiction; disabilities, disorders or special dietary

product Souvenaid®, whereas the placebo group

supplements; did not have a relative or friend that could
undertaken; already taking omega-3 fatty acids’ PUFA

received isocaloric control product for 24 weeks.

Medication for AD treatment was not allowed. A sub-
Recruitment: through specialist memory clinics
no dropouts but twodid not complete all visits

sample was assessed through EEG. In the NTB

memory domain, a significant increase was found in
or visited them at least 2 times a week

the intervention group compared to control group at

24 weeks (P = 0.023, additional alteration of 0.21,
Sample

IC95% −0.06–0.49). There was a trend for effect in

the NTB total composite in 24 weeks (P = 0.053). No
significant effect from the intervention was found in
the NTB execution function domain (P = 0.686).
between 16 and 30
Local: Bristol, UK
Initial sample: 19

EEG measures of functional connectivity were signifi-

cantly different in one of the bands – the delta band –
in favor of the intervention group (P = 0.011).
Table 2 Continued

Shinto et al. 15 studied 39 subjects with more than 55

years with probable AD in a randomized placebo-con-
trolled pilot with three arms. Two groups received
et al. 26

omega-3 fatty acids’ supplementation, one only

Authors

Phillips

omega-3 fatty acids (975 mg EPA and 675 mg

DHA), and the other with the addition of alpha

Nutritional Neuroscience 2017 7

Canhada et al. Omega-3 fatty acids’ supplementation in Alzheimer’s disease
lipoic acid (975 mg EPA, 675 mg DHA, and 600 mg
ALA); placebo group received soy oil. The interven-
tion lasted 12 months and medication for AD was
allowed. There were no differences in ADAS-cog and
ADL between placebo and omega-3 fatty acids (P =
0.86; P = 0.82) or between placebo and omega-3
fatty acids + ALA (P = 0.98; P = 0.15). In MMSE,
the mean alteration in 12 months between placebo
group and intervention group with only omega-3
fatty acids was not significant (−4.6 ± 1.4 vs. −4.3 ±
1.3 points; P = 0.80), whereas the difference between
placebo and omega-3 fatty acids + ALA was signifi-
cant (−4.6 ± 1.4 points for placebo vs. −1.0 ± 0.7
points for omega-3 fatty acids + ALA; P < 0.01).
The mean alteration in IADL in 12 months was sig-
nificant between placebo group and omega-3 fatty
acids group (4.2 ± 0.9 points for placebo group vs.
0.7 ± 1.0 points for omega-3 fatty acids group; P <
0.01) and between placebo and omega-3 fatty
acids + ALA (4.2 ± 0.9 points for placebo group vs.
0.9 ± 1.1 points for omega-3 fatty acids + ALA
group; P = 0.01).
Phillips et al. 26 assessed omega-3 fatty acids ‘sup-
plementation in 19 subjects with AD (mean age:
71.1 ± 4.8 years – all data refer to 76 patients, which
includes 57 with cognitive impairment and 19 with
AD). The intervention group received daily omega-3
fatty acids in the dosages of 625 mg DHA and
600 mg EPA and the placebo group received olive oil
for 4 months. Medication for AD treatment was
allowed. As a result, there was no significant statistical
difference at 4 months between groups in MMSES7
(P = 0.711), MMSEWB (P = 0.576), or BADLS
(P = 0.595).
Discussion
Recent literature reveals weak associations between
omega-3 fatty acids’ supplementation and cognitive
outcomes in AD. Most studies do not find statistically
significant results when supplementation is compared
to placebo. On the other hand, some benefit was
found in just a few evaluated scales.15,16,24 Omega-3
fatty acids’ supplementation seems more effective in
very mild AD.14
Some studies showed improvements with omega-3
fatty acids ‘supplementation in overall analyses, and
not only in subgroups. Chiu et al. 16 found better
results for the intervention group, compared to
placebo, in the CIBIC-plus scale. Shinto et al. 15
found better results in the MMSE scale with omega-
3 fatty acids in addition to ALA, and in the IADL
scale in both groups that received omega-3 fatty
acid’s supplementation, compared to placebo.
Scheltens et al. 24 also found better results with
omega-3 fatty acids in the memory domain of NTB
scale.
8 Nutritional Neuroscience 2017
The CIBIC-plus21 is a scale that provides a global
measure designed to detect changes not only in cogni-
tion, but also in overall function and behavior, thus
assessing dementia’s severity and progression. Only
Chiu et al. 16 used this scale to assess the impact of
omega-3 fatty acids’ supplementation, finding statisti-
cally significant improvements with the intervention
compared to placebo. However, as this same study
did not find benefits in other two scales that specifi-
cally measure the cognitive capacity – ADAS-cog
and MMSE – it is possible that the positive results in
CIBIC-plus are the reflection of omega-3 fatty acid’s
action in other systems, such as cardiovascular or
immune systems – in which the omega-3 fatty acids’
beneficial effects have already been reported.
From the studies that used MMSE scale as an
assessment method,14–17,26 only one demonstrated
statistically significant effects in favor of interven-
tion,15 but only when in combination with ALA.
MMSE22 assess cognitive function in the orientation,
memory, attention, calculation, language, and visual
construction areas. The mechanism that resulted in
the delay of cognitive decline progression remains
uncertain, so it is not possible to assert if the effects
were the result of the combination or only of ALA,
because there was no exclusive intervention with the
latter in that study.
ADCS-ADL scale19 was used in two studies.15,17
This scale measures the subject’s functional ability in
performing daily living activities. While Quinn
et al. 17 used the full scale and did not find statistical
significance, Shinto et al. 15 used a modified version
to measure ADL and IADL. ADL assessed basic
daily functions, such as bathing and eating, whereas
IADL assessed more complex skills, such as using
the phone and cooking meals. In this study, despite
the fact that placebo group has shown an apparent
superior decline, no significant difference was found
in ADL between placebo and omega-3 fatty acids or
between placebo and omega-3 fatty acids + ALA.
Regarding IADL, both groups that received omega-3
fatty acids obtained delay in functional decline when
compared with placebo. This scale measures more
complex daily functions, and maybe for this reason it
was more sensitive to Alzheimer’s progression than
ADL.15
From the seven studies included in this review, only
one used NTB scale for assessing cognitive function24
to detect changes in early stages of AD.23 The authors
found a significant increase in the NTB memory
domain in the intervention group with the product
Souvenaid® compared to placebo, but not in the
executive function and total composite score domains.
The effect observed in a subgroup of subjects whose
MMSE scores were the highest and cognitive decline
was the smaller14 corroborates findings from

epidemiological observational studies. Several cohort
studies suggest that fish consumption, omega-3 fatty
acids’ source, would have a role in Alzheimer’s preven-
tion, but not in the treatment when the disease is
already manifested.4,6–8 Subgroup analysis of subjects
with mild AD also allowed the conclusion that
improvements were originated in the memory
domain, one of the disease’s key symptoms that
marks the beginning of the symptomatology.
Some limitations in the studies may explain part of
their results and, as so, deserve consideration. First,
in at least three studies15,16,26 the sample size was too
small, which can limit statistical power. Second, loss
during the treatment period was frequent – in one of
the studies only 63%16 of the subjects completed the
follow-up. Two authors tested if dropout was different
between groups,16,17 not finding statistically significant
differences. Reasons for losing participants during the
follow-up included lack of adhesion from caregivers,
withdrawal of consent, adverse gastrointestinal
effects, other diseases, and death. Third, the high het-
erogeneity of methods used to assess aspects of
patient’s cognition, along with the heterogeneity in
interventions composition and dosages, makes it diffi-
cult to establish greater comparative analysis.
Other study characteristics can also contribute to
the absence of significant results of omega-3 fatty
acids in AD in some of these papers. Primarily, in
two of the studies16,26 the placebo included olive oil,
which is a source of monounsaturated fatty acids,
already shown by other authors as inversely associated
with cognitive decline. In this case, the placebo would
not be totally inert and, therefore, would limit the
differences compared to the intervention group.
Second, in five studies14,15,17,25,26 participants were
allowed to receive medications for AD treatment
along with omega-3 fatty acids, which could contrib-
ute to good outcomes also in the control group.
However, in these five studies there was no apparent
difference in the use of medications between groups,
and in two of them15,17 tests were applied to detect
differences and no statistical significance was found.
Third, the trials observed in this review had, as
exposure period to treatment, a variation between
4 and 18 months, a time considered appropriate from
the ethical point of view in this population, but that
can be too short since Alzheimer’s is a chronic
disease. Fourth, omega-3 fatty acids’ dosages could
have been insufficient to provide significant benefits.
Indeed, there is no consensus among AD studies
about dosages of EPA e DHA. In Chiu et al. 16,
1080 mg of EPA and 720 mg of DHA was sup-
plemented daily. In this study, there was an increase
in the DHA levels and total omega-3 fatty acids in
plasma and in membranes of erythrocytes, but not
in EPA levels. There was an increase of 1.5-fold in
Canhada et al. Omega-3 fatty acids’ supplementation in Alzheimer’s disease
plasma levels after 1.8 g/day of oil fish – smaller
than in other study, in which increases of 2.4- to 3.6-
folds were observed after 2.4 g/day of fish oil.14,25 In
addition, the study of Chiu et al. 16 was performed in
Taiwan, a country with a high fish consumption,27
so perhaps a higher omega-3 fatty acids’ dosage is
necessary to reach a significant contrast compared to
control group. Shinto et al. 15 used 975 mg EPA +
675 mg DHA, a quite similar dosage to the one used
by Chiu et al. 16, but with a DHA:EPA relation
much smaller than other studies.14,17,25 Phillips
et al. 26 used practically the same amounts for DHA
(625 mg) and EPA (600 mg). Freund-Levi et al. 14,25,
on the other hand, supplemented fish oil (DHA
1.7 g/day and EPA 0.6 g/day) in higher doses than
studies that revealed benefits in cardiovascular dis-
eases and AD prevention. The authors chose an elev-
ated DHA:EPA relation (2.8-folds more DHA than
EPA) based on studies that show DHA deficiency in
brains affected by AD and on studies that associate
the DHA ingestion with Aβ reduction in hippocampus
and parietal cortex in rats in a dose-dependent way.
These areas are the first affected by AD in the brain,
and they alter the verbal episodic memory. Scheltens
et al. 24 also administered a higher DHA quantity
throughout the use of the product Souvenaid®
(1200 mg DHA + 300 mg EPA), which contains
additional nutrients – potentially responsible for part
of the observed benefits. Quinn et al. 17, on the other
hand, did not observe significant impact with DHA
exclusive use (2 g/day). The high heterogeneity in
the dosages supplemented made unfeasible to
conduct a meta-analysis.
To our knowledge, this is the most recent systematic
review focusing exclusively in intervention studies,
with randomized clinical trials, controlled by
placebo, assessing omega-3 fatty acids’ supplemen-
tation in AD, regarding cognitive function outcomes.
These findings support other reviews, that previously
described omega 3’s supplementation in other popu-
lations and other outcomes,28–31 as also still inconclu-
sive, as for the treatment of AD.
Although few studies have shown alterations in
some of the cognitive function scales, it is not
enough to support, in a systematic way, omega-3
fatty acids’ supplementation in AD treatment. The
effects found in mild AD corroborate observational
epidemiological studies that show omega-3 fatty
acids’ benefits in the early stages of the disease, when
there is still a mild cerebral functional impairment.
In this sense, more studies are needed, with sufficient
sample size and longer intervention period, for differ-
ent stages of the disease, with the use of standardized
cognitive function scales, that also assess the depen-
dency level in daily activities, in which the effect of
each of the omega-3 fatty acids is evaluated, in
Nutritional Neuroscience 2017 9
Canhada et al. Omega-3 fatty acids’ supplementation in Alzheimer’s disease
sufficient doses, so that we can have a clearer con-
clusion of the real benefits of supplementation regard-
ing clinically relevant outcomes.
Disclaimer statements
Contributors None.
Funding None.
Conflicts of interest None.
Ethics approval None.
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