DFA: EPA/DHA and Cognitive Health (2011)


Samieri C, Feart C, Proust-Lima C, et al. Omega-3 acids and cognitive decline: Modulation by ApoEepsilon4 allele and depression. Neurobiol Aging. 2010 June. PMID 20570406

PubMed ID: 20570406
Study Design:
Prospective Cohort Study
B - Click here for explanation of classification scheme.
Quality Rating:
Positive POSITIVE: See Quality Criteria Checklist below.
Research Purpose:

The goal of this study was to examine the relationship between EPA and DHA plasma levels and cognitive decline over seven years in a cohort of elderly community dwellers. Cognitive decline was assessed by performance on tests of global cognition, verbal fluency, working memory and executive function, while considering depressive symptoms and ApoE-ε4 status.

Inclusion Criteria:
  • Non-institutionalized
  • Aged 65 years and older
  • Lived in the French city of Bordeaux
  • All participants signed informed consent.
Exclusion Criteria:

Not described

Description of Study Protocol:


Not described


This study was part of the three-city study, a prospective cohort study following vascular risk factors for dementia in 9,294 community dwellers in three French cities. The present study examines the Bordeaux sample of the three-city study (N=2,104). Baseline and two, four, and seven year follow-up assessments were completed on this cohort. Participants were administered a variety of tests as a measure of cognitive decline over seven years. Associations between EPA and DHA levels and cognitive decline were examined, taking into account depressive symptoms and ApoE-ε4 carrier status.

Statistical Analysis

  • Two-sided Student's tests: Compared mean plasma EPA and DHA and change in cognitive scores (by ApoE-ε4 carrier status and depressive symptoms)
  • Linear mixed models: Used to analyze changes in cognition over time from baseline
  • Associations of covariates with cognitive evolution from baseline were evaluated for each cognitive test both on the baseline mean score level and slope of cognitive change over time. 


  • Plasma EPA or DHA proportions transformed into Z scored
  • Depressive symptoms (high vs. low).

Adjustment factors

  • Age at baseline
  • Gender
  • Educational level
  • Marital status
  • ApoE-ε4
  • BMI
  • Weight loss more than 3kg
  • Smoking
  • Alcohol consumption
  • History of cardiovascular disease
  • Diabetes
  • Medication use
  • Anti-depressant use
  • Plasma triglycerides
  • Plasma vitamin E.
Data Collection Summary:

Timing of Measurements

  • Baseline: 1999-2000
  • Follow-up examinations were performed two, four and seven years after baseline
  • At baseline, sociodemographic information, lifestyle characteristics, medical symptoms, complaints, and conditions, neuropsychological testing, physical examination and blood sampling were performed
  • Cognitive assessments (MMSE, IST, BVRT, and TMT-A and TMT-b) were performed at baseline and at least two follow-up visits
  • Depressive symptoms measured at baseline
  • Plasma fatty acids assessed at baseline.

Dependent Variables

  • Cognitive assessments:
    • MMSE (index of global cognitive performance)
    • Isaacs Set Test (IST; assessment of semantic verbal fluency)
    • Benton Visual Retention Test (BVRT; assessment of working memory)
    • Trail-Making Test A and B (TMT-A and TMT-B; evaluation of executive functioning)
  • Assessment of depressive symptoms: CES-D (20-item scale to measure depressive symptoms in elderly; scores zero to 60; score of 17 or more in men and 23 or more in women was considered high depressive symptoms).
  • Other variables:
    • ApoE-ε4 allelle carrier status:
      • Measured genetic risk for dementia;
        • Carrier: Presence of at least one allele
        • Non-carrier: No allele
  • Visual impairment: Assessed at baseline with Parinaud test
  • Plasma vitamin E concentration: Measured by HPLC; marker for oxidative stress
  • Plasma triglycerides: Used as a proxy for overall lipidic status.

Independent Variables

  • Assessment of plasma fatty acids:
    • Percent EPA and percent DHA: Calculated as percentage of total fatty acids
    • Fasting blood samples collected at baseline visits.

Control Variables

  • Age at baseline
  • Gender
  • Educational level
  • Marital status
  • ApoE-ε4 status
  • BMI
  • Weight loss more than 3kg
  • Smoking
  • Alcohol consumption
  • History of cardiovascular disease
  • Diabetes
  • Medication use
  • Anti-depressant use (yes vs. no)
  • Plasma triglycerides
  • Plasma vitamin E.
Description of Actual Data Sample:
  • Initial N: 1,343  
  • Attrition (final N): 1,228 (those non-demented at baseline and completed the MMSE at least once at follow-up; percent men=38.7%
  • Age: Mean age: 74.7 years (4.9 SD)
  • Ethnicity: French residents of Bordeaux
  • Other relevant demographics: Non-demented subjects
    • ApoE-ε4 carriers: N=235, 19.3%
  • Anthropometrics: Mean BMI=26.4kg/m2 (4.2 SD)
  • Location: Bordeaux, France.


Summary of Results:

Key Findings

Annual change in cognitive scores according to baseline depressive symptoms and ApoE-ε4 status:

  • MMSE:
    • High depressive symptoms were significantly associated with lower baseline mean MMSE scores; high depressive symptoms: MMSE score=26.80 (SD=2.00); low depressive symptoms: MMSE score=27.60 (SD=2.00) (P<0.001)
    • High depressive symptoms were significantly associated with higher average annual decline in MMSE; high depressive symptoms: MMSE average annual change = -0.41 (SD=1.07); low depressive symptoms: MMSE average annual change = -0.12 (SD=0.55) (P<0.001)
    • MMSE scores did not differ significantly by ApoE-ε4 status at baseline
    • Higher annual declines in MMSE scores were observed in ApoE-ε4 carriers than non-carriers; high depressive: Average decline = -0.21 (SD=0.64); low depressive = -0.12 (SD=0.60) P<0.05
  • IST:
    • High depressive symptoms were significantly associated with lower mean IST scores at baseline; high depressive: IST score=28.10 (SD=6.90); low depressive IST score=29.90 (SD=6.20) (P<0.05)
    • Depressive status was not associated with average annual change in IST
    • IST scores were not associated with ApoE-ε4 status
  • BVRT:
    • High depressive symptoms were significantly associated with lower mean BVRT scores at baseline; high depressive BVRT score=10.80 (SD=2.5); low depressive BVRT score=11.40 (SD=2.10) (P<0.05)
    • Depressive status was not associated with average annual change in BVRT scores
    • BVRT scores were not associated with ApoE-ε4 status
  • TMT-A and TMT-B:
    • High depressive symptoms were significantly associated  with higher mean performance times on TMT-A and TMT-B scores
      • TMT-A: High depressive score=65.63 (SD=27.36); low depressive score=59.83 (SD=23.66); P<0.05
      • TMT-B: High depressive score=136.46 (SD=65.64); low depressive score=120.89 (SD=53.37); P<0.05
    • Depressive symptoms were not found to be associated with average annual changes in TMT-A and TMT-B scores 
    • Scores were not associated with ApoE-ε4 status.

Effects of plasma DHA on cognitive decline:

  • Plasma DHA not significantly associated with evolution of any cognitive test scores over time (adjusted for age, gender and education)
  • Plasma DHA not significantly associated with MMSE errors at baseline or decline in MMSE with time
  • IST performance: Scores were significantly associated with plasma DHA at baseline; but IST evolution was not found to be associated with DHA
  • TMT-A and TMT-B: Not associated with plasma DHA at baseline or over time
  • Relationship between plasma DHA and BVRT scores:
    • Significant interaction found between DHA proportion and ApoE-ε4 on the change of BVRT scores over time (P=0.02)
    • In non-carriers of ApoE-ε4, an increase in plasma DHA was not associated with BVRT performances over time 
    • In ApoE-ε4 carriers, a one-SD increase in plasma DHA was related to a slower decline in BVRT performances (β=0.061; SD=0.024; P=0.01); However, after exclusion of incident dementia cases, there was no longer a relationship between ApoE-ε4 status and BVRT change over time. (In elderly that remained dementia-free over the follow-up period, DHA was not associated with BVRT performance over time).

Effects of plasma EPA on cognitive decline:

  • Plasma EPA not associated with change in cognitive tests when adjusted for age, gender and education
  • Fully adjusted models: Plasma EPA was not associated with MMSE errors at baseline or decline in MMSE over time
  • IST scores: Higher plasma significantly associated with higher IST scores at baseline, but not evolution of IST scores
  • TMT-A and TMT-B: plasma EPA not associated with these scores
  • Relationship between plasma EPA and BVRT scores:
    • Independent interactions between plasma EPA and both depressive symptoms (P=0.05) and ApoE- ε4 (P=0.006) on the change of BVRT score over time were observed
    • In non-carriers with low depressive symptoms, plasma EPA was not related to evolution of BVRT scores (β=0.001; SD=0.012; P=0.93)
    • In ApoE- ε4 carriers with low depressive symptoms, higher EPA was associated with slower change in BVRT scores (β=0.076; SD=0.025; P=0.003)
    • In ApoE- ε4 non-carriers with high depressive symptoms, higher plasma EPA was associated with slower evolution of BVRT scores (β=0.096; SD=0.048; P<0.04)
    • In ApoE- ε4 carriers with high depressive symptoms, higher plasma EPA was associated with slower evolution of BVRT scores (β=0.171; SD=0.049; P<0.001
    • Exclusion of incident dementia cases and adjustment for visual impairment and total energy intake did not change results substantially for the relationship between plasma EPA and BVRT.

Other Findings

  • 7.8% of sample were found to have high depressive symptoms (CES-D score ≥17 in men and ≥23 in women
  • Lower baseline plasma EPA was significantly associated with higher depressive symptoms (P=0.02)
  • Lower baseline plasma DHA was not associated with higher depressive symptoms (P=0.95)
  • ApoE-ε4 carrier status:
    • Plasma EPA and DHA were not significantly different in the whole sample between ApoE-ε4 carriers and not carriers
    • Among those with high depressive symptoms, plasma EPA was lower, but not DHA, in carriers (borderline significance P=0.06)
    • Among participants with low depressive symptoms, plasma EPA did not differ by ApoE-ε4 status.
Author Conclusion:

The decline in visual working memory may be delayed in ApoE- ε4 carriers by EPA and DHA. EPA, but not DHA may impact the slowing of cognitive decline in depressed, older people.

Funding Source:
Government: The French National Research Agency; conseil Regional d'Aquitaine
Association France Alzheimer
Reviewer Comments:

Plasma EPA and DHA levels were only measured at baseline. It is possible that these levels could have changed over the course of the seven-year study.

Quality Criteria Checklist: Primary Research
Relevance Questions
  1. Would implementing the studied intervention or procedure (if found successful) result in improved outcomes for the patients/clients/population group? (Not Applicable for some epidemiological studies) Yes
  2. Did the authors study an outcome (dependent variable) or topic that the patients/clients/population group would care about? Yes
  3. Is the focus of the intervention or procedure (independent variable) or topic of study a common issue of concern to dieteticspractice? Yes
  4. Is the intervention or procedure feasible? (NA for some epidemiological studies) N/A
Validity Questions
1. Was the research question clearly stated? Yes
  1.1. Was (were) the specific intervention(s) or procedure(s) [independent variable(s)] identified? Yes
  1.2. Was (were) the outcome(s) [dependent variable(s)] clearly indicated? Yes
  1.3. Were the target population and setting specified? Yes
2. Was the selection of study subjects/patients free from bias? ???
  2.1. Were inclusion/exclusion criteria specified (e.g., risk, point in disease progression, diagnostic or prognosis criteria), and with sufficient detail and without omitting criteria critical to the study? ???
  2.2. Were criteria applied equally to all study groups? N/A
  2.3. Were health, demographics, and other characteristics of subjects described? Yes
  2.4. Were the subjects/patients a representative sample of the relevant population? ???
3. Were study groups comparable? Yes
  3.1. Was the method of assigning subjects/patients to groups described and unbiased? (Method of randomization identified if RCT) N/A
  3.2. Were distribution of disease status, prognostic factors, and other factors (e.g., demographics) similar across study groups at baseline? N/A
  3.3. Were concurrent controls or comparisons used? (Concurrent preferred over historical control or comparison groups.) N/A
  3.4. If cohort study or cross-sectional study, were groups comparable on important confounding factors and/or were preexisting differences accounted for by using appropriate adjustments in statistical analysis? Yes
  3.5. If case control study, were potential confounding factors comparable for cases and controls? (If case series or trial with subjects serving as own control, this criterion is not applicable.) N/A
  3.6. If diagnostic test, was there an independent blind comparison with an appropriate reference standard (e.g., "gold standard")? N/A
4. Was method of handling withdrawals described? Yes
  4.1. Were follow-up methods described and the same for all groups? Yes
  4.2. Was the number, characteristics of withdrawals (i.e., dropouts, lost to follow up, attrition rate) and/or response rate (cross-sectional studies) described for each group? (Follow up goal for a strong study is 80%.) Yes
  4.3. Were all enrolled subjects/patients (in the original sample) accounted for? Yes
  4.4. Were reasons for withdrawals similar across groups? Yes
  4.5. If diagnostic test, was decision to perform reference test not dependent on results of test under study? N/A
5. Was blinding used to prevent introduction of bias? ???
  5.1. In intervention study, were subjects, clinicians/practitioners, and investigators blinded to treatment group, as appropriate? N/A
  5.2. Were data collectors blinded for outcomes assessment? (If outcome is measured using an objective test, such as a lab value, this criterion is assumed to be met.) ???
  5.3. In cohort study or cross-sectional study, were measurements of outcomes and risk factors blinded? ???
  5.4. In case control study, was case definition explicit and case ascertainment not influenced by exposure status? N/A
  5.5. In diagnostic study, were test results blinded to patient history and other test results? N/A
6. Were intervention/therapeutic regimens/exposure factor or procedure and any comparison(s) described in detail? Were interveningfactors described? Yes
  6.1. In RCT or other intervention trial, were protocols described for all regimens studied? N/A
  6.2. In observational study, were interventions, study settings, and clinicians/provider described? Yes
  6.3. Was the intensity and duration of the intervention or exposure factor sufficient to produce a meaningful effect? Yes
  6.4. Was the amount of exposure and, if relevant, subject/patient compliance measured? Yes
  6.5. Were co-interventions (e.g., ancillary treatments, other therapies) described? N/A
  6.6. Were extra or unplanned treatments described? N/A
  6.7. Was the information for 6.4, 6.5, and 6.6 assessed the same way for all groups? Yes
  6.8. In diagnostic study, were details of test administration and replication sufficient? N/A
7. Were outcomes clearly defined and the measurements valid and reliable? Yes
  7.1. Were primary and secondary endpoints described and relevant to the question? Yes
  7.2. Were nutrition measures appropriate to question and outcomes of concern? Yes
  7.3. Was the period of follow-up long enough for important outcome(s) to occur? Yes
  7.4. Were the observations and measurements based on standard, valid, and reliable data collection instruments/tests/procedures? Yes
  7.5. Was the measurement of effect at an appropriate level of precision? Yes
  7.6. Were other factors accounted for (measured) that could affect outcomes? Yes
  7.7. Were the measurements conducted consistently across groups? Yes
8. Was the statistical analysis appropriate for the study design and type of outcome indicators? Yes
  8.1. Were statistical analyses adequately described and the results reported appropriately? Yes
  8.2. Were correct statistical tests used and assumptions of test not violated? Yes
  8.3. Were statistics reported with levels of significance and/or confidence intervals? Yes
  8.4. Was "intent to treat" analysis of outcomes done (and as appropriate, was there an analysis of outcomes for those maximally exposed or a dose-response analysis)? N/A
  8.5. Were adequate adjustments made for effects of confounding factors that might have affected the outcomes (e.g., multivariate analyses)? Yes
  8.6. Was clinical significance as well as statistical significance reported? Yes
  8.7. If negative findings, was a power calculation reported to address type 2 error? N/A
9. Are conclusions supported by results with biases and limitations taken into consideration? Yes
  9.1. Is there a discussion of findings? Yes
  9.2. Are biases and study limitations identified and discussed? Yes
10. Is bias due to study's funding or sponsorship unlikely? Yes
  10.1. Were sources of funding and investigators' affiliations described? Yes
  10.2. Was the study free from apparent conflict of interest? Yes