DFA: EPA/DHA and Cognitive Health (2011)

Study Design:
- Click here for explanation of classification scheme.
Quality Rating:
Research Purpose:

To examine the dietary consumption of fish and omega-3 polyunsaturated fatty acids (PUFA) in relation to long-term dementia risk over an average follow-up of 10 years in the Rotterdam Study.

Inclusion Criteria:
  • ≥55 years of age
  • Resident of Ommoord
  • Completion of cognitive screening
  • Free of dementia at baseline
  • Provision of valid dietary information at baseline.
Exclusion Criteria:
  • <55 years of age
  • Not a resident of Ommoord
  • No cognitive exam completed 
  • Dementia at baseline
  • Unable to provide valid dietary information at baseline
  • Resident of nursing home.
Description of Study Protocol:


Recruited from Ommoord, Rotterdam, Netherlands


  • Study of participants aged ≥55 years of age in the Rotterdam Study who were free of dementia and reported dietary information at baseline
  • Relationship between dietary consumption of fish and omega-3 PUFAs in relation to long-term dementia risk explored
  • Baseline examinations collected between 1990 and 1993 and follow-up examinations performed in 1993-1994, 1997-1999 and 2002-2004 with continuous monitoring for mortality and major morbidity.

Statistical Analysis

  • Age and sex adjusted Cox proportional hazard models and multivariate adjusted models to evaluate the risk of dementia and AD
  • Total fish intake assessed per three categories based on each participant's level of typical fish intake.


Data Collection Summary:

Timing of Measurements

  • Examination to obtain health and lifestyle information consisting of an extensive home interview and two clinical examinations conducted at baseline (1990-1993), 1993-1994, 1997-1999 and 2002-2004
  • Continuous monitoring for mortality and major morbidity
  • Diagnosis of dementia made following a three-step protocol at baseline and follow-up examinations; combined Mini-Mental State Examination (MMSE) and Geriatric Mental State schedule organic level, Camdex and evaluation by neurologist
    • MMSE scores <26 or Geriatric Mental State (GMS) schedule scores less than zero underwent the Camdex evaluation
    • GMS is a standardized, semi-structured interview for examining and recording mental state in elderly subjects which allows classification of patients by symptom profile and can demonstrate changes in profile over time
  • Diet measured at baseline examination using a two-step protocol including a self completed meal-based checklist and a dietitian administered validated semiquantitative food-frequency questionnaire
  • Information regarding education level, smoking habits and history of smoke, myocardial infarction and type 2 diabetes mellitus collected at baseline
  • Medications reviewed with interviewer at baseline
  • Height and weight, total plasma cholesterol and blood pressure were measured at the study center during baseline clinical exam.

Dependent Variables

Incidence of dementia

Independent Variables

  • Fish intake
  • Dietary intakes of omega-3 PUFAs.

Control Variables

  • Education level
  • Smoking habits
  • History of stroke, myocardial infarction and type 2 diabetes mellitus
  • Medications
  • Height and weight
  • Total plasma cholesterol
  • Blood pressure
  • Alcohol intake.


Description of Actual Data Sample:
  • Initial N: 6,444 participants
  • Attrition (final N): 5,395 participants
    • No fish intake group: 61.1% female
    • Low fish intake group: 58.7% female
    • High fish intake group: 57.6%
  • Age
    • No fish intake group: 68.3±8.2 years
    • Low fish intake group: 68±7.6 years
    • High fish intake group: 67±7.5 years
    • P<0.0001 between fish intake groups
  • Ethnicity: Dutch; no details discussed
  • Other relevant demographics:
    • Education Level
      • Low education level
        • No fish intake 35.5%
        • Low fish intake 36.3%
        • High fish intake 33.1%
      • Intermediate education level
        • No fish intake 28.4%
        • Low fish intake 28.7%
        • High fish intake 28.6%
      • High education level
        • No fish intake 36.1%
        • Low fish intake 35%
        • High fish intake 38.3%
  • Anthropometrics:
    • BMI
      • No fish intake: 26.2±3.5kg/m2
      • Low fish intake: 26.3±3.8kg/m2
      • High fish intake: 26.4±3.6kg/m2
  • Location: Ommoord, Rotterdam, Netherlands.


Summary of Results:

 Key Findings

  • No relation of total fish intake with long-term risk of dementia and AD in either age and sex adjusted or multivariate adjusted models
    • Dementia: P for trend=0.7, adjusted for potential confounders
    • AD: P for trend= 0.9, adjusted for potential confounders
  • Increasing dietary intakes of long chain omega-3 PUFAs were not associated with long-term risk of dementia or AD, regardless of whether adjustments were made for age alone or multiple potential confounders
  • Compared with participants in the lowest tertile of long-chain omega-3 intake, those in the highest tertile had a similar risk of dementia (HR: 0.97, 95% CI: 0.77, 1.21) after adjustment for possible confounders
  • Higher fish and long chain omega-3 intakes were modestly related to lower dementia risk in year zero through eight but no association was found over years nine through 14 (See second table below)
  • No differences found in the association of fish intake and dementia risk by age category (P=0.7).
  Total Fish Intake
Total Fish Intake
Low, 8.2 grams per day
Total Fish Intake
High, 29.6 grams per day
P for Trend
Dementia cases (N, percent) 157 (9.8%)  159 (8.4%)  149 (7.8%)   
 Dementia model
1.0 (reference)  0.91 (0.73, 1.14)  0.93 (0.74, 1.17)  0.5 
 Dementia model two 1.0  0.94 (0.75, 1.17)  0.95 (0.76, 1.19)  0.7 
AD cases (percent) 1.17 (7.3%)  133 (7%)  115 (6%)   
 Model one 1.0 (reference)  1.05 (0.83, 1.34)  0.99 (0.77, 1.29)  1.0 
 Model two 1.0  1.07 (0.83, 1.37)  0.99 (0.76, 1.29)  0.9 

Model One: Adjusted for age and sex

Model Two: Adjusted for age, sex, education, total energy intake, alcohol intake, smoking habits, BMI, high total cholesterol, hypertension at baseline, prevalent stroke, prevalent MI, prevalent type two diabetes, dietary intake of vitamin E and supplement use (fish, omega-3 or antioxidant supplements) 


  Number of incident cases
Years 0 to 8 years/years 9 to 14
Incident AD: hazard ratio
(95% CI), years 0 to 8
Incident AD: hazard ratio
(95% CI), years 9-14
Total fish intake: none 60/57 1.0 (reference) 1.0 (reference) 
Total fish intake: low 64/69 1.02 (0.71, 1.45 1.13 (0.8, 1.61) 
Total fish intake: high 44/71 0.78 (0.53, 1.16) 1.20 (0.85, 1.72) 
Total fish intake: P for trend   0.2 0.3 
Long-chain omega-3: tertile 1 71/59 1.0 (reference) 1.0 (reference) 
Long-chain omega-3: tertile 2 56/69 0.87 (0.61, 1.23) 1.07 (0.78, 1.47) 
Long-chain omega 3: tertile 3 41/69 0.76 (0.51, 1.13) 1.16 (0.84, 1.6) 
Long-chain omega 3: P for trend   0.2 0.4 

Other Findings

  • Observation of significant differences in several covariates across these categories, few differences appeared to be qualitatively meaningful and our large sample size could explain their statistical significance
  • Participants with greater fish intake tended to consume more alcohol.


Author Conclusion:

In the study's cohort of Dutch older adults, no evidence was found to prove that higher intakes of fish and omega-3 PUFAs from food sources were associated with long-term risk of dementia over an average 10 years of follow-up. The hypothesis was evaluated in a study population with moderate fish and omega-3 PUFA intake, making the results especially important for inference in other populations with moderate intake of these dietary factors. Future research should evaluate long-term follow-up in other cohorts and explore these relations in populations with higher overall omega-3 intakes.

Funding Source:
Government: Netherlands Organization for Scientific Research, National Institutes of Health
Reviewer Comments:
  • Due to observational study design, unable to rule out possibility that confounding may explain null results
  • Baseline diet may not reflect longer-term diet over the ten year follow-up period.
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) Yes
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? Yes
  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? Yes
  2.2. Were criteria applied equally to all study groups? Yes
  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? Yes
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) Yes
  3.2. Were distribution of disease status, prognostic factors, and other factors (e.g., demographics) similar across study groups at baseline? Yes
  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? N/A
  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? No
  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.) No
  5.3. In cohort study or cross-sectional study, were measurements of outcomes and risk factors blinded? No
  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? Yes
  6.6. Were extra or unplanned treatments described? Yes
  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? No
9. Are conclusions supported by results with biases and limitations taken into consideration? N/A
  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