DFA: EPA/DHA and Cognitive Health (2011)


 Huang TL, Zandi PP, et al. Benefits of fatty fish on dementia risk are stronger for those without APOE e4. Neurology 2005; 65: 1,409-1,414.

PubMed ID: 16275829
Study Design:
Case Control Study
C - Click here for explanation of classification scheme.
Quality Rating:
Positive POSITIVE: See Quality Criteria Checklist below.
Research Purpose:

To compare associations of lean fish vs. fatty fish (tuna or other fish) intake with dementia, Alzheimer disease (AD), and vascular dementia (VaD) and in relation to APOE epsilon4 status in the Cardiovascular Health Cognition Study (CHCS).

Inclusion Criteria:
  • Elderly people in Cardiovascular Health Cognition Study (CHCS)
  • All participants signed a informed consent at entry and at specified intervals during the study
  • Subjects who ate fish and participated in the Mini-Mental State Examination and brain MRI.
Exclusion Criteria:
  • Subjects with prevalent dementia at baseline or with MCI were eliminated
  • Subjects who lacked sufficient information to derive energy intake, had extreme energy intake values (<600 and >4,000kcal), were missing fish intake data, or responses from more than 12 food items on the Food Frequency Questionnaire (FFQ) were also eliminated
  • Subjects who failed tests of memory or more than one other cognitive domain (premorbid intelligence, language, visuoperceptual/visuoconstructional, executive function or motor).
Description of Study Protocol:


  • In 1998, the CHS Cognition Study (CHCS) was launched to assess the 3,602 subjects who had brain MRI in 1992 to 1994 and concurrently completed the Modified Mini-Mental State Examination (3MSE) 
  • The CHCS includes 227 subjects with prevalent dementia, 577 with mild cognitive impairment (MCI), 245 with incident pure AD, 62 with VaD, and 151 subjects with mixed AD and VaD.


  • Study design: Observational study
  • Fish intake was assessed by food frequency questionnaires. Incident dementia, AD, and VaD were determined through a series of cognitive tests, physician’s assessment and committee consensus.

Blinding used

Not applicable


Not applicable

Statistical Analysis

  •  Analysis of variance, trend tests, and X2 tests used to compare baseline characteristics of subjects who consumed different amounts of fish
  • Cox proportional hazards regression was used to compare risk ratios of three levels of fried fish intake across the years of follow-up:
    • A model including age at baseline, minority status, gender, presence of APOE ε4, energy intake, baseline BMI and region
    • A model to illustrate the attenuation of the hazard ratios (HRs) by education and income. Fried fish and tuna or other fish were analyzed separately and then together in the same models. Because the interaction between fish and APOE ε4 had P<0.10, we subsequently stratified by presence of APOE ε4.
  • All analyses were performed using Stata 8.0 (Statacorp, College Station, TX).

Data Collection Summary:

Timing of Measurements

The length of follow-up from time of MRI to onset of AD, dementia or death ranged between 0.1 and 8.4 years and averaged 5.4 years.

Dependent Variables

  • Incident dementia
  • AD
  • VaD; APOE ε4.

Independent Variables

  • Fish Intake
  • Age at baseline
  • Education
  • Race
  • Gender
  • Body mass index (BMI)
  • Most recent income.

Control Variables

  • Hazard ratios of dementia
  • AD
  • VaD with lean fried fish
  • Fatty fish
  • Total fish intake.
Description of Actual Data Sample:
  • Initial N: 5,201 participants
  • Attrition (final N):
    • 227 subjects with prevalent dementia
    • 577 with mild cognitive impairment (MCI)
    • 245 with incident pure AD
    • 62 with VaD
    • 151 subjects with mixed AD and VaD
  • Age: 65 years and older
  • Ethnicity: US population
  • Other relevant demographics:
    • Age at baseline
    • Education
    • Race
    • Gender
    • Most recent income
  • Anthropometrics: BMI
  • Location: Four US communities:
    • Forsyth County, NC
    • Washington County, MD
    • Sacramento, CA
    • Pittsburgh, PA.


Summary of Results:

 Key Findings

  • During the follow-up period, 378 (16.9%) of the 2,233 subjects developed dementia, with 190 (8.5%) developing AD, and 50 (2.4%) developing pure VaD
  • This group reported a mean consumption of 0.65 servings of fried fish and 2.3 servings of tuna or other fish per week
  • Subjects who were more educated or had higher incomes consumed more fatty fish and less lean fish (using trend tests, each analysis was significant at P<0.001) relative to those with less education or of lower socioeconomic status
  • Subjects who ate more fish, regardless of the type, also had higher overall energy intake (trend test, P<0.001).
  • There was a trend toward higher consumption of fried fish with greater BMI (P<0.001), and the association between higher fatty fish intake and greater BMI approached significance (P<0.07). Men consumed more fried fish than women, and women consumed more fatty fish than men (P<0.001 for each).
  • Consumption patterns of both types of fish also varied by study region, with subjects from California consuming the least lean fish and subjects in Pittsburgh consuming the most fatty fish. Minorities also tended to eat more fried fish than whites.
  • Modeling fried fish consumption and tuna or other fish consumption separately or in the same models did not have a substantial impact on the HRs
  • There was no significant difference in risk of dementia or AD with greater servings per week of fried fish either before or after controlling for fatty fish, age at baseline, minority status, gender, presence of APOE ε4, energy, BMI, region, education or income
  • Univariate models showed that eating tuna or other non-fried fish once per month to two times per week, compared to very low or no consumption, was associated with a non-significant 25% lower rate of dementia (95% CI: 0.55 to 1.03) and a 31% non-significant lower rate for AD (95% CI: 0.45 to 1.06), and consumption of these fish four times per week or more was significantly associated with protection against incident dementia (HR 0.63, 95% CI: 0.44 to 0.90) and AD (HR 0.56, 95% CI: 0.34 to 0.91) (see tables E-1 and E-2)
  • These associations were not significantly affected by further controlling for intake of fried fish, age at baseline, minority status, sex, presence of APOE ε4, energy, BMI and region
  • Total fish intake tended to have lower HRs with dementia and AD, but these were not significant. In the full model, consumption of more than one serving per month to two servings per week of total fish showed HRs of 0.87 (95% CI: 0.62 to 1.23) for dementia and 0.78 (95% CI: 0.48 to 1.28) for AD With univariate analysis, consuming 0.25 to two servings of fried fish increased the risk of pure VaD (HR 2.6, 95% CI: 1.39 to 4.96), but the risk associated with eating two to four servings of fried fish per week was not significant (HR 1.68, 95% CI: 0.74 to 3.84).
  • The HRs associated with consumption of fatty fish for VaD were similar to those of dementia but were not significant
  • The presence of the APOE ε4 allele and intake of either fried fish, fatty fish, or total fish on the outcome of dementia and found borderline significance with fatty fish (0.25 to two servings per week, P<0.08; two to four servings per week, P<0.28; more than four servings per week, P<0.09 relative to less than once per month)
  • Fatty fish appeared to have little or no association for individuals with APOE ε4 (HR for two to four servings per week 0.91, 95% CI: 0.48 to 1.71), but was associated with significantly
  • Lower hazard ratios for those without the allele (HR for two to four servings per week 0.60, 95% CI: 0.40 to 0.89)
  • After controlling for age at baseline, minority status, sex, energy, BMI and region, the association remained significant for APOE ε4–negative individuals. A significant reduction in hazards was associated with fatty fish for those without, but not with, APOE ε4.
  • Controlling for the same variables mentioned above had very little effect on HRs or significance. Dementia was significantly lost after adding income and education to the models.
Author Conclusion:
  • In the Cardiovascular Health Cognition Study, fatty fish appeared to be associated with a greater reduction in dementia and AD than leaner fish, support the hypothesis that DHA is the primary protective nutrient in fish
  • This study is also unique in that it presents findings stratified by APOE ε4, suggesting that the presence of the ε4 allele may modify the relationship of fatty fish to dementia and AD
  • Several studies have now found that fish and DHA are associated with a lower incidence of dementia, and there are multiple neurobiologic pathways by which DHA could be protective, suggesting that clinical trials are warranted to confirm the potentially protective effects of fish and omega-3 fatty acid intake, particularly among individuals at risk of AD.
Funding Source:
Government: NIH grant T32-MH14592 and NIH/NIDDK grant T32 DK75610,National Heart, Lung, and Blood Institute, and grant AG15928 from the National Institute on Aging; USDA Agricultural Research Service under contract no. 53-3K06-5-10
Charles A. King Trust, Bank of America
Reviewer Comments:
  • The study is based on a large population. Study results are reliable for application.
  • However, further controlled RCTs are required to study the effect of EPA/DHA and EPA, DHA and AA on the neurological sensitive markers
  • Some of the biological markers related to dementia, AD, VaD are also required to correlate with scales and APOE ε4 status.
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? 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? Yes
3. Were study groups comparable? N/A
  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? N/A
  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.) Yes
  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? N/A
  4.1. Were follow-up methods described and the same for all groups? N/A
  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%.) N/A
  4.3. Were all enrolled subjects/patients (in the original sample) accounted for? N/A
  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? N/A
  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? N/A
  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? N/A
  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? N/A
  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? N/A
  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? N/A
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? N/A
  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