DFA: EPA/DHA and Cognitive Health (2011)


Schaefer EJ, Bongard V, Beiser AS, et al. Plasma phosphatidylcholine docosahexaenoic acid content and risk of dementia and Alzheimers disease. Arch Neurol. 63: 1,545-1,1550.

Study Design:
Prospective Cohort Study
B - Click here for explanation of classification scheme.
Quality Rating:
Neutral NEUTRAL: See Quality Criteria Checklist below.
Research Purpose:
  • To determine whether plasma phosphatidylcholine (PC) DHA content is related to the risk of dementia and Alzheimer Disease (AD)
  • To determine whether plasma PC DHA content is related to dietary DHA and fish intake.
Inclusion Criteria:
  • Subset of subjects from the Framingham Heart Study
  • 55-88 years of age
  • Alive and free of dementia at the 20th biennial examination (1986-1988)
  • Plasma fatty acid samples were available.
Exclusion Criteria:
Description of Study Protocol:


From existing subjects in the Framingham Heart Study meeting the inclusion criteria listed above.


Subjects free of dementia and between the ages of 55-88 years were selected at baseline (20th biennial examination period for the Framingham Heart Study). Of this population, those who underwent the 20th examination and had at least one year of follow-up data were selected for the dementia study (1,208 subjects). Of these 899 had plasma fatty acid samples and were included in the data analysis. Subjects were followed biennially and screened using the Mini-Mental State Examination (MMSE). Those scoring below education-based cut offs or declined at least three points from the most previous exam underwent neurological and neuropsychological examination. For each case of possible dementia a review by two or more neurologists was conducted to determine the type of dementia and date of dx. AD was diagnosed if specific nationally validated criteria were met.

A 126-item FFQ was used to assess dietary DHA and fish intakes at baseline (20th examination of the Framingham Heart Study). This was available for 488 subjects.

Blinding used 

Not applicable


Not applicable

Statistical Analysis

Cox proportional hazards regression analysis was used to assess the relationship of plasma PC DHA and incident dementia. Relative risk (RR) of all-cause dementia in subjects with baseline plasma PC DHA levels in the upper quartile compared with subjects who had levels in the lower three quartiles were estimated after adjusting for confounding factors. Similar analysis was conducted for RR of AD. Likewise, similar analysis was conducted for RR of all-cause dementia or AD associated with baseline dietary DHA and fish intakes.

Data Collection Summary:

Timing of Measurements 

Cognitive screening (MMS score) and plasma fatty acids were measured at baseline for all subjects.  Dietary DHA and fish intake were determined at baseline for a subset of the subjects. Subjects were followed forward on a biennial basis for cognitive screening and diagnosis of dementia or AD as appropriate. 

Dependent Variables

  • All-cause dementia
  • AD.

Independent Variables

  • Plasma PC DHA
  • Dietary intake of DHA and fish.

Control Variables

  • Age
  • Sex
  • ApoE e4
  • Plasma homocysteine concentration
  • Education level.
Description of Actual Data Sample:
  • Initial N: 1,208 subjects who completed the 20th biennial examination of the Framingham Heart Study
  • Attrition (final N): 899 (26% attrition) were included because they had plasma fatty acid data and at least one year of follow up data; 328 (36.5%) male
  • Age: 76±5 years
  • Ethnicity: Not given
  • Other relevant demographics: 68.2% high school graduates
  • Anthropometrics: Not Applicable
  • Location: Massachusetts.
Summary of Results:

 Key Findings

  • Longitudinal follow-up was up to 16 years with a mean of 9.1years
  • 99 subjects developed dementia (71 with AD) during follow-up
  • No difference in RR of all-cause dementia between subjects in quartile 1 and those in quartiles 2 and 3 based on plasma PC DHA levels; after adjusting for age and sex those in quartile 4 (highest amount of plasma PC DHA) had almost 1/2 of the RR as those in quartile 1. See table below. This difference was lost when adjusting for apoE e4, homocysteine concentration and education level.
  • The RR for all-cause dementia was 47% (0.53) less for those in the highest quartile of plasma PC DHA compared to all three lower quartiles after adjusting for all confounding variables
  • RR for AD ranged from 0.59-0.61 when the top quartile was compared with the lower three quartiles without significance
  • Analysis of dietary DHA and fish intake in the subset of 488 subjects and plasma levels of PC DHA indicated a significant (both P<0.001) association by quartile. Fish intake ranged from 1.3-3.0 servings per week.

Relative Risk of all-cause dementia and plasma PC DHA levels by quartile

Variable RR (95% CI)* P value RR (95% CI)* P value

Effect of 1 SD of log-transformed plasma PC DHA

0.04 0.80
Quartile 4


0.04 0.52


Quartile 4 compared with quartiles 1-3






 *Adjusted for age and sex

+ Adjusted for age, sex, apoE e4, homocysteine concentration and education level

Other Findings


Author Conclusion:

The top quartile of plasma PC DHA level was associated with a significant (47%) reduction in risk of developing all-cause dementia.

Funding Source:
Government: NIH, NHLBI
Martek Biosciences Corpt, Pfizer, France
Pharmaceutical/Dietary Supplement Company:
University/Hospital: Dept. of Agricultural Research Service at U. Conn.
Reviewer Comments:
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) N/A
  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? 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? No
3. Were study groups comparable? ???
  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? ???
  3.3. Were concurrent controls or comparisons used? (Concurrent preferred over historical control or comparison groups.) No
  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%.) No
  4.3. Were all enrolled subjects/patients (in the original sample) accounted for? Yes
  4.4. Were reasons for withdrawals similar across groups? ???
  4.5. If diagnostic test, was decision to perform reference test not dependent on results of test under study? Yes
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.) N/A
  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? ???
  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? ???
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