By David Kiefer, MD

Clinical Assistant Professor, Department of Family Medicine, University of Wisconsin; Clinical Assistant Professor of Medicine, Arizona Center for Integrative Medicine, University of Arizona, Tucson

Dr. Kiefer reports he is a consultant for WebMD.

SYNOPSIS: A sub-analysis of the AREDS2 randomized, controlled trial that involved supplemental omega-3 fatty acids failed to find benefit on cognitive function over 5 years.

SOURCE: Chew EY, et al. Effect of omega-3 fatty acids, lutein/zeaxanthin, or other nutrient supplementation on cognitive function: The AREDS2 randomized clinical trial. JAMA 2015;314:791-801.

Summary Points

  • This was a sub-analysis of the AREDS2 research trial, a cohort of 3501 people out of the total 4203 AREDS2 participants.
  • A total of 2461 people underwent composite cognition statistical analyses to determine the primary outcome variable, the effect of n-3 supplementation on cognition.
  • The authors found that 1 g of supplemental EPA + DHA added to a vitamin supplement for age-related macular degeneration did not prevent cognitive decline.

There is no paucity of the need for interventions to stave off, or treat, cognitive decline as people age. Recent statistics put the worldwide prevalence of dementia at 35.6 million people in 2010, with steep projected increases.1,2 The authors of this study lead with the sobering fact that the prevalence of dementia in the United States in 2013 was 5.2 million, and it is expected to quadruple in the next 40 years. Pharmaceuticals have a role and efficacy for some, but not all, people. It would seem that omega-3 fatty acid (n-3) supplementation would be a useful intervention, due to some encouraging epidemiological data, a biochemical connection in which docosahexaenoic acid (DHA) is a known constituent of neural tissue, and the fact that low DHA levels have been found in people with Alzheimer’s disease. However, this study’s authors point out that randomized, controlled trials examining n-3 supplementation have had mixed results for treatment effectiveness. Hence, the current trial, an offshoot of a well-designed clinical trial, was undertaken to shed light on this topic.

The Age-Related Eye Disease Study 2 (AREDS2) ( is a randomized, controlled trial involving 4203 people that was designed to study the effect of n-3 and/or lutein/zeaxanthin in treating age-related macular degeneration (AMD). The study collected data on cognition at baseline and every 2 years, for a mean follow-up of 5 years, so it was thought to be an excellent opportunity to study n-3 supplementation.

People were included in this study if they were at risk of progressing to late AMD, namely, if they had a bilateral large drusen, or one large drusen and AMD in the other eye. After enrollment, people were randomized in a double-masked, placebo-controlled, 2 × 2 factorial design in the following fashion (see Table 1): All study participants were offered some version of the original AREDS formula, either original AREDS (vitamin C, 500 mg; vitamin E, 400 IU; beta carotene, 15 mg; zinc oxide, 80 mg; and cupric oxide, 2 mg); original AREDS formulation minus beta carotene; original AREDS formulation with low zinc (25 mg); or original AREDS formulation minus beta carotene and low zinc. The randomization involved n-3 (DHA 350 mg, and eicosapentaenoic acid [EPA] 650 mg) and/or lutein 10 mg plus zeaxanthin 2 mg.

Table 1: Study Randomization

All patients


AREDS minus beta carotene

AREDS with low zinc
(25 mg zinc oxide)

AREDS minus beta carotene and with low zinc (25 mg zinc oxide)

Then, further randomization




n-3 plus lutein/zeaxanthin

1832 people (no n-3)

1909 people (with n-3)

1235 people included in the composite cognition analysis

1226 people included in the composite cognition analysis

* AREDS formula = vitamins C, 500 mg; vitamin E, 400 IU; beta carotene, 15 mg; zinc oxide, 80 mg; and cupric oxide, 2 mg

Cognitive function testing consisted of a 30-minute phone survey, thought to correlate well with in-clinic assessments, and used the same cognitive testing as in AREDS, including an abbreviated conglomeration of the Hearing Handicap Inventory, the CES-D (Center for Epidemiologic Studies’ Depression Scale), and the TICS (Telephone Interview of Cognitive Status). An additional seven cognitive tests were used, totaling 10, but only eight were used in scoring the overall cognition; it is unclear why the authors excluded two of the tests from the scoring metric. The z scores (a statistical analysis) of each of the eight included tests were combined to make a composite cognition score. The primary outcome was then the yearly change in this composite cognition score; a higher positive score indicated a better result, whereas a higher negative score indicated a worsening of cognition with time. This score ranged from -17 to 22. The authors stated that the study was only significantly powered to analyze n-3 vs no n-3; an assessment of the effect of other nutrients (lutein, zeaxanthin, zinc, beta-carotene) was not statistically possible.

The results were based on original participants who had baseline cognition data, adequate follow-up testing, complete tests, and complete demographic information. The mean age of the participants in the cognition arm of AREDS2 was 72.7 years, and 57.5% were women; the total participants who underwent cognitive testing was 3501, out of the 4203 total AREDS2 participants. Even less of the original cohort had sufficient data and follow-up to allow composite cognition z score calculation; the information from a total of 2461 people underwent such analyses. The baseline composite z score between no n-3 and n-3 groups was 0.4 and 0.3, respectively, with a difference of -0.19 (-0.73 to -0.36; P = 0.38), essentially identical. People with higher baseline composite cognition z scores were more likely to be women, white, younger, have a higher income, and were less likely to have hypertension, coronary artery disease, congestive heart failure, myocardial infarction, and stroke. Interestingly, statin use was correlated with a lower baseline composite cognitive z score (-0.1 vs 0.7 for no statin use, P < 0.001).

Over the course of the AREDS2 study, cognition declined in all study groups, which was computed as a composite cognition z score change per year during the study period. Addressing the primary treatment outcome (n-3 effect), the yearly composite cognition z score change was -0.19 (-0.25 to -0.13) and -0.18 (-0.24 to -0.12) in the n-3 and non-n-3 groups, respectively, with an inter-group P value of 0.63 (no significant difference). As predicted, due to the under-powered nature of the secondary variables, no statistically significant differences were noted between the groups lutein/zeaxanthin vs lutein/zeaxanthin, high zinc vs low zinc, and beta-carotene vs no beta-carotene.


It has been difficult to stay abreast of the latest research on n-3s, partly due to the immense quantity of publications on the topic, but also because of the see-sawing of results. The effect of n-3 on cognition exemplifies just that. On one hand are favorable animal studies and mechanistic data,3 as well as positive clinical trials,4 but this is then balanced (cancelled out) by the pooling of data into meta-analyses and systematic reviews, which are more lukewarm or cold as to the cause-effect in adults.5,6

Does this article help healthcare providers or the general public come to a conclusion about this topic? Possibly. On the one hand, this study has a lot of moving parts and is difficult to interpret. For example, not only is the initial cohort split into four different doses of the original AREDS formula, but then there are four randomly determined groups, two of which are combined to provide the n-3 effect data. The statistical analyses seem adequate, the factorial design organized, but nonetheless it is a dizzying collection of variables. On the more positive side, this is a longitudinal study (5 years), the likes of which are rare to be seen in these days of dwindling research dollars. There is significant attrition, not necessarily perfectly accounted for, but the number of study participants is impressive and lends some credibility to the outcome data provided.

Two more issues relevant to settling the omega-3 cognition issue once and for all deserve mention. The AREDS and AREDS2 cohorts are people with intermediate or late age-related macular degeneration, which may or may not resemble the typical healthcare provider’s patient panel. In addition, the sub-cohort analyzed here was predominantly white (+97%) and college to post-college educated, again not reflective of the United States as a whole. There may be few, if any, patients who fit the profile studied in this trial; generalizability is clearly an issue. Furthermore, the n-3 dose deserves tight scrutiny. DHA is the n-3 fraction thought to have the most relevancy to brain physiology, yet was only being supplemented at 350 mg daily. And the total n-3 dose, 1000 mg, is in the realm of the American Heart Association recommendation for secondary prevention of coronary artery disease, but well below the 2-4 g daily of DHA+EPA necessary to treat conditions such as arthritis and hypertriglyceridemia. Was this study underdosed? Possibly, but the ideal n-3 dose is hidden in a wide range of doses used in individual randomized, controlled trials, that melts away with the pooling of data in meta-analyses to which many of us turn for clinical guidance. To further add to this complexity, this study did not detail the study participants’ diets, a key component to know the extent to which the n-3 supplementation is actually supplementing.

All told, this study provides little significant clinical information relevant to the use of n-3. Most experts would agree that the dose discussed in this article is safe, carrying a slight “pocket book” adverse effect, but with no benefit for the cohort of people studied here. Let your negotiation with your patients about n-3 use for cognition preservation take precedence over any general clinical guideline until the flaws mentioned above are remedied in the next n-3 study and guide, in a better way, our clinical decision making.


  1. Coley N, et al. Nutrition and cognition in aging adults. Clin Geriatr Med 2015;31:453-464.
  2. Gill SS, Seitz DP. Lifestyles and cognitive health: What older individuals can do to optimize cognitive outcomes. JAMA 2015;314:774-775.
  3. Rathod RS, et al. Beneficial effects of omega-3 fatty acids and vitamin B12 supplementation on brain docosahexaenoic acid, brain-derived neurotrophic factor, and cognitive performance in the second-generation Wistar rats. Biofactors 2015;41:261-272.
  4. Strike SC, et al. A high omega-3 fatty acid multinutrient supplement benefits cognition and mobility in older women: A randomized, double-blind, placebo-controlled pilot study. J Gerontol A Biol Sci Med Sci 2015; Aug 11 [Epub ahead of print].
  5. Cooper RE, et al. Omega-3 polyunsaturated fatty acid supplementation and cognition: A systematic review and meta-analysis. J Psychopharmacol 2015;29:753-763.
  6. Jiao J. Effect of n-3 PUFA supplementation on cognitive function throughout the life span from infancy to old age: A systematic review and meta-analysis of randomized controlled trials. Am J Clin Nutr 2014;100:1422-1436. doi: 10.3945/ajcn.114.095315. Epub 2014 Oct 15.