Effect of Omega-3 Fatty Acids, Lutein/Zeaxanthin, or Other Nutrient Supplementation on Cognitive Function: The AREDS2 Randomized Clinical Trial

Abstract

Importance: Observational data have suggested that high dietary intake of saturated fat and low intake of vegetables may be associated with increased risk of Alzheimer disease.

Objective: To test the effects of oral supplementation with nutrients on cognitive function.

Design, setting, and participants: In a double-masked randomized clinical trial (the Age-Related Eye Disease Study 2 [AREDS2]), retinal specialists in 82 US academic and community medical centers enrolled and observed participants who were at risk for developing late age-related macular degeneration (AMD) from October 2006 to December 2012. In addition to annual eye examinations, several validated cognitive function tests were administered via telephone by trained personnel at baseline and every 2 years during the 5-year study.

Interventions: Long-chain polyunsaturated fatty acids (LCPUFAs) (1 g) and/or lutein (10 mg)/zeaxanthin (2 mg) vs placebo were tested in a factorial design. All participants were also given varying combinations of vitamins C, E, beta carotene, and zinc.

Main outcomes and measures: The main outcome was the yearly change in composite scores determined from a battery of cognitive function tests from baseline. The analyses, which were adjusted for baseline age, sex, race, history of hypertension, education, cognitive score, and depression score, evaluated the differences in the composite score between the treated vs untreated groups. The composite score provided an overall score for the battery, ranging from -22 to 17, with higher scores representing better function.

Results: A total of 89% (3741/4203) of AREDS2 participants consented to the ancillary cognitive function study and 93.6% (3501/3741) underwent cognitive function testing. The mean (SD) age of the participants was 72.7 (7.7) years and 57.5% were women. There were no statistically significant differences in change of scores for participants randomized to receive supplements vs those who were not. The yearly change in the composite cognitive function score was -0.19 (99% CI, -0.25 to -0.13) for participants randomized to receive LCPUFAs vs -0.18 (99% CI, -0.24 to -0.12) for those randomized to no LCPUFAs (difference in yearly change, -0.03 [99% CI, -0.20 to 0.13]; P = .63). Similarly, the yearly change in the composite cognitive function score was -0.18 (99% CI, -0.24 to -0.11) for participants randomized to receive lutein/zeaxanthin vs -0.19 (99% CI, -0.25 to -0.13) for those randomized to not receive lutein/zeaxanthin (difference in yearly change, 0.03 [99% CI, -0.14 to 0.19]; P = .66). Analyses were also conducted to assess for potential interactions between LCPUFAs and lutein/zeaxanthin and none were found to be significant.

Conclusions and relevance: Among older persons with AMD, oral supplementation with LCPUFAs or lutein/zeaxanthin had no statistically significant effect on cognitive function.

Trial registration: clinicaltrials.gov Identifier: NCT00345176.

Figure 1. CONSORT Figure

The CONSORT Figure Showing the AREDS2 participants Included in the Analyses of the the Ancillary Cognitive Function Study LCPUFAs: Long Chain Polyunsaturated Fatty Acids Reasons for declining consent for the Ancillary Cognitive Function Testing were not collected.

Figure 2

Results of the mixed models regression for the change per year in cognitive function test scores from baseline for each of the nutrients tested: A. Comparison of the main effects of omega-3 LCPUFAs vs. no omega-3 LCPUFAs. LCPUFAs: Long Chain Polyunsaturated Fatty Acids TICS: Telephone Interview of Cognitive Status Composite score. A composite score was constructed by including the score of the TICS and all the cognitive tests by converting all test results into z-scores and then averaging the z-scores. The composite score was computed to obtain an overall score for the battery of cognitive function tests, ranging from −22 to 17, with higher scores representing better function. Telephone Interview Cognitive Status-Modified (TICS-M) is a version of the Mini Mental State Examination. The score for TICS ranges from 0 to 39 points. See supplementary methods for explanation for the scores of the other cognitive function tests. Worse means a deterioration of the score for that given nutrient and better means an improved score for those randomized to omega3 fatty acids, DHA/EPA. These analyses are adjusted for the following baseline covariates: age, gender, race, education, smoking, hypertension, congestive heart failure, and depression scale. B: Comparison of the main effects of lutein/zeaxanthin vs. no lutein/zeaxanthin. Lut/Zea: Lutein/Zeaxanthin TICS: Telephone Interview of Cognitive Status Composite score. A composite score was constructed by including the score of the TICS and all the cognitive tests by converting all test results into z-scores and then averaging the z-scores. The composite score was computed to obtain an overall score for the battery of cognitive function tests, ranging from −22 to 17, with higher scores representing better function. Telephone Interview Cognitive Status-Modified (TICS-M) is a version of the Mini Mental State Examination. The score for TICS ranges from 0 to 39 points. See supplementary methods for explanation for the scores of the other cognitive function tests. Worse means a deterioration of the score for that given nutrient and better means an improved score for those randomized to lutein/zeaxanthin. These analyses are adjusted for the following baseline covariates: age, gender, race, education, smoking, hypertension, congestive heart failure, and depression scale. C: Comparison of the main effects of high zinc vs. low zinc. TICS: Telephone Interview of Cognitive Status Composite score. A composite score was constructed by including the score of the TICS and all the cognitive tests by converting all test results into z-scores and then averaging the z-scores. The composite score was computed to obtain an overall score for the battery of cognitive function tests, ranging from −22 to 17, with higher scores representing better function. Telephone Interview Cognitive Status-Modified (TICS-M) is a version of the Mini Mental State Examination. The score for TICS ranges from 0 to 39 points. See supplementary methods for explanation for the scores of the other cognitive function tests. Worse means a deterioration of the score for that given nutrient and better means an improved score for those randomized to zinc. These analyses are adjusted for the following baseline covariates: age, gender, race, education, smoking, hypertension, congestive heart failure, and depression scale. D: Comparison of the main effects of beta-carotene vs. no beta-carotene. TICS: Telephone Interview of Cognitive Status Composite score. A composite score was constructed by including the score of the TICS and all the cognitive tests by converting all test results into z-scores and then averaging the z-scores. The composite score was computed to obtain an overall score for the battery of cognitive function tests, ranging from −22 to 17, with higher scores representing better function. Telephone Interview Cognitive Status-Modified (TICS-M) is a version of the Mini Mental State Examination. The score for TICS ranges from 0 to 39 points. See supplementary methods for explanation for the scores of the other cognitive function tests. Worse means a deterioration of the score for that given nutrient and better means an improved score for those randomized to beta-carotene. These analyses are adjusted for the following baseline covariates: age, gender, race, education, smoking, hypertension, congestive heart failure, and depression scale.

Figure 2

Results of the mixed models regression for the change per year in cognitive function test scores from baseline for each of the nutrients tested: A. Comparison of the main effects of omega-3 LCPUFAs vs. no omega-3 LCPUFAs. LCPUFAs: Long Chain Polyunsaturated Fatty Acids TICS: Telephone Interview of Cognitive Status Composite score. A composite score was constructed by including the score of the TICS and all the cognitive tests by converting all test results into z-scores and then averaging the z-scores. The composite score was computed to obtain an overall score for the battery of cognitive function tests, ranging from −22 to 17, with higher scores representing better function. Telephone Interview Cognitive Status-Modified (TICS-M) is a version of the Mini Mental State Examination. The score for TICS ranges from 0 to 39 points. See supplementary methods for explanation for the scores of the other cognitive function tests. Worse means a deterioration of the score for that given nutrient and better means an improved score for those randomized to omega3 fatty acids, DHA/EPA. These analyses are adjusted for the following baseline covariates: age, gender, race, education, smoking, hypertension, congestive heart failure, and depression scale. B: Comparison of the main effects of lutein/zeaxanthin vs. no lutein/zeaxanthin. Lut/Zea: Lutein/Zeaxanthin TICS: Telephone Interview of Cognitive Status Composite score. A composite score was constructed by including the score of the TICS and all the cognitive tests by converting all test results into z-scores and then averaging the z-scores. The composite score was computed to obtain an overall score for the battery of cognitive function tests, ranging from −22 to 17, with higher scores representing better function. Telephone Interview Cognitive Status-Modified (TICS-M) is a version of the Mini Mental State Examination. The score for TICS ranges from 0 to 39 points. See supplementary methods for explanation for the scores of the other cognitive function tests. Worse means a deterioration of the score for that given nutrient and better means an improved score for those randomized to lutein/zeaxanthin. These analyses are adjusted for the following baseline covariates: age, gender, race, education, smoking, hypertension, congestive heart failure, and depression scale. C: Comparison of the main effects of high zinc vs. low zinc. TICS: Telephone Interview of Cognitive Status Composite score. A composite score was constructed by including the score of the TICS and all the cognitive tests by converting all test results into z-scores and then averaging the z-scores. The composite score was computed to obtain an overall score for the battery of cognitive function tests, ranging from −22 to 17, with higher scores representing better function. Telephone Interview Cognitive Status-Modified (TICS-M) is a version of the Mini Mental State Examination. The score for TICS ranges from 0 to 39 points. See supplementary methods for explanation for the scores of the other cognitive function tests. Worse means a deterioration of the score for that given nutrient and better means an improved score for those randomized to zinc. These analyses are adjusted for the following baseline covariates: age, gender, race, education, smoking, hypertension, congestive heart failure, and depression scale. D: Comparison of the main effects of beta-carotene vs. no beta-carotene. TICS: Telephone Interview of Cognitive Status Composite score. A composite score was constructed by including the score of the TICS and all the cognitive tests by converting all test results into z-scores and then averaging the z-scores. The composite score was computed to obtain an overall score for the battery of cognitive function tests, ranging from −22 to 17, with higher scores representing better function. Telephone Interview Cognitive Status-Modified (TICS-M) is a version of the Mini Mental State Examination. The score for TICS ranges from 0 to 39 points. See supplementary methods for explanation for the scores of the other cognitive function tests. Worse means a deterioration of the score for that given nutrient and better means an improved score for those randomized to beta-carotene. These analyses are adjusted for the following baseline covariates: age, gender, race, education, smoking, hypertension, congestive heart failure, and depression scale.

Figure 3. Results of the Odds of Having a Score of less than 30 for the Telephone Interview of Cognitive Status (TICS) for the Four Nutrients evaluated, using Repeated Measures Logistic Regression

LCPUFAs: Long Chain Polyunsaturated Fatty Acids Lut/Zea: Lutein/Zeaxanthin Telephone Interview Cognitive Status-Modified (TICS-M) is a version of the Mini Mental State Examination. The score for TICS ranges from 0 to 39 points. A dichotomous outcome from the TICS is defined as follows: 1) TICS total < 30 points defines low cognitive function and 2) TICS total ≥30 defines normal cognitive function. “Worse” means a deterioration of the TICS score (large proportion with low cognitive function) for that given nutrient and “better” means an improved TICS (smaller proportion with low cognitive function) for that given nutrient. Models were adjusted for: baseline age, sex, race, history of hypertension, education, baseline cognitive score and baseline depression score.