Concerning the remarks of Dr Renzi-Hammond and colleagues, our study was designed to evaluate the main effects of the individual nutrients, specifically omega-3 LCPUFAs. We agree that this was not a placebo-controlled study. We described the fact that the majority of participants were using some form of AREDS supplements that contained antioxidant vitamins C, E, and beta-carotene, which were tested in previous trials of cognition with no definitive beneficial effects.1 We were mainly interested in the relationship between omega-3 LCPUFAs and cognitive function and the study was powered for this primary hypothesis. We evaluated the other nutrients as secondary hypotheses. Because the study was powered for LCPUFAs does not mean it was insufficiently powered for other outcomes. Our study of 3000 participants is one of the largest populations assessed for cognition, far exceeding previous studies of lutein/zeaxanthin. Renzi-Hammond and colleagues also questioned the use of a composite score as an outcome for the measurement of cognitive decline because of the potential loss of domain specificity. It is common practice in large-scale studies of cognition to present an overall score for cognition, particularly when there is no a priori hypothesis about specific functions. In fact, we presented both the composite score and the results of each individual test conducted for each nutrient evaluated. Each specific domain tested showed no effect of the oral supplements. Dr Yurko-Mauro and colleagues directed our attention to a recent systematic review of observational epidemiological studies and a meta-analysis of clinical trials of omega-3 LCPUFAs.2 In the systematic review, some studies demonstrated an association of higher dietary intake of fish with reduced cognitive impairment. The meta-analysis of 15 trials was driven by only 2 studies that demonstrated beneficial effects. One study of 36 participants with mild cognitive impairment showed that omega-3 LCPUFAs improved memory over 1 year.3 The second study of 480 participants with mild cognitive impairment supplemented with 900 mg of omega-3 LCPUFAs for 24 weeks demonstrated some benefits on verbal recognition but not on other domains.4 By contrast, the AREDS2 population was at low risk for cognitive impairment and received a lower dose of omega-3 LCPUFAs, accounting for the differences between AREDS2 and these studies. We respectfully disagree with Yurko-Mauro and colleagues that the analyses of the low TICS-M scores (
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