This large, randomized controlled trial examined the effect of treatment with antioxidants or zinc and copper on cognitive function in nondemented elderly adults. Compared with placebo treatment, antioxidants with or without zinc and copper did not have a significant effect on cognitive performance at the end of the trial. There also were no significant differences in the likelihood of having cognitive impairment, as assessed by the 3MS, across all treatment groups.
Our results stand in contrast to those from several observational studies that have reported a beneficial effect of either antioxidant supplements or dietary intake on cognitive function or risk of dementia in the elderly population.1,4,5
However, other observational studies have not observed a protective effect of antioxidant supplement use and cognitive outcomes in elderly persons.6,7
A randomized controlled trial of vitamin E for the management of AD demonstrated a reduced risk of dementia severity, death, or being placed in a nursing home in the group assigned to 2,000 IU of vitamin E daily. However, there was no improvement on cognitive test scores in the treated group.8
Our results are consistent with that trial in that we also did not find a benefit of antioxidants on cognitive scores. However, we did not find any association with antioxidant treatment and likelihood of having cognitive impairment. This may be because of differences in antioxidant doses (e.g., 400 IU of vitamin E compared with 2,000 IU) or because of our patient population being nondemented and having more intact cognitive abilities.
Other studies have reported that high levels of zinc9
induce β-amyloid to form clumps resembling the amyloid plaques seen in AD and that patients with AD have higher serum levels of copper compared with control subjects.10
Our finding of no harmful effect on cognitive function of high-dose zinc supplementation along with 2 mg of copper in the AREDS population is reassuring, especially because many patients with AMD are now treated with this combination.
Cognitive function was not the primary outcome of our study, and this has led to a number of study limitations. The cognitive testing occurred at the end of the trial; therefore, we can only assess the cross-sectional comparison of treatment groups, and thus we cannot determine whether antioxidant or copper and zinc treatment influences the rate of cognitive decline. Randomization to the various treatment groups, which resulted in equivalence of the treatment groups in a large number of baseline characteristics, is likely, but not definitely, to lead to equal variation of cognitive function in each treatment group. Another limitation is that not all participants in the trial had cognitive testing, although participation in the cognitive ancillary study did not differ by treatment group and so probably does not interfere with our assessment of treatment effects. We also cannot be certain that our results pertain to older adults without eye disease, although there is no biologic explanation why these groups would respond differently to treatment.