In this prospective study, we found no overall relation between plasma carotenoids or tocopherols or retinol levels measured when women were, on average, in their mid 60’s and cognitive function assessed 10 years later. Individual antioxidant vitamins were also not generally associated with cognitive function or decline.
We observed suggestive associations in secondary analyses that merit further investigation in future studies. First, we observed suggestions that those with higher plasma carotenoids performed better at cognitive tests in the stratum of women not taking any supplements at blood draw. It is possible that women who achieve high levels of carotenoids just from dietary sources are getting a larger variety of carotenoids that may act synergistically against brain oxidation. There is evidence that a mixture of carotenoids, as would be found in dietary sources, are more effective than individual carotenoids; such a synergistic antioxidant effect appears to be particularly strong for carotenoids mainly in diet, such as lutein and lycopene. [39
]. However, because of the borderline significant results and reduced power within strata, it is possible that our findings within women not taking supplements may be due to chance.
Second, we observed a suggestive interaction between α-tocopherol and γ-tocopherol; γ-tocopherol is mainly from the diet, and plasma and tissue γ-tocopherol levels are lowered with α-tocopherol supplementation.[25
] Consistent with this, we did observe a possible trend of higher γ-tocopherol levels associated with better cognition among those with lower than median α- tocopherol levels, 92% of whom were not taking vitamin E supplements. This is supportive of the hypothesis that different tocopherols interact in their metabolism and absorption and may thus exert independent effects on cognitive decline. [32
] Again, however, our results were borderline significant and should be interpreted with caution.
An important strength of this study is the prospective design and the long-term follow-up period between blood-draw and cognitive testing. Impairments in cognition develop over many years, thus earlier exposures may have particular significance. In addition, plasma measurements have some key advantages over diet surveys, as they are not subject to errors due to recall, and better capture bioavailable nutrient levels.[19
] Finally, we were able to adjust for a wide variety of potential confounding factors.
Limitations of our study should be considered. In this observational study, confounding may be an issue. However, we conducted numerous analyses to explore confounding; we adjusted for potential confounding factors at blood draw as well as at cognitive interview, and we stratified analyses by vitamin use or smoking status. Moreover, in this cohort of health professionals, with similar access to healthcare and health knowledge, many opportunities for confounding are inherently reduced. Nonetheless, it is not possible to rule out confounding in observational studies. On the other hand, the homogeneity of our study population who are all health professionals and mostly Caucasian, may limit the generalizeability of the results to other populations with different education levels and racial / ethnic backgrounds. In addition, the analyses were based on antioxidant levels from a single plasma measure, which may not represent long-term exposure, and may thus bias results toward the null. Data from similar cohorts[42
] suggest that the correlations between repeated measurements of plasma antioxidants over time were high: e.g., intraclass correlations between single carotenoid measurements and average concentrations over a 3-year period ranged from 0.63 to 0.85, demonstrating that single samples reasonably reflect longer-term vitamin status. Finally, our analyses of cognitive decline were limited to a maximum of four years over which we measured decline. Thus, there may not yet be sufficient cognitive decline to identify modest relations with risk factors as longer follow-up is generally needed to observe clinically significant decline in cognition.[27
] Although with approximately 10 years between blood draw and the initial cognitive assessment, our analyses of the initial cognitive interview likely reflect results from a long-term prospective study, nevertheless, we will re-examine this analysis with additional follow-up.
Few previous studies have examined antioxidants in plasma, and these have been mostly cross-sectional. In an Austrian study (n=1,769) in which 10 antioxidants were assayed, α-tocopherol was significantly associated with better performance on the Mattis Dementia Rating Scale (p=0.02), and α-carotene, β-carotene, β-cryptoxanthin and retinol all demonstrated non-significant inverse relations.[37
] The NHANES study found a significant association between low serum vitamin E and poor memory among 4,809 subjects, with no relation for several other antioxidants.[33
] In the Rotterdam Study[9
] where plasma carotenoids in 203 healthy older persons were measured and related to white matter lesions on MRI (which are associated with cognitive impairment), those with higher overall carotenoid levels had less severe periventricular white matter lesions. Thus, cross-sectional data are supportive of higher levels of plasma antioxidants, particularly tocopherols, being associated with better cognition, but it is likely in cross-sectional studies that poor cognition resulted in poor diet, rather than the reverse, thus results from cross-sectional studies are very difficult to interpret.
In the one prospective study of plasma antioxidants and cognitive decline over 7 years that we could find, the MacArthur Study of Successful Aging (n=455) reported that higher beta-carotene was related to less cognitive decline, but only among 23% of the population with APOE e4 allele.[18
] However, the subset of subjects with an e4 allele was very small and the interaction could have been due to chance. Nonetheless, we do not have available APOE genotypes for our subjects in this analysis, thus future research on a possible interaction is needed.
In conclusion, in this population of generally well-nourished and healthy aging women, plasma carotenoid and tocopherol levels measured when women in their sixties were not associated with their cognitive function or decline ten years later. Further research is needed of specific subgroups however, such as those with high antioxidant intakes solely from diet rather than supplements, and more investigation is needed of the inter-relations of γ and α-tocopherol.