This population-based cross-sectional study found a negative relationship between CDAI and risk of cognitive impairment among 2523 American elderly. Additionally, we identified a non-linear relationship between CDAI and cognitive impairment, particularly in AFT and global cognition assessments. Additionally, these negative associations were consistent among most stratified groups, providing evidence for the role of dietary antioxidants in cognitive impairment.
The previous research on the association between dietary or supplement intake of antioxidants, and cognitive decline or dementia has been inconsistent [11, 20, 28]. Our findings align with a prospective cohort study conducted among Chinese individuals in Singapore. [10]This study revealed a 16% reduction in the risk of cognitive impairment in the highest quartile of the CDAI group, where the mini-mental state examination was utilized to assess cognitive impairment. Moreover, within the component nutrients, the dietary intake of vitamin C, vitamin E, carotenoids, and flavonoids is inversely correlated with cognitive impairment. [25]Another study based on the NHANES database calculated the TAC of eight antioxidant vitamins from dietary intake, suggesting the higher dietary antioxidant potential was associated with a reduced risk of cognitive impairment. Additionally, this study observed a subtle non-linear relationship in the dose-response analysis between TAC and impaired cognition. [20]Another study from the Chicago Health and Aging Project (CHAP), conducted over an average follow-up of 3.2 years, revealed a negative association between cognitive decline and both dietary and supplemental vitamin E intake. However, there was limited evidence of such an association with vitamin C or carotenoids. Our study also found no association between the risk of cognitive impairment and dietary intake of vitamin A or vitamin C based on DSST, CERAD, and global cognition.
However, some cohort studies and randomized control trials (RCT) have not identified a correlation between dietary antioxidant capacity and cognition or dementia [28, 29]. A cohort study involving 16,010 nurses' health reported that although higher antioxidant capacity (dietary and supplements) was associated with better cognitive performance during the initial interviews, a follow-up after 4 years revealed no relationship between dietary antioxidant scores and cognitive decline [28]. A sub-experiment of an RCT study [29] found that supplement intake of Vitamin E and beta-carotene was not associated with slower rates of cognitive change. However, Vitamin C was found to be more protective against cognitive change among women who experienced new cardiovascular events during the trial. Another RCT reported that supplements containing antioxidants with or without zinc and copper did not have a significant effect on cognitive performance [30]. While the results of many clinical trials are mixed, interestingly, even in RCTs where antioxidant supplements did not yield favorable outcomes, those containing a mix of antioxidants remained proportionally the most successful [31]. Indeed, what is most beneficial for the brain is not individual nutrients, but rather the dietary pattern and the optimal combination of various essential nutrients [8, 32].
CDAI is a commonly used and composite score for assessing the overall level of dietary antioxidants, supplementing the limitations of TAC, which is restricted to a single antioxidant active element in the body. Recently, two cross-sectional studies have found a positive correlation between CDAI and biological aging [33, 34]. Several studies have identified a protective role of CDAI in age-related degenerative diseases, such as cardiovascular diseases and osteoporosis[35, 36]. Oxidative stress has been widely acknowledged as a significant contributing factor to dementia, serving as a bridge connecting all mechanisms and pathways of dementia [37]. The imbalance in oxidative stress can lead to the accumulation of ROS, involvement in the amyloid cascade reaction, disruption of mitochondrial function, excessive phosphorylation of tau, formation of neurofibrillary tangles, activation, and release of neuroinflammatory cells, disruption of metal ion homeostasis, ultimately resulting in apoptosis of neurons, leading to cognitive dysfunction or further progression into dementia [38]. With aging, the efficiency of the endogenous antioxidant system within the body tends to decline, and the brain becomes more sensitive to oxidative stress [39]. Additionally, the regulation of oxidative stress in the body relies on exogenous antioxidant nutrients [40], including but not limited to vitamin E, vitamin C, carotenoids, and trace minerals (such as manganese, copper, selenium, and zinc) [41]. Research has indicated that antioxidant therapy can alleviate oxidative stress, reduce reactive oxygen species production, decrease the release of pro-inflammatory factors, mitigate inflammatory responses, and alleviate cellular damage [42].
There are some strengths of our study. It is the first study to find an L-shaped relationship between CDAI and cognitive impairment based on the NHANES dataset. Additionally, we considered several possible confounders in this study. Further, a non-linear relationship between CDAI and cognitive impairment was detected, suggesting a suitable range of CDAI for better cognitive performance. Our study provided additional evidence for the association between dietary antioxidants and cognitive impairment.
Still, our study has limitations. First, all participants were Americans aged ≥ 60 years and the findings may not be generalizable to younger or populations due to the role of the environment in cognitive impairment. Second, we defined cognitive impairment based on the DSST, AFT, and CERAD, instead of the golden standard (European Consortium Criteria) for screening dementia [43]. However, DSST, AFT and CERAD were able to evaluate the cognition from multiple domains (processing speed, sustained attention, working memory, executive function, and immediate and delayed memory), and we create a composite z-score to establish a global cognition to prevent the floor and ceiling effects and other sources of measurement error [20]. Third, the dietary information was obtained from the 24h recall which could result in recall bias. Fourth, we didn’t take into account the bioavailability and oxidative activity of antioxidant nutrients, such as vitamins A and E, which may underestimate the overall efficacy of CDAI. Fifth, some residual confounders may exist, such as antioxidant supplements, and medication interference. However, nutritional supplement surveys were not used because approximately 90% of the participants didn’t report the dietary supplement during the past 30 days. Finally, we could not make any causal inferences due to the cross-sectional study design. In the future, we need more longitudinal or RCT studies to confirm or refute our findings.