Discussion
This study documents that brain NP high in carotenoids was consistently associated with better performance on multiple cognitive domains, activities of daily living, and lower depression among non-demented older adults in the GCS. Results also confirm previously established positive relationships between serum and brain concentrations of carotenoids in this group of subjects independent of their cognitive status (27). Given that serum concentrations of carotenoids likely reflect their habitual intake in the oldest old as previously discussed (27), our findings in the present study underscore the timing of intervention with diet high in carotenoid content before the onset of age-related dementia. This is further supported by the fact that nutrient concentrations and NP scores were not different between demented and non-demented subjects. Our exploratory findings also corroborate previous findings where serum levels of carotenoids are positively associated with better cognition in aging subjects (26, 32, 57–60). Specifically, higher serum lutein concentration was reported to be associated with better performance on language (32), which is similar to the correlation between NP2 and language score in this study.
The present analysis investigated concentrations of nutrients in the brain, the organ most relevant to cognition, as compared to previous studies that have established dietary or serum NPs with similar exploratory approaches (10, 11, 13, 15). Although the relationship between better adherence to a priori hypothesized intake patterns (such as MeDi, HDI, HEI, DASH, MIND) and lower risk of cognitive decline have been established (2), a priori hypothesized NPs are difficult with brain concentrations since little is known regarding nutrient uptake across the BBB and nutrient metabolism in neural tissue. For instance, SFAs and MUFAs can be de novo synthesized in the liver and CNS and may not reflect intake levels (61), and among n-3 PUFAs, DHA preferentially accumulates in neural tissue (62, 63). While substitution of SFA and trans-FA intakes with MUFAs and PUFAs decreases risk of age-related cognitive impairment in many prospective cohorts (64), our findings with brain content cannot be directly compared with intake levels of SFAs and MUFAs. It has also been reported that higher SFA content in membranes is usually associated with higher PUFA content to maintain membrane stability (65, 66), which likely explains the high correlation between SFA and unsaturated FA observed in the GCS brain tissues. Similarly, retinol is thought to be either taken up into the brain by STRA6, a retinol-binding protein-receptor detected at the BBB or derived directly from the cleavage of provitamin A carotenoids (β-carotene and β-cryptoxanthin) by the enzyme BCO1 detected in human brain (67, 68). It remains unknown how much each source contributes to vitamin A content in the brain. Moreover, a previous report on vitamin K metabolism in rat cerebellum also suggests that neural MK-4 content is regulated by the enzyme UBIAD1 (69). Overall, findings of nutrient levels in neural tissue need to be cautiously interpreted for dietary recommendations, especially for nutrients that can be derived from other substrates and nutrients whose levels are tightly regulated in the brain. Data on dietary intake in the GCS have been previously reported (70). However, the dietary assessment was subjective and might have overestimated or underestimated food intake, particularly in this population with varying degrees of cognitive performance. As a result, dietary intake data were not incorporated into the present analysis.
Age-related cognitive impairment, notwithstanding mixed clinical pathologies, shares molecular signatures of increased oxidative stress and neuroinflammation (71, 72). Both carotenoids and n-3 PUFAs, especially lutein and DHA both of which are selectively accumulated in the brain, have been proposed to interfere with the progression of cognitive impairment in aging, presumably owing to their antioxidative and anti-inflammatory properties (73, 74). Consistent with previous studies investigating neural concentrations of individual nutrients, a significant relationship was observed with lower carotenoids (mainly lutein and zeaxanthin) among cognitively impaired or demented subjects (26, 75–78). However, as previously discussed by Zamroziewicz and Barbey (22), univariate analytical approach with individual nutrients may be confounded by the effect of NPs and does not address the potentially interactive effects of multiple nutrients on cognitive health. An exploratory trial demonstrates that a combination of lutein and DHA supplements statistically improved performance on memory and learning in cognitively unimpaired elder women after 4 months whereas lutein or DHA supplement alone did not (79). Moreover, most individuals predominantly acquire nutrients from dietary sources that consist of a complex combination of nutrients. While a 6-month intervention with a lutein and zeaxanthin supplement failed to improve cognitive outcomes in subjects with or without Alzheimer's disease (80), a daily intervention with an avocado (a highly bioavailable source of 0.5 mg lutein and zeaxanthin, along with being a good source of potassium, B vitamins, vitamins C, E, K, MUFAs, and other non-essential phytochemicals) for 6 months has shown to improve cognitive performance on the Spatial Working Memory and the Stockings of Cambridge in non-demented subjects with low baseline intake of lutein-rich foods (81, 82). In the present analysis, a multivariate analysis approach (PCA) has been adopted to address correlations among nutrients and inspect the nutrition variable as NPs which reflect how multiple nutrients may synergistically function in the context of cognitive functioning and age-related cognitive impairment. This is an important step in the field of nutritional cognitive neuroscience toward the application of emerging technologies (such as metabolomics and brain magnetic resonance imaging) to systematically identify underlying mechanisms that mediate the effect that a combination of nutrients have on clinical outcomes (22, 32).
We acknowledge that this exploratory study is limited by a relatively small sample size (which is reflected by borderline significant p-values in Supplementary Table 4B) of mostly Caucasian women, and the inability to control for other covariates that may affect cognitive function such as alcohol and smoking history, physical activity, social interactions, and genetics (83). However, nutrient profiles and concentrations in this current analysis are similar to those of other cohorts of older adults (29–31, 84–88). NP1, described mostly by high fat content, was not associated with cognition in this population. Previous studies have reported benefits of diets high in n-3 PUFAs, especially DHA, on cognitive health (33, 89). While it is more appropriate to use absolute concentrations of FAs in the PCA, relative concentrations of FAs (i.e., FA composition) may be more relevant to the biological function of the brain. Additionally, it is unclear if the FA compositions in the brain of this cohort of the oldest old were in the normal range, since altered fatty acid compositions among cognitively impaired or demented subjects were reported (29–31), but no difference were observed between those with and without dementia in this study.
Other nutrients and dietary compounds such as B vitamins, vitamin D, minerals, and polyphenols that may be beneficial to cognitive health were also not examined in this study (90), but propose the opportunity to expand the scope of investigation. Nutrients that are not present in the brain but sharing common dietary sources with carotenoids and n-3 PUFAs, such as fibers in fruits, vegetables, nuts and seeds, may provide additional benefits to the central nervous system by functioning systemically through the regulation of reverse cholesterol transport, gut microbiota, and gut-brain axis signaling (91, 92). Finally, a cross-sectional study does not address a causal and longitudinal relationship between nutrition and cognition. A reverse causation where cognitive impairment leads to changes in nutrient uptake and metabolism—for example through BBB breakdown—is possible (23). However, dietary intervention in human trials and animal studies have indicated a significant impact that nutrition has on cognitive health in aging (93–95).
In summary, this report is the first to adopt a multivariate analysis approach to address the co-existence of nutrients and dietary compounds in the brain when investigating the relationship between nutrition and cognitive function in an aging population. Our findings support beneficial effects of a NP higher in carotenoids potentially derived from a diet rich in fruits and vegetables similar to the MeDi and DASH diets, on lowering the risk of age-related cognitive impairment and dementia previously reported (2, 93, 94). As compared to symptoms of nutritional deficiency which could be caused by an inadequate intake of one single nutrient and manifest within a short period of time, we are aware of the need to assess diet as a dietary pattern or NP in a context of complex outcomes such as age-related cognitive impairment (20–22). The synergistic and cumulative effect of nutrients on a person's risk of chronic diseases have recently been highlighted in the Dietary Guidelines for Americans 2015–2020 and 2020–2025 (96, 97).