Association between dietary vitamin E intake and cognitive decline among old American: National Health and Nutrition Examination Survey

This study aimed to investigate changes in vitamin E intake in older adults with low cognitive performance using NHANES. An increased dietary intake of vitamin E has been associated with decreased cognitive impairment in individuals over 60 years old. The dose–response curve showed an L-shaped association between dietary vitamin E intake and cognitive decline in US adults, with an inflection point of approximately 9.296 mg/day. These findings highlight the importance of including vitamin E-rich foods in the diet, particularly for older adults who may be at a higher risk of cognitive impairment. However, further research is needed to confirm these results and to better understand the mechanisms underlying the relationship between vitamin E and cognitive function. Numerous studies have reported that vitamin E plays a key role in nervous system development and neurotransmitter production. This study aimed to investigate changes in vitamin E intake in older adults with low cognitive performance using NHANES. In this cross-sectional study, we examined a sample of 2255 American adults aged 60 and over between 2011 and 2014. We collected dietary data by averaging two recalls for dietary use to determine vitamin E intake. We assessed cognitive function using five tests and analyzed the association between these variables using a multivariate logistic regression model. A total of 2255 participants aged ≥ 60 years from the National Health and Nutrition Examination Survey (NHANES) for the 2011–2014 cycle were included in the analysis. Vitamin E intake was negatively associated with cognitive function. In the Z test, with each 1 mg/day increase in dietary intake of vitamin E, there was a 6% decrease in the correlation with cognitive impairment (OR = 0.94, 95% CI 0.91–0.97) in the fully fitted model (OR = 0.94, 95% CI 0.91–0.97). These findings remained consistent when analyzing the exposure as a categorical variable. In comparison to Q1, Q4 showed a 53% reduction in the incidence of cognitive impairment in the Z test (OR = 0.47, 95% CI 0.33–0.67).No significant statistical interaction between the variables was found. An increased dietary intake of vitamin E has been associated with decreased cognitive impairment in individuals over 60 years old. The dose–response curve showed an L-shaped association between dietary vitamin E intake and cognitive decline in US adults, with an inflection point of approximately 9.296 mg/day.


Introduction
In recent decades, there has been a significant increase in the aging population globally, primarily due to socioeconomic development [1].As the population ages, age-related issues, such as cognitive decline and Alzheimer's disease (AD), are becoming more prevalent and significant concerns in aging societies worldwide [2,3].Therefore, there is a growing need to investigate ways to maintain and enhance cognitive performance in older individuals to alleviate the burden on governments and health services [4].
Numerous approaches have been evaluated for improving cognitive functioning in the elderly, but there is no clear evidence of which method is most effective [5].One essential preventive measure for improving cognitive decline is through dietary interventions, as several dietary factors have been studied [6][7][8].
Vitamin E is a crucial trace element that is primarily obtained through food and dietary supplements.In humans, beta-tocopherol is the predominant form of vitamin E found in tissues and circulation [9].Vitamin E is involved in antiinflammatory activities, gene expression, cellular signaling, and cell proliferation, among other essential functions [10].Several studies have demonstrated that vitamin E deficiencies are associated with impaired motor coordination, cognitive function, ataxia, and lipid peroxidation [11,12].However, the recommended dose of vitamin E for dietary intake with low cognitive performance remains controversial, and an exact dose-effect relationship has not been established.Therefore, in this study, we aimed to investigate the relationship between vitamin E and subtypes of low cognitive performance in elderly individuals using data from the National Health and Nutrition Examination Survey.

Data sources and study population
A cross-sectional study design was employed using data from NHANES.This study uses data from NHANES 2011-2012 and NHANES 2013-2014.Subjects with incomplete cognitive information were excluded.Participants with incomplete vitamin E intake questionnaires were also excluded.A total of 2255 older people who were over 60 years old were included [13].NHANES conducts annual surveys of a nationally representative sample of the U.S. population using a complex, multilevel, multilevel cluster probability design [14].Sociodemographic data such as age, sex, household income, and education level were collected through health interviews, as well as health-related lifestyle variables such as alcohol consumption, smoking, and physical activity [15,16].All participants provided written informed consent prior to participation, and the study was approved by the NCHS Research Ethics Review Board (https:// wwwn.cdc.gov/ nchs/ nhanes/ defau lt.aspx) [17].This study followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guidelines [18].

Dietary vitamin E intake
The NHANES study utilized a 24-h food recall questionnaire, which was open to all study participants, to collect detailed information on all foods consumed in the past 24 h, including the type and amount of food.All NHANES participants were eligible to participate in two 24-h dietary recall interviews, and the collected data were used to determine the amount of vitamin E each participant consumed daily.The first dietary recall interview is collected in-person in the Mobile Examination Center (MEC) and the second interview is collected by telephone 3-10 days later [19].The average daily intake of vitamin E was calculated by averaging the 2 days of recall.In 2000, the dietary reference intake for vitamin E was established with an estimated average requirement (EAR) of 12 mg/day [20].Participants were grouped according to their intake of vitamin E based on the recommended daily intake.The NHANES is an ongoing cross-sectional survey series conducted by the National Center for Health Statistics (NCHS) of the Centers for Disease Control and Prevention.

Cognitive function
The NHANES study used several cognitive function tests to assess memory and executive abilities in participants.The Alzheimer's Disease Word Learning Registry Consortium immediate and delayed verbal list learning (IR and DR) test evaluates the ability to learn new linguistic information through three consecutive learning attempts and one delayed recall [21].The Animal Fluency Test (AFT) assesses verbal and executive abilities by asking participants to name as many animals as possible within 1 min, with each named animal earning 1 point [16].The Digit Symbol Substitution Test (DSST) is a timed test that measures processing speed and executive function by requiring participants to transcribe symbols that match digits using a legend [22].The study then constructed test-specific Z scores using sample means and standard deviations of test results to obtain an overall composite Z score for cognitive function.[16].

Covariates
In our analysis, we incorporated various potential confounding factors, including age, race, gender, poverty-income ratio, education, body mass index, heart failure, coronary disease, angina, stroke, hypertension, smoking, alcohol, and diabetes.The older age group was further divided into three subgroups (60-69, 70-79, and ≥ 80 years), while sex was divided into male and female groups [23].Race included Mexican Americans, other Hispanics, non-Hispanic whites, non-Hispanic blacks, non-Hispanic Asians, and other (multi) ethnic groups.We measured socioeconomic status using the poverty-income ratio (PIR), which we divided into low-(PIR < 1.3) and middle-high (PIR ≥ 1.3) groups.We also considered education, dividing it into lower than high school education and higher than high school education [24].To assess co-morbidity-related covariates, we looked at doctor-diagnosed CVD (coronary thrombosis, heart failure, angina, and/or stroke) [25].We also examined alcohol consumption and smoking status.Smoking status was categorized into non-smoking and smoking, and alcohol use was categorized into non-alcohol use and alcohol use [26].To assess diabetes, we asked participants, "Have you ever been told you have diabetes or high blood sugar?"Workers who answered "yes" to this question were considered diabetic [27].Finally, hypertension status (HTN) was determined based on medication history or the current systolic pressure of ≥ 140 mmHg or diastolic pressure of ≥ 90 mmHg [28].Overall, by including these potential confounding variables in our analysis, we aimed to control for their potential effects on the relationship between our independent variable(s) and the outcome of interest.

Statistical analysis
We employed the Chi-square test and one-way analysis of variance to compare the characteristics of the study participants at baseline.Continuous variables were reported as mean and standard deviation (SD) or median and interquartile range (IQR), while categorical variables were expressed as population proportions and percentages.To assess the statistical differences among dietary vitamin E intake for baseline characteristic analysis, we utilized one-way ANOVA and Chi-square tests.For multiple comparisons, pairwise comparisons with Bonferroni correction were conducted.The recommended dietary vitamin E intake values for our population were used in this study.
Participants were divided into two groups: below recommended vitamin E intake and normal recommended vitamin E intake.
Binary logistic regression models (odds ratio [OR] and 95% confidence interval [CI]) were employed to evaluate the impact of dietary vitamin E intake on cognitive decline, while adjusting for major covariates.These covariates included age, race, gender, poverty-income ratio, education, body mass index, heart failure, coronary disease, angina, stroke, hypertension, smoking, alcohol, and diabetes.To handle the non-linear relationship between dietary vitamin E intake and cognitive decline, generalized additive models and smooth curve fitting were utilized.Additionally, two-piecewise binary logistic regression models/linear regression models were employed to explore non-linearity.
For subgroup analyses, hierarchical binary logistic regression models were used, transforming continuous variables into categorical variables based on clinical cutoffs or quantiles.Interaction tests were performed, and effect adjustment tests were conducted on subgroup measures, followed by likelihood ratio tests.A sensitivity analysis was also carried out, examining the association between vitamin E intake and cognitive function using first-day intake and second-day intake as independent variables, respectively.Data analysis was performed using R-4.1.1 (R Foundation for Statistical Computing, Vienna, Austria) and FREE Statistics (version 1.7).Statistical significance was set at P values less than 0.05 using a two-tailed test.The study adhered to the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline.

Baseline characteristics of selected participants
In the 2011-2014 cycle, a total of 19,931 participants were initially included in the study.Exclusions were made for individuals under 60 years old (n = 16,299), those with missing cognitive data (n = 698), those with missing dietary data (n = 410), and finally those with missing covariates (n = 269).Ultimately, a total of 2255 participants met the eligibility criteria and were included in the study.Figure 1 provides a flowchart illustrating the search strategy and selection process in detail.We conducted an analysis based on recommended vitamin E intake, categorizing participants as either below or above the recommended intake.
Of all participants, 52.1% were female, 55.0% were between 60 and 70 years old, 51.4% were Non-Hispanic White, and the average BMI was 29.3 ± 6.5 (Table 1).Furthermore, compared to those with below recommended vitamin E intake, participants with higher vitamin E intake were more likely to be younger (within the 60-70 age range), male, Non-Hispanic White, have higher education, a higher PIR (≥ 1.3), higher alcohol consumption, and higher cognitive scores.As shown in Supplement Table 1, the mean intake of vitamin E based on two 24-h food recalls was 8.1 mg/day, with a standard deviation (SD) of 5.2 mg/day.Furthermore, among elderly individuals with vitamin E intake lower than the recommended intake, the proportions of people with cognitive impairment were 21.8% in the IR test, 24.9% in the DR test, 22.8% in the AFT test, 27.4% in the DSST test, and 26% in the Z test, as presented in Supplement Table 2.

Relationship between dietary vitamin E intake and low cognitive performance
Table 2 shows the association between dietary vitamin E intake and low cognitive performance.With regards to dietary factors, our studies have suggested a protective effect of vitamin E intake against low cognitive performance and a possible inverse association with vitamin E intake.Multivariate logistic regression models adjusted for age, race, gender, poverty-income ratio, education, body mass index, heart failure, coronary disease, angina, stroke, hypertension, smoking, stroke, alcohol, diabetes.In the Z test, with each 1 mg/day increase in dietary intake of vitamin E, there was a 6% decrease in the correlation with cognitive impairment (OR = 0.94, 95% CI 0.91-0.97) in the fully fitted model (OR = 0.94, 95% CI 0.91-0.97).Results did not change when exposure was analyzed as a categorical variable.Compared with Q1, Q3 were found to decrease 38% incidence of cognitive impairment in Z test{odds ratio [OR] 0.62 (OR = 0.94, 95% CI 0.91-0.97),Q4 has the risk of cognitive impairment decreases 53% (OR = 0.94, 95% CI 0.91-0.97).In addition, the same phenomenon can be observed in other test as well.In a fully adjusted model, for every unit increase in vitamin E, the correlation with cognitive impairment decreased by 4% (IR test, OR = 0.96, 95% CI 0.93-0.99),5% (DR test, OR = 0.95, 95% CI 0.92-0.97),5% (AFT test, OR = 0.95, 95% CI 0.93-0.98),and 6% (DSST test, OR = 0.94, 95% CI 0.91-0.96).The findings remained consistent when the exposure variable was examined as a categorical variable.

Dose-response relationships
As shown in Fig. 2, L-shaped dose-response relationships were found between dietary vitamin E intake and the risk of low cognitive performance (Z test, P for non-linearity = 0.022).Low cognitive performance fell clearly when the dietary vitamin E intake was less than approximately 9.296 mg, reaching a plateau when dietary vitamin E intake reached approximately 9.296 mg/day.In the threshold analysis, the OR for developing low cognitive performance was 0.88 (95% CI 0.82-0.943,P < 0.001) in participants with a dietary vitamin E intake < 9.296 mg/day (Table 3).Analysis of the diagnostic threshold suggested the relative risk of low cognitive performance decreases by 12% for every 1 mg increase in dietary vitamin E consumption.In addition, the dose-response relationships for other tests are listed in the Supplement Figs. 1, 2, 3, 4.

Subgroup analysis
The study also evaluated potential modifiers of the association between dietary vitamin E intake and low cognitive performance, including age (60-70 vs. 70-80 vs. > 80), gender (male vs. female), protein intake ratio (< 1.3 vs. > 1.3), hypertension (yes vs. no), alcohol use (yes vs. no), smoking status (yes vs. no), and BMI (< 25 vs. 25-30 vs. > 30 kg/m 2 ).Multivariate logistic regression was used to assess heterogeneity among subgroups, and likelihood ratio testing was performed to examine interactions between subgroups and dietary vitamin E intake.However, no significant interactions were found, and therefore no interaction term was included in the final multivariable analysis (Fig. 3).

Sensitivity analysis
A sensitivity analysis was conducted to assess the robustness of the results.Logistic regression analysis was utilized to investigate the association between the intake from the first 24-h recall and the intake from the second 24-h recall as independent variables, and their relationship with cognitive impairment.The results of this analysis can be found in Supplementary Tables 3 and 4. The findings from our study indicated an inverse association between vitamin E intake and cognitive impairment.

Discussion
This study analyzed data collected from a cross-sectional study conducted between 2011 and 2014, focusing on older adults.We utilized logistic multifactor regression to estimate the odds ratio (OR) for dietary vitamin E intake and its association with the risk of low cognitive performance.Our findings suggest a negative correlation between low cognitive risk and dietary vitamin E consumption.Additionally, we observed an L-shaped relationship between dietary vitamin E intake and the risk of low cognitive performance, with a significant non-linearity.This study utilized multivariate-adjusted logistic regression analysis to investigate the relationship between vitamin E intake and the risk of low cognitive symptoms.Our results indicate that even after adjusting for multiple confounding variables, there remains an inverse association between vitamin E intake and low cognitive symptoms.Previous studies have also explored the connection between aging, cognition, and multivitamins.For instance, Lin Hong yuan's study found that cognitive impairment in older Chinese individuals was linked to low plasma HDL cholesterol, low antioxidant capacity and α-tocopherol levels, and a diet low in fish and high in red meat [29].Other research highlights the importance of diet and nutrition in promoting healthy aging and preventing age-related cognitive decline.Adequate nutrition is a key factor in maintaining cognitive function in older adults [30].
However, there is currently a gap in the literature regarding the impact of vitamin E intake during different stages of life.Therefore, we believe that our study fills this gap, at least to some extent.While previous evidence supporting our findings has been scattered, our results are biologically plausible.There may be two potential mechanisms at play: reducing immune inflammation and affecting energy metabolism.
Several basic studies have explored the role of immune inflammation.Beibei Sun's research has shown that sulforaphane and vitamin E can mitigate cognitive decline and oxidative damage in lactating lead-exposed puppies [31].Meanwhile, research conducted by Japanese scholar Keita Takahashi has found that deficiencies in vitamins C and E can lead to impaired fear memory, possibly due to neuroinflammation in the brain [32].
Furthermore, energy metabolism is closely linked to cognitive function.One study has shown that chronic vitamin E deficiency impairs cognitive function in adult zebrafish due to dysregulated lipid and energy metabolism in the brain [33].Another study suggests that embryonic vitamin E deficiency can lead to persistent behavioral deficits resulting from persistent lipid peroxidation and subsequent metabolic disturbances that cannot be resolved by vitamin E supplementation [34].Combining gene expression and metabolomics data from zebrafish embryos at 24-h post-fertilization revealed reduced activity of targets of rapamycin (mTOR) signaling mechanisms, which may affect metabolism and neurodevelopment.Further research is needed to evaluate the effects of vitamin E deficiency on neurogenesis and subsequent impacts on learning and behavior [35].
Importantly, our findings have important implications.One major advantage of this study is that it enables the determination of an entire dose-effect curve.This is a unique study that evaluates the dose-response relationship between dietary vitamin E intake and low cognitive values.Through IR, DR, and Z tests, we discovered an L-shaped relationship This suggests that more vitamin E in the neural system is not necessarily better.We found that a vitamin E intake of at least 60 IU per day can enhance the immune response, while an intake of 200-400 IU per day can reduce the adhesion of platelets to blood vessel walls.Based on its role in regulating these functions, it has been suggested that vitamin E plays a key role in the prevention of cardiovascular disease [36].
As such, it may be beneficial to encourage the consumption of foods that are rich in vitamin E, such as nuts, seeds, vegetable oils, and green leafy vegetables [37].A dietary pattern that includes fruits and vegetables, which are rich in antioxidants like vitamin E, vitamin C, and beta-carotene, may also be helpful in maintaining cognitive function in older adults [38].
In general, the method used in this study has the following advantages.First, multiple dimensions (CERAD-DR, CERAD-IR, DSST, and AFT) were used for the cognitive function tests, and ingeniously coordinated observational and cognitive abilities using Z scores.In addition, we adjusted for numerous confounding variables by consulting earlier studies and conducting analyses.A dose-response analysis to examine the association between vitamin E intake and cognitive function was also conducted.
Although our study possesses many unique strengths, it also has some limitations.First, as it is an observational study, we could not exclude residual confounding, despite the fact that we adjusted for potential covariates as much as possible.Second, since the dietary data were collected from a self-reported 24-h dietary review, biases in recollection and self-reporting may exist.However, this methodology was previously validated as reported in the literature [39,40].Moreover, other oral vitamin E preparations and gamma-tocopherol may also be important for evaluating the actual intake of vitamin E. However, in the NHANES database, only vitamin E is taken as the actual intake of vitamin E α-tocopherol, lacking other oral evaluations and gammatocopherol.This may have a partial impact on the results, and we will use our own database for related research in the future.Finally, the cross-sectional design of the study precludes causal inference.Larger longitudinal cohort studies should be conducted to further investigate this association.

Conclusion
In summary, this study suggests that a higher dietary intake of vitamin E may independently associated with cognitive decline in individuals over 60 years old.The dose-response curve indicates that there is an optimal intake level of vitamin E, with an inflection point of approximately 9.296 mg/ day.These findings highlight the importance of including vitamin E-rich foods in the diet, particularly for older adults who may be at a higher risk of cognitive impairment.However, further research is needed to confirm these results and to better understand the mechanisms underlying the relationship between vitamin E and cognitive function.

Fig. 1
Fig.1 Flowchart detailing the selection process for patients included in this retrospective analysis

Fig. 2
Fig. 2 Association between dietary vitamin E intake and low cognitive performance odds ratio in Z test.Solid and dashed lines represent the predicted value and 95% confidence intervals.Adjusted for age, race, gender, poverty-income ratio, education, body mass index, heart failure, coronary disease, angina, stroke, hypertension, smoking, stroke, alcohol, diabetes.Z test is average of IR, DR, AFT, DSST; CI confidence interval, OR odds ratios, Ref reference

Table 1
Characteristics

Table 1 (
Recommended intake of vitamin E 12 mg/day % weighted proportion, CERAD Consortium to Establish a Registry for Alzheimer's disease, CERAD-DR delayed recall in CERAD trial, CERAD-IR immediate recall in CERAD trial, DSST Digit Symbol Substitution Test, SD standard deviation, AFT Animal Fluency Test.Z test is average of IR, DR, AFT, DSST a P values of multiple comparisons were corrected by the False Discovery Rate method

Table 2
Multivariable logistic regression to assess the association of VE intake with cognitive score VE enter as a continuous variable per 1 mg/day increase Model 1: No adjustment Model 2: Adjusted for age, race, gender, poverty-income ratio, education Model3: Adjusted for age, race, gender, poverty-income ratio, education, body mass index, heart failure, coronary disease, angina, stroke, hypertension, smoking, stroke, alcohol, diabetes

Table 3
Threshold effect analysis of relationship of dietary vitamin E intake and low cognitive performance in Z test Adjusted for age, race, gender, poverty-income ratio, education, hypertension, body mass index, smoking, stroke alcohol and diabetes Stratified analyses of the association between low cognitive performance and vitamin E according to baseline characteristics in Z test.Note: The P value for interaction represents the likelihood of interaction between the variable and vitamin E. OR odds ratio, CI confidence interval