Association Between High Serum Tetrahydrofolate and Low Cognitive Functions in the United States: A Cross-Sectional Study

Background: The relationship between serum folate status and cognitive functions is still controversial. Objective: To evaluate the association between serum tetrahydrofolate and cognitive functions. Methods: A total of 3,132 participants (60-80 years old) from the 2011-2014 NHANES were included in this cross-sectional study. The primary outcome measurewas cognitive function assessment, determined by the Consortium to Establish a Registry for Alzheimer's Disease Word Learning Test (CERAD-WL), CERAD-Delayed Recall Test (CERAD-DR), Animal Fluency Test (AF), Digit Symbol Substitution Test (DSST), and global cognitive score. Generalized linear model (GLM), multivariate logistic regression models, weighted generalized additive models (GAM), and subgroup analyses were performed to evaluate the association between serum tetrahydrofolate and low cognitive functions. Results: In GLM, and the crude model, model 1, model 2 of multivariate logistic regression models, increased serum tetrahydrofolate was associated with reduced cognitive functions via AF, DSST, CERAD-WL, CERAD-DR, and global cognitive score (p < 0.05). In GAM, the inflection points were 1.1, 2.8, and 2.8 nmol/L tetrahydrofolate, determined by a two-piece wise linear regression model of AF, DSST, and global cognitive score, respectively. Also, in GAM, there were no nonlinear relationship between serum tetrahydrofolate and low cognitive functions, as determined by CERAD-WL or CERAD-DR. The results of subgroup analyses found that serum tetrahydrofolate levels and reduced cognitive functions as determined by AF had significant interactions for age and body mass index. The association between high serum tetrahydrofolate level and reduced cognitive functions as determined using DSST, CERAD-WL, CERAD-DR, or global cognitive score had no interaction with the associations between cognition and gender, or age, or so on. Conclusion: High serum tetrahydrofolate level is associated with significantly reduced cognitive function.