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

Article type: Research Article

Authors: Fan, Yaohua^{a; 1} | Liu, Wen^{b; 1} | Chen, Si^{c; 1} | Li, Mengzhu^a | Zhao, Lijun^a | Wu, Chunxiao^a | Liu, Helu^{a; *} | Zhu, Meiling^{a; *}

Affiliations: [a] Shenzhen Hospital of Integrated Traditional Chinese and Western Medicine, Guangzhou University of Chinese Medicine, Shenzhen, China | [b] Department of Ophthalmology Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou, China | [c] The First Clinical College, Guangzhou University of Chinese Medicine, Guangzhou, China

Correspondence: [*] Correspondence to: Dr. Helu Liu and Meiling Zhu, Shenzhen Hospital of Integrated Traditional Chinese and Western Medicine, Guangzhou University of Chinese Medicine. No.3, Shajing Lane, Baoan District, Shenzhen, Guangdong Province, 518000 China. Tel.: +86 0755 27201982; E-mail: liuhelu@21cn.com. (H. Liu) and E-mail: meilingzhu2020@126.com. (M. Zhu)

Note: [1] These authors contributed equally to this work.

Abstract: 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 measure was 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 non-linear 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.

Keywords: Analysis of non-linear relationship, cognitive functions, dementia, multiple logistic regression, NHANES, serum tetrahydrofolate

DOI: 10.3233/JAD-220058

Journal: Journal of Alzheimer's Disease, vol. 89, no. 1, pp. 163-179, 2022