Circulating folate concentrations and the risk of mild cognitive impairment: A prospective study on the older Chinese population without folic acid fortification
Jingzhu Fu
Department of Nutrition & Food Science, School of Public Health, Tianjin Medical University, Tianjin, China
Tianjin Key Laboratory of Environment, Nutrition and Public Health, Tianjin, China
Contribution: Data curation (lead), Formal analysis (lead), Investigation (equal), Methodology (lead), Writing - original draft (lead), Writing - review & editing (equal)
Search for more papers by this authorQian Liu
Department of Nutrition & Food Science, School of Public Health, Tianjin Medical University, Tianjin, China
Tianjin Key Laboratory of Environment, Nutrition and Public Health, Tianjin, China
Contribution: Formal analysis (supporting), Investigation (equal), Writing - original draft (supporting)
Search for more papers by this authorYun Zhu
Tianjin Key Laboratory of Environment, Nutrition and Public Health, Tianjin, China
Department of Epidemiology & Biostatistics, School of Public Health, Tianjin Medical University, Tianjin, China
Contribution: Conceptualization (supporting), Formal analysis (supporting), Methodology (supporting), Writing - original draft (supporting), Writing - review & editing (equal)
Search for more papers by this authorChangqing Sun
Neurosurgical Department of Baodi Clinical College of Tianjin Medical University, Tianjin, China
Contribution: Investigation (supporting)
Search for more papers by this authorHuilian Duan
Department of Nutrition & Food Science, School of Public Health, Tianjin Medical University, Tianjin, China
Tianjin Key Laboratory of Environment, Nutrition and Public Health, Tianjin, China
Contribution: Investigation (equal)
Search for more papers by this authorLing Huang
Department of Nutrition & Food Science, School of Public Health, Tianjin Medical University, Tianjin, China
Tianjin Key Laboratory of Environment, Nutrition and Public Health, Tianjin, China
Contribution: Investigation (equal)
Search for more papers by this authorDezheng Zhou
Department of Nutrition & Food Science, School of Public Health, Tianjin Medical University, Tianjin, China
Tianjin Key Laboratory of Environment, Nutrition and Public Health, Tianjin, China
Contribution: Investigation (equal)
Search for more papers by this authorZehao Wang
Department of Nutrition & Food Science, School of Public Health, Tianjin Medical University, Tianjin, China
Tianjin Key Laboratory of Environment, Nutrition and Public Health, Tianjin, China
Contribution: Investigation (equal)
Search for more papers by this authorJing Zhao
Department of Nutrition & Food Science, School of Public Health, Tianjin Medical University, Tianjin, China
Tianjin Key Laboratory of Environment, Nutrition and Public Health, Tianjin, China
Contribution: Investigation (equal)
Search for more papers by this authorZhenshu Li
Department of Nutrition & Food Science, School of Public Health, Tianjin Medical University, Tianjin, China
Tianjin Key Laboratory of Environment, Nutrition and Public Health, Tianjin, China
Contribution: Investigation (equal)
Search for more papers by this authorFei Ma
Tianjin Key Laboratory of Environment, Nutrition and Public Health, Tianjin, China
Department of Epidemiology & Biostatistics, School of Public Health, Tianjin Medical University, Tianjin, China
Contribution: Conceptualization (supporting), Writing - review & editing (supporting)
Search for more papers by this authorWen Li
Department of Nutrition & Food Science, School of Public Health, Tianjin Medical University, Tianjin, China
Tianjin Key Laboratory of Environment, Nutrition and Public Health, Tianjin, China
Contribution: Conceptualization (equal), Writing - review & editing (supporting)
Search for more papers by this authorHuan Liu
Department of Nutrition & Food Science, School of Public Health, Tianjin Medical University, Tianjin, China
Tianjin Key Laboratory of Environment, Nutrition and Public Health, Tianjin, China
Contribution: Conceptualization (supporting), Writing - review & editing (supporting)
Search for more papers by this authorXumei Zhang
Department of Nutrition & Food Science, School of Public Health, Tianjin Medical University, Tianjin, China
Tianjin Key Laboratory of Environment, Nutrition and Public Health, Tianjin, China
Contribution: Conceptualization (supporting), Writing - review & editing (supporting)
Search for more papers by this authorYongjie Chen
Tianjin Key Laboratory of Environment, Nutrition and Public Health, Tianjin, China
Department of Epidemiology & Biostatistics, School of Public Health, Tianjin Medical University, Tianjin, China
Contribution: Conceptualization (supporting), Data curation (supporting), Writing - review & editing (supporting)
Search for more papers by this authorGuangshun Wang
Department of Tumor, Baodi Clinical College of Tianjin Medical University, Tianjin, China
Contribution: Conceptualization (supporting), Writing - review & editing (supporting)
Search for more papers by this authorCorresponding Author
Yue Du
Tianjin Key Laboratory of Environment, Nutrition and Public Health, Tianjin, China
Department of Social Medicine and Health Management, School of Public Health, Tianjin Medical University, Tianjin, China
Correspondence
Guowei Huang, Department of Nutrition and Food Science, School of Public Health, Tianjin Medical University, No. 22 Qixiangtai Road, Heping District, Tianjin 300070, China.
Email: [email protected]
Yue Du, Department of Social Medicine and Health Management, School of Public Health, Tianjin Medical University, Tianjin, China.
Email: [email protected]
Contribution: Conceptualization (supporting), Writing - review & editing (supporting)
Search for more papers by this authorCorresponding Author
Guowei Huang
Department of Nutrition & Food Science, School of Public Health, Tianjin Medical University, Tianjin, China
Tianjin Key Laboratory of Environment, Nutrition and Public Health, Tianjin, China
Correspondence
Guowei Huang, Department of Nutrition and Food Science, School of Public Health, Tianjin Medical University, No. 22 Qixiangtai Road, Heping District, Tianjin 300070, China.
Email: [email protected]
Yue Du, Department of Social Medicine and Health Management, School of Public Health, Tianjin Medical University, Tianjin, China.
Email: [email protected]
Contribution: Conceptualization (lead), Funding acquisition (lead), Project administration (lead), Supervision (lead)
Search for more papers by this authorJingzhu Fu
Department of Nutrition & Food Science, School of Public Health, Tianjin Medical University, Tianjin, China
Tianjin Key Laboratory of Environment, Nutrition and Public Health, Tianjin, China
Contribution: Data curation (lead), Formal analysis (lead), Investigation (equal), Methodology (lead), Writing - original draft (lead), Writing - review & editing (equal)
Search for more papers by this authorQian Liu
Department of Nutrition & Food Science, School of Public Health, Tianjin Medical University, Tianjin, China
Tianjin Key Laboratory of Environment, Nutrition and Public Health, Tianjin, China
Contribution: Formal analysis (supporting), Investigation (equal), Writing - original draft (supporting)
Search for more papers by this authorYun Zhu
Tianjin Key Laboratory of Environment, Nutrition and Public Health, Tianjin, China
Department of Epidemiology & Biostatistics, School of Public Health, Tianjin Medical University, Tianjin, China
Contribution: Conceptualization (supporting), Formal analysis (supporting), Methodology (supporting), Writing - original draft (supporting), Writing - review & editing (equal)
Search for more papers by this authorChangqing Sun
Neurosurgical Department of Baodi Clinical College of Tianjin Medical University, Tianjin, China
Contribution: Investigation (supporting)
Search for more papers by this authorHuilian Duan
Department of Nutrition & Food Science, School of Public Health, Tianjin Medical University, Tianjin, China
Tianjin Key Laboratory of Environment, Nutrition and Public Health, Tianjin, China
Contribution: Investigation (equal)
Search for more papers by this authorLing Huang
Department of Nutrition & Food Science, School of Public Health, Tianjin Medical University, Tianjin, China
Tianjin Key Laboratory of Environment, Nutrition and Public Health, Tianjin, China
Contribution: Investigation (equal)
Search for more papers by this authorDezheng Zhou
Department of Nutrition & Food Science, School of Public Health, Tianjin Medical University, Tianjin, China
Tianjin Key Laboratory of Environment, Nutrition and Public Health, Tianjin, China
Contribution: Investigation (equal)
Search for more papers by this authorZehao Wang
Department of Nutrition & Food Science, School of Public Health, Tianjin Medical University, Tianjin, China
Tianjin Key Laboratory of Environment, Nutrition and Public Health, Tianjin, China
Contribution: Investigation (equal)
Search for more papers by this authorJing Zhao
Department of Nutrition & Food Science, School of Public Health, Tianjin Medical University, Tianjin, China
Tianjin Key Laboratory of Environment, Nutrition and Public Health, Tianjin, China
Contribution: Investigation (equal)
Search for more papers by this authorZhenshu Li
Department of Nutrition & Food Science, School of Public Health, Tianjin Medical University, Tianjin, China
Tianjin Key Laboratory of Environment, Nutrition and Public Health, Tianjin, China
Contribution: Investigation (equal)
Search for more papers by this authorFei Ma
Tianjin Key Laboratory of Environment, Nutrition and Public Health, Tianjin, China
Department of Epidemiology & Biostatistics, School of Public Health, Tianjin Medical University, Tianjin, China
Contribution: Conceptualization (supporting), Writing - review & editing (supporting)
Search for more papers by this authorWen Li
Department of Nutrition & Food Science, School of Public Health, Tianjin Medical University, Tianjin, China
Tianjin Key Laboratory of Environment, Nutrition and Public Health, Tianjin, China
Contribution: Conceptualization (equal), Writing - review & editing (supporting)
Search for more papers by this authorHuan Liu
Department of Nutrition & Food Science, School of Public Health, Tianjin Medical University, Tianjin, China
Tianjin Key Laboratory of Environment, Nutrition and Public Health, Tianjin, China
Contribution: Conceptualization (supporting), Writing - review & editing (supporting)
Search for more papers by this authorXumei Zhang
Department of Nutrition & Food Science, School of Public Health, Tianjin Medical University, Tianjin, China
Tianjin Key Laboratory of Environment, Nutrition and Public Health, Tianjin, China
Contribution: Conceptualization (supporting), Writing - review & editing (supporting)
Search for more papers by this authorYongjie Chen
Tianjin Key Laboratory of Environment, Nutrition and Public Health, Tianjin, China
Department of Epidemiology & Biostatistics, School of Public Health, Tianjin Medical University, Tianjin, China
Contribution: Conceptualization (supporting), Data curation (supporting), Writing - review & editing (supporting)
Search for more papers by this authorGuangshun Wang
Department of Tumor, Baodi Clinical College of Tianjin Medical University, Tianjin, China
Contribution: Conceptualization (supporting), Writing - review & editing (supporting)
Search for more papers by this authorCorresponding Author
Yue Du
Tianjin Key Laboratory of Environment, Nutrition and Public Health, Tianjin, China
Department of Social Medicine and Health Management, School of Public Health, Tianjin Medical University, Tianjin, China
Correspondence
Guowei Huang, Department of Nutrition and Food Science, School of Public Health, Tianjin Medical University, No. 22 Qixiangtai Road, Heping District, Tianjin 300070, China.
Email: [email protected]
Yue Du, Department of Social Medicine and Health Management, School of Public Health, Tianjin Medical University, Tianjin, China.
Email: [email protected]
Contribution: Conceptualization (supporting), Writing - review & editing (supporting)
Search for more papers by this authorCorresponding Author
Guowei Huang
Department of Nutrition & Food Science, School of Public Health, Tianjin Medical University, Tianjin, China
Tianjin Key Laboratory of Environment, Nutrition and Public Health, Tianjin, China
Correspondence
Guowei Huang, Department of Nutrition and Food Science, School of Public Health, Tianjin Medical University, No. 22 Qixiangtai Road, Heping District, Tianjin 300070, China.
Email: [email protected]
Yue Du, Department of Social Medicine and Health Management, School of Public Health, Tianjin Medical University, Tianjin, China.
Email: [email protected]
Contribution: Conceptualization (lead), Funding acquisition (lead), Project administration (lead), Supervision (lead)
Search for more papers by this authorJingzhu Fu, Qian Liu and Yun Zhu contributed equally to this work.
Funding information
This work was supported by grants from the National Natural Science Foundation of China (No. 81730091)
Abstract
Background
The longitudinal association between serum folate concentrations and the risk of cognitive impairment remains unclear in populations with low folate levels. We examined the association between serum folate concentrations and mild cognitive impairment (MCI) in older adults in China, where mandatory fortification of foods with folic acid has not been implemented. We further explored if homocysteine (Hcy) and leukocyte telomere length (LTL) mediate the association between serum folate and MCI.
Methods
We performed a longitudinal analysis of 3974 participants aged ≥60 years from the Tianjin Elderly Nutrition and Cognition (TENC) cohort study. The associations between serum folate level and the risk of cognitive impairment overall and stratified by apolipoprotein E (APOE) ε4 genotypes were evaluated using multivariable Cox proportional hazards models. The mediating effects of Hcy and LTL on the folate–MCI association were explored via a path analysis approach.
Results
Within a 3-year follow-up, we documented 560 incident MCI cases. After multivariable adjustment, higher serum folate concentrations were associated with lower incidence of MCI, with hazard ratios (95% confidence interval) across quartiles of folate (from lowest to highest concentrations) of 1.00 (reference), 0.66 (0.52, 0.83), 0.57 (0.45, 0.73), 0.66 (0.52, 0.84), respectively (p for trend <0.001). In mediation analyses, the status of serum folate deficiency and MCI were correlated via two intermediary pathways, Hcy and Hcy-telomere (p < 0.05).
Conclusions
Lower folate concentrations, independently of APOE genotype, were associated with increased risk of MCI among elderly Chinese people, a population with relatively low folate intake. Our data were compatible with the mediation hypothesis that the association between folate status and MCI was mediated by Hcy and LTL.
CONFLICT OF INTEREST
The authors have declared no conflicts of interest.
Open Research
DATA AVAILABILITY STATEMENT
Data described in the manuscript, code book, and analytic code will be made available to editors upon request either before or after publication for checking. For data access, researchers can contact the corresponding authors (E-mail: [email protected]).
Supporting Information
Filename | Description |
---|---|
ene15474-sup-0001-Supinfo.docxWord 2007 document , 693.8 KB |
Appendix S1 |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
REFERENCES
- 1Roberts R, Knopman DS. Classification and epidemiology of MCI. Clin Geriatr Med. 2013; 29: 753-772.
- 2Ducker GS, Rabinowitz JD. One-carbon metabolism in health and disease. Cell Metab. 2017; 25: 27-42.
- 3Molloy AM, Daly S, Mills JL, et al. Thermolabile variant of 5,10-methylenetetrahydrofolate reductase associated with low red-cell folates: implications for folate intake recommendations. Lancet. 1997; 349: 1591-1593.
- 4Jacques PF, Bostom AG, Williams RR, et al. Relation between folate status, a common mutation in methylenetetrahydrofolate reductase, and plasma homocysteine concentrations. Circulation. 1996; 93: 7-9.
- 5Wei S, Gao L, Jiang Y, et al. The apolipoprotein e epsilon4 allele-dependent relationship between serum lipid levels and cognitive function: a population-based cross-sectional study. Front Aging Neurosci. 2020; 12: 44.
- 6Pusceddu I, Herrmann M, Kirsch SH, et al. One-carbon metabolites and telomere length in a prospective and randomized study of B- and/or D-vitamin supplementation. Eur J Nutr. 2017; 56: 1887-1898.
- 7Hagg S, Zhan Y, Karlsson R, et al. Short telomere length is associated with impaired cognitive performance in European ancestry cohorts. Transl Psychiatry. 2017; 7:e1100.
- 8Fu J, Liu Q, Du Y, et al. Age- and sex-specific prevalence and modifiable risk factors of mild cognitive impairment among older adults in china: a population-based observational study. Front Aging Neurosci. 2020; 12:578742.
- 9Petersen RC. Mild cognitive impairment as a diagnostic entity. J Intern Med. 2004; 256: 183-194.
- 10Katzman R, Zhang MY, Ouang Ya Q, et al. A Chinese version of the mini-mental state examination; impact of illiteracy in a Shanghai dementia survey. J Clin Epidemiol. 1988; 41: 971-978.
- 11Zhang MY, Katzman R, Salmon D, et al. The prevalence of dementia and Alzheimer's disease in Shanghai, China: impact of age, gender, and education. Ann Neurol. 1990; 27: 428-437.
- 12Ritchie K, Artero S, Touchon J. Classification criteria for mild cognitive impairment: a population-based validation study. Neurology. 2001; 56: 37-42.
- 13Perneczky R, Pohl C, Sorg C, et al. Complex activities of daily living in mild cognitive impairment: conceptual and diagnostic issues. Age Ageing. 2006; 35: 240-245.
- 14Religa D, Styczynska M, Peplonska B, et al. Homocysteine, apolipoproteine E and methylenetetrahydrofolate reductase in Alzheimer's disease and mild cognitive impairment. Dement Geriatr Cogn Disord. 2003; 16: 64-70.
- 15Cawthon RM. Telomere measurement by quantitative PCR. Nucleic Acids Res. 2002; 30:e47.
- 16Fu J, Liu Q, Zhang M, et al. Association between methionine cycle metabolite-related diets and mild cognitive impairment in older Chinese adults: a population-based observational study. Nutr Neurosci. 2022; 25: 1495-1508.
- 17Xia Y, Zhang Q, Liu L, et al. Intermediary effect of inflammation on the association between dietary patterns and non-alcoholic fatty liver disease. Nutrition. 2020; 71:110562.
- 18Yang Y, Wang G, Pan X. China food composition. 2nd ed. Peking University Medical Press; 2009.
- 19Craig CL, Marshall AL, Sjostrom M, et al. International physical activity questionnaire: 12-country reliability and validity. Med Sci Sports Exerc. 2003; 35: 1381-1395.
- 20Chobanian AV, Bakris GL, Black HR, et al. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 Report. JAMA. 2003; 289: 2560-2572.
- 21Zung WW. A self-rating depression scale. Arch Gen Psychiatry. 1965; 12: 63-70.
- 22Fountoulakis KN, lacovides A, Samolis S, et al. Reliability, validity and psychometric properties of the Greek translation of the Zung Depression Rating Scale. BMC Psychiatry. 2001; 1: 6.
- 23 (U.S.) IoM, Intakes. SCotSEoDR, Panel on Folate OBV, and Choline., Nutrients. SoURLo. Dietary reference intakes for thiamin, riboflavin, niacin, vitamin B₆, folate, vitamin B₁₂, pantothenic acid, biotin, and choline. National Academy Press; 1998.
- 24Shi B, Choirat C, Coull BA, VanderWeele TJ, Valeri L. CMAverse: a suite of functions for reproducible causal mediation analyses. Epidemiology. 2021; 32: e20-e22.
- 25Zhou X, Wang Q, An P, et al. Relationship between folate, vitamin B12, homocysteine, transaminase and mild cognitive impairment in China: a case-control study. Int J Food Sci Nutr. 2020; 71: 315-324.
- 26Ma F, Wu T, Zhao J, et al. Plasma homocysteine and serum folate and vitamin b12 levels in mild cognitive impairment and Alzheimer's disease: a case-control study. Nutrients. 2017; 9: 725.
- 27Hama Y, Hamano T, Shirafuji N, et al. Influences of folate supplementation on homocysteine and cognition in patients with folate deficiency and cognitive impairment. Nutrients. 2020; 12: 3138.
- 28Ravaglia G, Forti P, Maioli F, et al. Homocysteine and folate as risk factors for dementia and Alzheimer disease. Am J Clin Nutr. 2005; 82: 636-643.
- 29Wang Q, Zhao J, Chang H, Liu X, Zhu R. Homocysteine and folic acid: risk factors for Alzheimer's disease-an updated meta-analysis. Front Aging Neurosci. 2021; 13:665114.
- 30Moore K, Hughes CF, Ward M, Hoey L, McNulty H. Diet, nutrition and the ageing brain: current evidence and new directions. Proc Nutr Soc. 2018; 77: 152-163.
- 31Larsson SC, Traylor M, Malik R, Dichgans M, Burgess S, Markus HS. Modifiable pathways in Alzheimer's disease: Mendelian randomisation analysis. BMJ. 2017; 359:j5375.
- 32Cai C, Xiao R, Van Halm-Lutterodt N, et al. Association of MTHFR, SLC19A1 genetic polymorphism, serum folate, vitamin B12 and Hcy status with cognitive functions in Chinese adults. Nutrients. 2016; 8: 665