Effects of folic acid supplementation on cognitive function and Aβ-related biomarkers in mild cognitive impairment: a randomized controlled trial
Abstract
Purpose Observational studies have frequently reported that low blood folate concentrations are associated with poor cognitive performance. Our previous studies have shown the potential beneficial effect on the metabolite levels of methionine cycle and peripheral blood inflammatory cytokines from 6- and 12-month folic acid supplementation on cognitive function in mild cognitive impairment (MCI). This study aims to continue exploring the effect of 24-month folic acid supplementation on cognitive function and pathological mechanism in MCI.Methods 180 individuals with MCI were identified and randomly divided into intervention (folic acid 400 µg/day, n = 90) and convention (n = 90) groups. Cognitive function (WAIS-RC) and blood Aβ-related biomarkers were measured at baseline and at 6, 12, 18, and 24 months. Data were analyzed using generalized estimating equation. This trial has been registered with Trial Number: ChiCTR-TRC-13003227.Results During the follow-up, scores of full scale IQ, verbal IQ, and subdomains of Information and Digit Span were significantly higher in the intervention group than those in the convention group (P < 0.05). In the intervention group, blood homocysteine, S-adenosylhomocysteine (SAH), Aβ-42, and the expression of APP-mRNA were decreased (P < 0.05), while S-adenosylmethionine (SAM), SAM/SAH ratio, and the expression of DNA methyltransferase mRNA were increased (P < 0.05).Conclusion Folic acid supplementation appears to improve cognitive function and reduce blood levels of Aβ-related biomarkers in MCI. Larger-scale double-blind placebo-controlled randomized trials of longer duration are needed.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In a recent randomised controlled trial in 180 subjects with mild cognitive impairment, those receiving folic acid (400 μg/day) for 2 years exhibited better cognitive performance (full scale and verbal intelligence, memory) than the placebo-treated group.
“in a recent randomised controlled trial in 180 subjects with mild cognitive impairment, those having received folic acid (400 µg/day) for 2 years exhibited better cognitive performance (full scale and verbal intelligence, memory) when compared with the placebo-treated group [202].”
From Vitamins and Minerals for Energy, Fatigue and Cognition: A Narrative Review of the Biochemical and Clinical Evidence (2020) · cites this paper as [202]
Cites
Molecular Mechanisms of Depression: Perspectives on New Treatment Strategies
Lang, U. E., & Borgwardt, S. (2013) · Cellular Physiology and Biochemistry · doi:10.1159/000350094 · Cited by 8,501 · see citing works
Current concepts in mild cognitive impairment
Petersen, R. C., Doody, R., Kurz, A., Mohs, R. C., Morris, J. C., Rabins, P. V., Ritchie, K., Rossor, M., Thal, L., & Winblad, B. (2001) · Archives of Neurology · doi:10.1001/archneur.58.12.1985 · Cited by 4,781 · see citing works
Cardiovascular Survey Methods.
Rose, G., & Blackburn, H. (1968) · Annals of Internal Medicine · doi:10.7326/0003-4819-69-6-1335_2 · Cited by 3,065 · see citing works
Two Shorter Forms of the CES-D Depression Symptoms Index
Kohout, F. J., Berkman, L. F., Evans, D. A., & Cornoni‐Huntley, J. C. (1993) · Journal of Aging and Health · doi:10.1177/089826439300500202 · Cited by 2,292 · see citing works
Petersen, R. C., Stevens, J. C., Ganguli, M., Tangalos, E. G., Cummings, J. L., & DeKosky, S. T. (2001) · Neurology · doi:10.1212/wnl.56.9.1133 · Cited by 2,065 · see citing works
The Role of DNA Methylation in Mammalian Epigenetics
Jones, P. A., & Takai, D. (2001) · Science · doi:10.1126/science.1063852 · Cited by 2,063 · see citing works
Translating cell biology into therapeutic advances in Alzheimer's disease
Selkoe, D. J. (1999) · Nature · doi:10.1038/399a023 · Cited by 1,588 · see citing works
Prevention of Neural-Tube Defects with Folic Acid in China
Berry, R. J., Li, Z., Erickson, J. D., Li, S., Moore, C. A., Wang, H., Mulinare, J., Zhao, P., Wong, L.-Y., Gindler, J., et al. (1999) · New England Journal of Medicine · doi:10.1056/nejm199911113412001 · Cited by 1,353 · see citing works
Prevention of Neural-Tube Defects with Folic Acid in China
(1999) · New England Journal of Medicine · doi:10.1056/nejm199912093412424 · Cited by 1,075 · see citing works
Sinclair, K. D., Allegrucci, C., Singh, R., Gardner, D. S., Sebastian, S., Bispham, J., Thurston, A., Huntley, J. F., Rees, W. D., Maloney, C. A., et al. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0707258104 · Cited by 812 · see citing works
Durga, J., van Boxtel, M. P., Schouten, E. G., Kok, F. J., Jolles, J., Katan, M. B., & Verhoef, P. (2007) · The Lancet · doi:10.1016/s0140-6736(07)60109-3 · Cited by 758 · see citing works
Plasma and Cerebrospinal Fluid Levels of Amyloid β Proteins 1-40 and 1-42 in Alzheimer Disease
Mehta, P. D., Pirttilä, T., Mehta, S. P., Sersen, E. A., Aisen, P. S., & Wisniewski, H. M. (2000) · Archives of Neurology · doi:10.1001/archneur.57.1.100 · Cited by 582 · see citing works
Epigenetic changes may contribute to the formation and spontaneous regression of retinoblastoma
Greger, V., Passarge, E., H�pping, W., Messmer, E. P., & Horsthemke, B. (1989) · Human Genetics · doi:10.1007/bf00286709 · Cited by 573 · see citing works
DeMattos, R. B., Bales, K. R., Cummins, D. J., Paul, S. M., & Holtzman, D. M. (2002) · Science · doi:10.1126/science.1067568 · Cited by 563 · see citing works
Prevalence, Awareness, Treatment, and Control of Hypertension in China
Gu, D., Reynolds, K., Wu, X., Chen, J., Duan, X., Muntner, P., Huang, G., Reynolds, R. F., Su, S., Whelton, P. K., et al. (2002) · Hypertension · doi:10.1161/01.hyp.0000040263.94619.d5 · Cited by 550 · see citing works
Self-citationHomocysteine, B Vitamins, and Cognitive Impairment
Smith, A. D., & Refsum, H. (2016) · Annual Review of Nutrition · doi:10.1146/annurev-nutr-071715-050947 · Cited by 524 · see citing works
de Jager, C. A., Oulhaj, A., Jacoby, R. J., Refsum, H., & Smith, A. D. (2011) · International Journal of Geriatric Psychiatry · doi:10.1002/gps.2758 · Cited by 461 · see citing works
Plasma Aβ40 and Aβ42 and Alzheimer’s disease: Relation to age, mortality, and risk
Mayeux, R., Honig, L. S., Tang, M.-X., Manly, J., Stern, Y., Schupf, N., & Mehta, P. D. (2003) · Neurology · doi:10.1212/01.wnl.0000091890.32140.8f · Cited by 434 · see citing works
Fuso, A., Seminara, L., Cavallaro, R. A., D’Anselmi, F., & Scarpa, S. (2004) · Molecular and Cellular Neuroscience · doi:10.1016/j.mcn.2004.09.007 · Cited by 408 · see citing works
Tucker, K. L., Qiao, N., Scott, T. M., Rosenberg, I. H., & Spiro, A. (2005) · American Journal of Clinical Nutrition · doi:10.1093/ajcn.82.3.627 · Cited by 351 · see citing works
Tucker, K. L., Qiao, N., Scott, T., Rosenberg, I., & Spiro, A. (2005) · The American Journal of Clinical Nutrition · doi:10.1093/ajcn/82.3.627 · Cited by 351 · see citing works
Homocysteine and brain atrophy on MRI of non-demented elderly
den Heijer, T., Vermeer, S. E., Clarke, R., Oudkerk, M., Koudstaal, P. J., Hofman, A., & Breteler, M. M. B. (2002) · Brain · doi:10.1093/brain/awg006 · Cited by 282 · see citing works
Kado, D. M., Karlamangla, A. S., Huang, M.-H., Troen, A., Rowe, J. W., Selhub, J., & Seeman, T. E. (2005) · The American Journal of Medicine · doi:10.1016/j.amjmed.2004.08.019 · Cited by 268 · see citing works
Folic acid, ageing, depression, and dementia
Reynolds, E. H. (2002) · BMJ · doi:10.1136/bmj.324.7352.1512 · Cited by 240 · see citing works
Bryan, J., Calvaresi, E., & Hughes, D. (2002) · Journal of Nutrition · doi:10.1093/jn/132.6.1345 · Cited by 240 · see citing works
The Worldwide Challenge of the Dementias: A Role for B Vitamins and Homocysteine?
Smith, A. D. (2008) · Food and Nutrition Bulletin · doi:10.1177/15648265080292s119 · Cited by 216 · see citing works
Clarke, R., Bennett, D., Parish, S., Lewington, S., Skeaff, M., Eussen, S. J. P. M., Lewerin, C., Stott, D. J., Armitage, J., Hankey, G. J., et al. (2014) · American Journal of Clinical Nutrition · doi:10.3945/ajcn.113.076349 · Cited by 206 · see citing works
Nutrition and neurodegeneration: epidemiological evidence and challenges for future research
Guyonnet, S., Secher, M., & Vellas, B. J. (2013) · British Journal of Clinical Pharmacology · doi:10.1111/bcp.12058 · Cited by 187 · see citing works
Biochemical markers related to Alzheimer’s dementia in serum and cerebrospinal fluid
Teunissen, C. E., de Vente, J., Steinbusch, H. W. M., & Bruijn, C. D. (2002) · Neurobiology of Aging · doi:10.1016/s0197-4580(01)00328-1 · Cited by 167 · see citing works
Plasma total homocysteine and memory in the elderly: The Hordaland Homocysteine study
Nurk, E., Refsum, H., Tell, G. S., Engedal, K., Vollset, S. E., Ueland, P. M., Nygaard, H. A., & Smith, A. D. (2005) · Annals of Neurology · doi:10.1002/ana.20645 · Cited by 153 · see citing works
Wald, D. S., Kasturiratne, A., & Simmonds, M. C. (2010) · The American Journal of Medicine · doi:10.1016/j.amjmed.2010.01.017 · Cited by 126 · see citing works
Dronse, J., Fließbach, K., Bischof, G. N., von Reutern, B., Faber, J., Hammes, J., Kuhnert, G., Neumaier, B., Onur, O. A., Kukolja, J., et al. (2016) · Journal of Alzheimer s Disease · doi:10.3233/jad-160316 · Cited by 118 · see citing works
Fioravanti, M., Ferrario, E., Massaia, M., Cappa, G., Rivolta, G., Grossi, E., & Buckley, A. E. (1997) · Archives of Gerontology and Geriatrics · doi:10.1016/s0167-4943(97)00028-9 · Cited by 115 · see citing works
Salminen, A., Haapasalo, A., Kauppinen, A., Kaarniranta, K., Soininen, H. S., & Hiltunen, M. O. (2015) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2015.05.001 · Cited by 105 · see citing works
Ma, F., Wu, T., Zhao, J., Song, A., Liu, H., Xu, W., & Huang, G. (2016) · Scientific Reports · doi:10.1038/srep37486 · Cited by 105 · see citing works
Self-citationSeppälä, T. T., Herukka, S., Hänninen, T., Tervo, S., Hallikainen, M., Soininen, H. S., & Pirttilä, T. (2010) · Journal of Neurology Neurosurgery & Psychiatry · doi:10.1136/jnnp.2010.205757 · Cited by 95 · see citing works
Gonda, T. A., Kim, Y., Salas, M. C., Gamble, M. V., Shibata, W., Muthupalani, S., Sohn, K., Abrams, J. A., Fox, J. G., Wang, T. C., et al. (2012) · Gastroenterology · doi:10.1053/j.gastro.2011.12.058 · Cited by 82 · see citing works
REVISION OF WECHSLER'S ADULT INTELLIGENCE SCALE IN CHINA
Yao-xian, G. (1983) · Acta Psychologica Sinica · Cited by 71 · see citing works
Wolters, M., Hickstein, M., Flintermann, A., Tewes, U., & Hahn, A. (2005) · Preventive Medicine · doi:10.1016/j.ypmed.2004.11.007 · Cited by 66 · see citing works
Ma, F., Wu, T., Zhao, J., Han, F., Marseglia, A., Liu, H., & Huang, G. (2015) · The Journals of Gerontology Series A · doi:10.1093/gerona/glv183 · Cited by 65 · see citing works
Self-citationFolic acid administration inhibits amyloid β-peptide accumulation in APP/PS1 transgenic mice
Li, W., Liu, H., Yu, M., Zhang, X., Zhang, M., Wilson, J. X., & Huang, G. (2015) · The Journal of Nutritional Biochemistry · doi:10.1016/j.jnutbio.2015.03.009 · Cited by 62 · see citing works
Self-citationAn abnormality of plasma amyloid protein precursor in Alzheimer's disease
Bush, A. I., Whyte, S., Thomas, L. D., et al. (1992) · Annals of Neurology · doi:10.1002/ana.410320110 · Cited by 59 · see citing works
Tan, C.-C., Wang, C., & Tan, L. (2014) · Current Alzheimer Research · doi:10.2174/1567205011666141001114140 · Cited by 56 · see citing works
Plasma amyloid precursor protein is decreased in Alzheimerʼs disease
Martins, R. N., Muir, J. L., Brooks, W. S., et al. (1993) · Neuroreport · doi:10.1097/00001756-199306000-00040 · Cited by 44 · see citing works
Vascular factors and epigenetic modifications in the pathogenesis of Alzheimer's disease
Leszek, J., Sochocka, M., & Gąsiorowski, K. (2012) · Journal of the Neurological Sciences · doi:10.1016/j.jns.2012.09.010 · Cited by 34 · see citing works
A Population Model of Folate-Mediated One-Carbon Metabolism
Duncan, T. M., Reed, M. C., & Nijhout, H. F. (2013) · Nutrients · doi:10.3390/nu5072457 · Cited by 34 · see citing works
Serum Folate and B12 Levels in Association With Cognitive Impairment Among Seniors
Michelakos, T. P., Kousoulis, A. A., Katsiardanis, K., Dessypris, N., Anastasiou, A. L., Katsiardani, K.-P., Kanavidis, P., Stefanadis, C., Papadopoulos, F. C., & Petridou, E. T. (2013) · Journal of Aging and Health · doi:10.1177/0898264313482488 · Cited by 31 · see citing works
Li, H., Lv, C., Zhang, T., Chen, K., Chen, C., Gai, G., Hu, L., Wang, Y., & Zhang, Z. (2014) · Current Alzheimer Research · doi:10.2174/156720501108140910123112 · Cited by 28 · see citing works
Smith, D. E. C., Smulders, Y. M., Blom, H. J., et al. (2012) · Clinical Chemistry and Laboratory Medicine (CCLM) · doi:10.1515/cclm-2012-0056 · Cited by 28 · see citing works
Parkinson's and Alzheimer's diseases: Focus on mild cognitive impairment
Korczyn, A. D. (2015) · Parkinsonism & Related Disorders · doi:10.1016/j.parkreldis.2015.09.053 · Cited by 13 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Tardy, A.-L., Pouteau, E., Marquez, D., Yilmaz, C., & Scholey, A. (2020) · Nutrients · doi:10.3390/nu12010228 · Cited by 541 · see citing works
McCleery, J., Abraham, R. P., Denton, D. A., Rutjes, A. W., Chong, L.-Y., Al-Assaf, A. S., Griffith, D. J., Rafeeq, S., Yaman, H., Malik, M. A., et al. (2018) · Cochrane Database of Systematic Reviews · doi:10.1002/14651858.cd011905.pub2 · Cited by 162 · see citing works
- Authors
- Ma, F., Li, Q., Zhou, X., Zhao, J., Song, A., Li, W., Liu, H., Xu, W., & Huang, G.
- Affiliations
- Tianjin Medical University (CN)
- Karolinska Institutet (SE)
- Corresponding author
- Huang, Guowei
- Venue
- European Journal of Nutrition
- Published
- 2017-12-18
- Volume
- 58
- Issue
- 1
- Pages
- 345-356
- ISSN
- 1436-6207 (ISSN-L)
- 1436-6215
- OpenAlex
- W2781371180
- Cited by
- 90
- References
- 50
- Citations by year
- 2026: 8 · 2025: 7 · 2024: 12 · 2023: 12 · 2022: 10 · 2021: 25 · 2020: 8 · 2019: 5 · 2018: 3
- FWCI
- 3.83
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- European Journal of Nutrition (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Tianjin Science and Technology Support Program (15ZCZDSY01040)
- the National Natural Science Foundation of China (81130053)
- Tianjin 13th five plan and TMU talent project (2016KJ0304)
- Topics
- Health Sciences › Medicine › Rheumatology › Folate and B Vitamins Research
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Keywords
- folic acid supplementation, mild cognitive impairment, cognitive function, amyloid-beta, homocysteine, S-adenosylhomocysteine, S-adenosylmethionine, methionine cycle, DNA methyltransferases, amyloid-beta 42, blood biomarkers, long-term supplementation
- MeSH terms
- Aged, Cognition, Female, Folic Acid, Follow-Up Studies, Humans, Male, Biomarkers, Cluster Analysis, DNA Methylation, Dietary Supplements, Amyloidogenic Proteins, Cognitive Dysfunction
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
