Is There a Link Between Low Folate Levels and Dementia?

Is There a Link Between Low Folate Levels and Dementia?

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Katie Stone - Naturopath

Written By:

Katie Stone - Naturopath
Dr. Conor Sheehy - PharmD, BCPS

Medical Reviewer:

Dr. Conor Sheehy - PharmD, BCPS
Kari Asadorian - BSN, RN

Edited By:

Kari Asadorian - BSN, RN
Last updated:

Is there a Link Between Low Folate Levels and Dementia?

Recent research has shown that folate deficiency is common among older adults, with several studies suggesting a link between low folate, declining cognitive function, and mortality.


A 2018 study1 in Ireland revealed that one in seven adults over 50 is deficient in folate, and one in eight is deficient in vitamin B12. Both nutrients are essential for proper cognitive function, nerve function, and the production of red blood cells and DNA.


Further studies suggest that folate intake below the Recommended Daily Intake (RDA) may increase the risk2 of mild cognitive impairment and dementia later. However, some experts3 dispute this claim.


This article will explore the research that supports the link between low folate and dementia. We will also discuss recommendations for improving folate status, whether this is effective, and implications for those with MTHFR mutations.

Low Blood Folate’s Association with Cognitive Decline

Research into the association between folate and cognitive decline remains somewhat inconsistent.4 Some observational studies have found that higher B vitamin intake is associated with a lower risk of dementia, while others have found no link. However, there is also substantial evidence to suggest that folate deficiency increases the likelihood of cognitive decline5 and reduces neurological function.


A large cohort study6 found folate deficiency was associated with a 68% increased risk of dementia and a 2.98-fold increased risk of all-cause mortality - even when other conditions such as diabetes, vitamin B12 deficiency, cognitive decline, and depression were accounted for. However, the study authors also suggested that further research was needed.


A study involving 370 people without dementia7 aged 75 years and older found that both vitamin B12 and folate may be involved in developing Alzheimer’s disease. Still, the association was only detected when both vitamins were taken into account.

Could Low Folate be a Symptom Rather than a Risk Factor?

The high incidence of low folate in those with dementia may also be a result of reverse causation. The deficiency is a consequence of preclinical dementia rather than its cause. This theory is based on the fact that the neuropathological processes of dementia often begin many years before diagnosis,8 during which cardiometabolic changes, including weight loss, are common.


Older adults may be at a higher risk of nutrient deficiencies due to lower food intake,9 physiological and metabolic dysfunctions, medications,10 and other age-associated factors.


Having a higher body mass index during midlife may increase the risk of dementia, but some researchers suggest that weight loss during the preclinical dementia phase may make it difficult to identify these effects. Unintentional weight loss is common in patients with dementia11 and has also been linked to poorer disease outcomes.


Ultimately, a lower BMI before the onset of dementia could result in low folate, making it a symptom of preclinical disease12 rather than the actual cause of dementia.

Could Folate Supplementation be Helpful?

Some researchers have suggested that folate levels should be monitored in older adults, and a deficiency should be treated13 as part of a therapeutic strategy. However, debate continues14 as to whether folate and/or vitamin B supplementation can improve cognition or slow the rate of brain atrophy in Alzheimer’s and/or mild cognitive impairment by lowering homocysteine levels.


Folate supplementation may indeed be beneficial. One study showed that folate works alongside Donepezil in improving cognition15 and markers of inflammation. As inflammation is central in the pathogenesis of dementia, folate supplementation may help reduce the risk.


Studies have shown that folic acid supplementation to patients with mild cognitive impairment can significantly improve cognitive performance,16 including information processing speed and memory, which typically decline with age.


The Baltimore Longitudinal Study of Aging17 found that adequate folate significantly decreased the risk of Alzheimer’s disease. The 35.1% of participants who met their daily folate requirements had a 60% reduced risk of developing Alzheimer’s. A similar study18 found that as folate concentration in Red Blood Cells (RBCs) increased, the individual’s relative risk of cognitive impairment and dementia decreased.


A 2021 systematic review19 and meta-analysis indicated that folate levels are lower in Alzheimer’s patients than in controls. Also, sufficient intake of folate was a protective factor against Alzheimer’s.


However, a meta-analysis20 of 11 trials and 22,000 individuals concluded that B-vitamins do not influence cognitive aging in older people.

What are the Implications for People with MTHFR?

MTHFR mutations result in abnormal intracellular folic acid metabolism,21 which may result in low folate. Adequate levels of folate22 and B12 are needed to maintain not only normal homocysteine levels but for proper methylation reactions.


Several studies have associated dementia with elevated homocysteine levels23 and concurrent low levels of folate and vitamin B12. MTHFR gene mutations are also found to occur in most elderly patients with memory loss24.


Elevated homocysteine is considered a strong risk factor25 for dementia and cognitive decline in the elderly, particularly in association with low levels of folate and cobalamin.


One study suggested that the MTHFR C677T gene may be linked26 to Alzheimer’s disease (AD) pathogenesis. A meta-analysis of 11 studies found a strong association between vascular dementia and the C677T27 gene polymorphism.


However, another study found that MTHFR C677T was not associated28 with an increased risk of vascular dementia or Alzheimer’s disease.


Despite this inconclusive evidence, those with MTHFR mutations would be well-advised to maintain folate levels through supplementation with methylfolate. Methylfolate is a bioavailable form of the nutrient that has been shown to bypass the MTHFR deficiency.29 It requires no further conversion and is available for immediate use in the body.


Choosing the right methylfolate supplement can be tricky. Some of the best-known methylfolate formulations are available in the Methyl-Life® range, along with additional cognitive support in the form of multivitamins and B12. Methyl-Life® also offers a Brain Bundle, which includes their best-selling L-Methylfolate (5mg) and Active B12 Hydroxocobalamin (2.5mg) in one convenient 3-month-supply package.


Methyl-Life® also provides comprehensive information about each of its products, especially folate’s role in supporting the mind and body.

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$39.00

  • Bioactive L-Methylfolate 3 Mg & Methylated B12
  • Great for Bypassing MTHFR Mutations
  • 3rd-Party Tested for Purity, Potency & Safety
  • 90 Vegan, Non-GMO, Chewable Mint Tablets

Product Recommendations

MTHFR Actives - L-Methylfolate + Hydroxy B12 Sublingual

MTHFR Actives - L-Methylfolate + Hydroxy B12 Sublingual

$58.00

  • Easy Starting Dosage Levels for MTHFR Newbies
  • Bioidentical L-Methylfolate for Immediate Absorption & Use
  • Bioactive Vitamin B12 Sublingual, Hydroxy Form
  • 3rd-Party Tested for Purity & Safety, Vegan & Non-GMO

References

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    https://ebmh.bmj.com/content/25/2/63

  14. Mengzhe You, Xia Zhou, Wenwen Yin, Ke Wan, Wei Zhang, Chenchen Li, Mingxu Li, Wenhao Zhu, Xiaoqun Zhu, Zhongwu Sun; "The Influence of MTHFR Polymorphism on Gray Matter Volume in Patients With Amnestic Mild Cognitive Impairment"; Frontiers in Neuroscience; 2021

    https://www.frontiersin.org/articles/10.3389/fnins.2021.778123/full

  15. Hui Chen, Shuai Liu, Lu Ji, Tianfeng Wu, Yong Ji, Yuying Zhou, Miaoyan Zheng, Meilin Zhang, Weili Xu, Guowei Huang; "Folic Acid Supplementation Mitigates Alzheimer's Disease by Reducing Inflammation: A Randomized Controlled Trial"; Mediators of inflammation; 2016 Jun

    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4909909/

  16. Fei Ma, Tianfeng Wu, Jiangang Zhao, Aili Song, Huan Liu, Weili Xu, Guowei Huang; "Folic acid supplementation improves cognitive function by reducing the levels of peripheral inflammatory cytokines in elderly Chinese subjects with MCI"; scientific reports; 2016 Nov

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    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3375831/

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  19. Xiaohong Zhang, Guangyi Bao, Debiao Liu, Yu Yang, Xuezhi Li, Gaomei Cai, Yan Liu, Yili Wu; "The Association Between Folate and Alzheimer's Disease: A Systematic Review and Meta-Analysis"; Frontiers in Neuroscience; 2021 Apr

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  20. Robert Clarke, Derrick Bennett, Sarah Parish, Sarah Lewington, Murray Skeaff, Simone J P M Eussen, Catharina Lewerin, David J Stott, Jane Armitage, Graeme J Hankey, Eva Lonn, J David Spence, Pilar Galan, Lisette C de Groot, Jim Halsey, Alan D Dangour, Rory Collins, Francine Grodstein; B-Vitamin Treatment Trialists’ Collaboration; "Effects of homocysteine lowering with B vitamins on cognitive aging: meta-analysis of 11 trials with cognitive data on 22,000 individuals"; The American journal of clinical nutrition; 2014 Aug

    https://pubmed.ncbi.nlm.nih.gov/24965307/

  21. ScienceDirect.com; "Methylenetetrahydrofolate Reductase"

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  22. Christian E Cajavilca, Rajan R Gadhia, Gustavo C Román; "MTHFR Gene Mutations Correlate with White Matter Disease Burden and Predict Cerebrovascular Disease and Dementia"; Brain sciences; 2019 Aug

    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6770069/

  23. Christian E Cajavilca, Rajan R Gadhia, Gustavo C Román; "MTHFR Gene Mutations Correlate with White Matter Disease Burden and Predict Cerebrovascular Disease and Dementia"; Brain sciences; 2019 Aug

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  24. Gustavo C Román, Oscar Mancera-Páez, Camilo Bernal; "Epigenetic Factors in Late-Onset Alzheimer’s Disease: MTHFR and CTH Gene Polymorphisms, Metabolic Transsulfuration and Methylation Pathways, and B Vitamins"; International journal of molecular sciences; 2019 Jan

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  26. Mengzhe You, Xia Zhou, Wenwen Yin, Ke Wan, Wei Zhang, Chenchen Li, Mingxu Li, Wenhao Zhu, Xiaoqun Zhu, Zhongwu Sun; "The Influence of MTHFR Polymorphism on Gray Matter Volume in Patients With Amnestic Mild Cognitive Impairment"; Frontiers in Neuroscience; 2021 Nov

    https://www.frontiersin.org/articles/10.3389/fnins.2021.778123/full

  27. National Library of Medicine

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Katie Stone - Naturopath

About the Author

Katie is a qualified Naturopath (BNatMed) and freelance writer from New Zealand. She specializes in all things health and wellness, particularly dietary supplements and nutrition. Katie is also a dedicated runner and has completed more half-marathons than she can count!

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