Legacy AI grade · Sources dated 2026-06-09. Not expert reviewed. Coverage is limited to the listed sources. About the new summary workflow
Folate for Methylation Disorder
Verdict: Published with Warning
Across 6 PubMed studies, the evidence for Folate in Methylation Disorder grades Tier C — weak evidence. Effective, but with safety or population caveats.
C 🟠 C Weak Evidence Published with Warning
Why this grade7-layer evidence engine
Folate for methylation disorders is not anchored by methylation-specific Cochrane evidence. PMID 28816346 addresses homocysteine-lowering for cardiovascular-event prevention, not MTHFR outcomes.
Supporting MAs and observational studies address homocysteine or CVD surrogates, not clinical methylation-disorder endpoints. L11 independently grades B while published tier is C.
Tier C appropriately limits the claim. Correct documented deficiency under medical supervision; do not self-treat methylation disorders with routine folate supplementation.
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Scoring transparency
All scores computed by a 7-layer evidence engine — fully auditableRaw score 0.54
D
C
B
A
S
← counter-evidence / ineffectiveeffective / strong evidence →
Final grade
C · Published with Warning
Confidence
86%
Highly consistent evidence
Evidence level
E3
Cochrane 28816346 covers CVD events not MTHFR/methylation-disorder outcomes
▸View the full decision path (audit trail)
- compute_raw_score — 加權公式: L2×0.30 + L3×0.25 + L5×0.25 + L11×0.10 + L1×0.10 = 0.542
- tier_from_score — 依分數區間映射至 tier letter
- apply_hec_rules — 高品質 SR/MA 顯示 positive (1 篇 > 0 negative)
- tier_strict_requirement_check — Tier 條件達標，未降階
- detect_disputes — 偵測到 0 個 hard + 0 個 soft dispute
- decide_status — 依 tier + dispute 結果決定 status
PubMed studies (6)L2 · primary research & systematic reviews
Homocysteine-lowering interventions for preventing cardiovascular events (Cochrane Review, 3rd update)
Finding: Folate-based homocysteine-lowering (B9 alone or with B6/B12) showed NO effect on myocardial infarction (RR 1.02, 95%CI 0.95-1.10) or all-cause mortality (RR 1.01, 95%CI 0.96-1.06) but a small reduction in stroke (RR 0.90, 95%CI 0.82-0.99), all high-quality evidence.
View on PubMed Folic acid supplementation for stroke prevention: A systematic review and meta-analysis of 21 randomized clinical trials worldwide
Finding: Folic acid supplementation significantly reduced stroke risk by 10% (RR 0.90, 95%CI 0.83-0.98), with benefit concentrated in non-fortified/partially-fortified regions (RR 0.83) and absent where grain is fortified (RR 1.04, P-interaction=0.003).
View on PubMed Meta Analysis of Methylenetetrahydrofolate Reductase (MTHFR) C677T polymorphism and its association with folate and colorectal cancer
Finding: MTHFR 677TT genotype was associated with lower CRC risk vs CC (OR 0.89, 95%CI 0.85-0.93, P<0.00001), and high folate intake was protective in TT carriers (OR 0.68, 95%CI 0.48-0.96, P=0.03), though authors caution on retrospective-study limitations.
View on PubMed The effects of folinic acid and l-methylfolate supplementation on serum total homocysteine levels in healthy adults
Finding: Both folinic acid and l-methylfolate significantly lowered tHcy with no between-arm difference, and the reduction was significantly greater in MTHFR 677TT carriers; folinic acid raised serum folate more and outperformed l-methylfolate specifically in 677CT carriers.
View on PubMed Association between serum 5-methyltetrahydrofolate and homocysteine in Chinese hypertensive participants with different MTHFR C677T polymorphisms: a cross-sectional study
Finding: Below 10 ng/mL, higher serum 5-MTHF was inversely associated with homocysteine, with the strongest effect in MTHFR 677TT carriers (TT beta=-1.19, P<0.001; CT beta=-0.20, P=0.011; CC beta=-0.14, P=0.087).
View on PubMed Supplementation with Folic Acid or 5-Methyltetrahydrofolate and Prevention of Neural Tube Defects: An Evidence-Based Narrative Review
Finding: Folic acid has demonstrated NTD-prevention efficacy, but the authors conclude there are essentially NO clinical studies establishing 5-MTHF efficacy/dosage/safety for NTD prevention, so it cannot yet be recommended as an equivalent alternative.
View on PubMed Regulatory & authoritative positionsL4/L5 · FDA / EMA / NIH ODS / Cochrane / Mayo …
L4a US FDA
Supportive
Health claims relating folate to risk of neural tube defects may be made on the label or in labeling of foods, including dietary supplements, provided that the requirements in this section are met. source↗
L4b EU EFSA
Supportive
L4c UK NHS
Neutral
It's recommended that all women who could get pregnant should take a 400 microgram folic acid supplement daily before pregnancy and until they're 12 weeks pregnant. source↗
L4d TW TFDA / 衛福部
Supportive
孕期缺乏葉酸，會增加胎兒腦及脊髓先天性神經管缺陷的風險。育齡婦女及準備懷孕婦女可在準備階段每日攝取400微克，懷孕期間每日攝取600微克。 source↗
L4e WHO
Neutral
Current evidence suggests that folic acid supplementation in the periconceptional period, either alone or in combination with other vitamins and minerals, can prevent neural tube defects. source↗
L5a NIH Office of Dietary Supplements
Supportive
L5b Mayo Clinic
Neutral
There's no specific treatment for the gene change itself. If you have high homocysteine levels, treatment recommendations are the same whether you have a MTHFR variant or not. Your provider might recommend taking B6, B12 and folic acid supplements. source↗
L5c Cleveland Clinic
Supportive
You don't need special types of folate. ... You don't need to avoid folic acid. ... Pregnancy care providers usually recommend taking folic acid supplements before and during pregnancy. ... Your provider might recommend taking B6, B12 and folic acid supplements. source↗
L5e Specialty Society (condition-mapped)
Supportive
To lower homocysteine levels, your health care provider will usually recommend taking vitamin B supplements that include folic acid, which is a form of folate. However, if you have the gene variant MTHFR, your provider may recommend methylfolate (5-MTHF) instead since your body may be able to use this form more easily. Studies show that taking folic acid greatly reduces the risk of neural tube … source↗