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Longevity Library · Lab reference

Written by Daniel Tagge, MD
Updated October 7, 2026
Reviewed October 10, 2026
35 sources · Measured in µmol/L

System: Epigenetics

HomocysteinePlasma total homocysteine · tHcy · Hcy

Cohorts put the lowest mortality and dementia risk below about 9 to 11 µmol/L and the risk rises continuously above that, but lowering homocysteine with B vitamins reduced stroke by about 10 percent in trials and did not reduce heart attacks, death or cognitive decline, so homocysteine is best read as a marker of B12, folate and riboflavin status, kidney function and methylation rather than as a treatment target.

Homocysteine is an amino acid that builds up when the methylation cycle runs short of folate, B12, riboflavin or B6, or when the kidneys clear it slowly. Laboratories print upper limits from about 11 to 15 µmol/L. In cohorts, risk climbs steadily from about 9 upward; in trials, vitamins that lowered it prevented some strokes and no heart attacks. The number is most useful for what it says about the vitamins and the kidneys behind it.

01 · The scale

Where the laboratory range and the evidence sit.

Continuous risk in cohorts with the lowest mortality below about 9 and the lowest dementia risk below about 11 µmol/L; in randomized trials, B vitamins that lowered it by a quarter cut stroke by about 10 percent and did not change heart attacks, deaths or cognition.

051015202530

  1. Common laboratory reference range

    0 to 15 µmol/L · Typical US laboratories; Morris 2017

  2. Lowest mortality in the Hordaland cohort

    0 to 9 µmol/L · Vollset 2001

  3. Mortality 1.3 to 1.4 times the lowest group

    9 to 12 µmol/L · Vollset 2001

  4. Mortality about twice the lowest group; Alzheimer's risk nearly doubled above 14

    12 to 15 µmol/L · Vollset 2001; Seshadri 2002

  5. Mortality 2.3 to 3.6 times the lowest group; B12, folate, kidney or drug cause likely

    15 and above µmol/L · Vollset 2001; Savage 1994; de Jager 2010

  • Laboratory range
  • Evidence supports
  • Guideline goal or unstudied
  • Higher risk in studies
Scale in µmol/L. Some reports print mg/L; 0.41 mg/L is about 3 µmol/L. Bands show where studies found something, not a recommendation for any one person.

02 · What it is

What Homocysteine measures.

Homocysteine is a sulfur-containing amino acid made every time methionine donates a methyl group. It is recycled back to methionine by a folate- and B12-dependent step, with the folate form supplied by an enzyme (MTHFR) that needs riboflavin, or broken down through a B6-dependent path. Its concentration in plasma therefore reflects the functional status of folate, B12 and B6 together, which is why an international consensus group calls it a nutrient-dependent biomarker rather than a disease in itself.1,2Grade A

It is a sensitive marker of B12 and folate deficiency. In 434 episodes of confirmed B12 deficiency, homocysteine was raised in 95.9 percent and methylmalonic acid in 98.4 percent, and only one patient had both normal; homocysteine was raised in 91 percent of 123 episodes of folate deficiency. The British haematology guideline uses homocysteine as a second-line test for B12 status, noting it is less specific than methylmalonic acid because other things raise it too.3,4Grade A

Those other things are well mapped. In 1,960 adults of the Framingham Offspring cohort, homocysteine was 11 percent higher in men than women and 23 percent higher at age 65 and over than under 45; it rose with serum creatinine, cigarettes smoked, alcohol, caffeine and antihypertensive use, and was 18 percent lower in people taking B-vitamin supplements. The Hordaland study of more than 18,000 Norwegians found the same determinants, with physical activity, moderate alcohol and good folate or B12 status on the lowering side.5,6Grade B

03 · The laboratory range

What a laboratory calls normal.

About 5 to 15 µmol/L, with the upper limit printed anywhere from about 11 to 15 depending on the laboratory.

After the United States began fortifying grain with folic acid in 1996 to 1997, the mean homocysteine in the Framingham Offspring cohort fell from 10.1 to 9.4 µmol/L among non-supplement users and the share above 13 fell from 18.7 to 9.8 percent. In the national survey that followed (9,196 adults, 1999 to 2002), age-adjusted means were 8.4 in non-Hispanic white, 8.9 in non-Hispanic Black and 8.1 in Mexican American adults, higher in men and in older people. Most of the cohort and trial literature predates fortification, so its baselines run higher than a US adult's today.7,8Grade B

The upper reference limit is generally between 10 and 15 µmol/L and varies with age and assay, in the words of the 2017 homocystinuria guideline. The dementia consensus statement treats anything above 11 as moderately raised, and the Hordaland investigators note that clinical associations are usually seen above 15 but that for most conditions the relation is continuous with no threshold. A printed 'normal' therefore tells a reader less than the number itself.9,1,6Grade A

04 · The evidence

What the studies support.

Pooling individual data from 30 observational studies with 5,073 ischemic heart disease events and 1,113 strokes, a 25 percent lower usual homocysteine (about 3 µmol/L) was associated with 11 percent lower heart disease risk and 19 percent lower stroke risk after adjustment for the usual risk factors. The associations were stronger in studies that drew blood after the disease than in prospective ones, and the authors called homocysteine at most a modest independent predictor. A second meta-analysis put the odds per 5 µmol/L higher at 1.32 for heart disease and 1.59 for stroke in prospective studies, and 1.60 for venous thrombosis in genetic studies.10,11Grade A

In 4,766 Norwegians aged 65 to 67 followed for a median of 4.1 years, mortality rose stepwise with homocysteine. Against people below 9 µmol/L, cardiovascular death was 1.3, 2.1, 2.6 and 3.5 times higher at 9 to 11.9, 12 to 14.9, 15 to 19.9 and 20 or above, and non-cardiovascular death 1.4, 1.9, 2.3 and 3.6 times; each 5 µmol/L carried 49 percent higher all-cause mortality. This is an association in a cohort drawn before folate fortification, adjusted for the usual confounders, not proof that homocysteine itself does the harm.12Grade B

Genetics give a mixed verdict. People with two copies of the common MTHFR 677T variant run about 1.9 µmol/L higher homocysteine (15,635 people) and had 1.26 times the odds of stroke in 13,928 people, close to what the cohorts predicted. But in 59,995 people the genotype's effect on homocysteine was 3.1 µmol/L in low-folate Asia and 0.13 in fortified countries, and the stroke odds followed (1.68 versus 1.03). For heart disease, 19 unpublished datasets with 48,175 cases showed no effect at all (odds ratio 1.02), against 1.15 in published studies, which the authors read as publication bias: lifelong moderate elevation has little or no effect on coronary disease.13,14,15Grade B

The randomized trials settled the heart question. In HOPE-2, 5,522 people aged 55 and over with vascular disease or diabetes took 2.5 mg folic acid, 50 mg B6 and 1 mg B12 or placebo for five years: homocysteine fell 2.4 µmol/L, the primary outcome was 18.8 versus 19.8 percent (relative risk 0.95), stroke fell (0.75) and unstable-angina admissions rose (1.24). In NORVIT, 3,749 people after a heart attack lowered homocysteine 27 percent with folic acid and B12 over 40 months and had no fewer events (risk ratio 1.08), with a trend to harm from the triple combination (1.22). Pooling 8 trials and 37,485 people, a 25 percent reduction over 5 years gave rate ratios of 1.01 for major vascular events, 1.03 for coronary events, 0.96 for stroke and 1.02 for death.16,17,18Grade A

Stroke is the one outcome that moved. The 2017 Cochrane review of 15 trials and 71,422 people found no effect on myocardial infarction (risk ratio 1.02) or death (1.01) but a reduction in stroke from 5.1 to 4.3 percent (0.90), all rated high-quality evidence. In VITATOPS, 8,164 people with recent stroke or TIA took 2 mg folic acid, 25 mg B6 and 0.5 mg B12 for a median 3.4 years; the composite endpoint was 15 versus 17 percent (0.91, p=0.05). The benefit concentrates where folate is low: in the China Stroke Primary Prevention Trial, 20,702 adults with hypertension and no prior stroke took enalapril with or without 0.8 mg folic acid for 4.5 years, and first stroke fell from 3.4 to 2.7 percent (hazard ratio 0.79) with no change in heart attack (1.04) or death (0.94). Across 21 trials and 115,559 people, folic acid cut stroke 10 percent overall (risk ratio 0.90), more in unfortified regions (0.83) and not at all (1.04) in fortified ones.19,20,21,22Grade A

For the brain, the cohorts and the trials disagree. In 1,092 Framingham adults without dementia (mean age 76) followed for 8 years, each standard deviation of homocysteine carried 1.4 times the risk of dementia and 1.8 times the risk of Alzheimer's disease, and a level above 14 µmol/L nearly doubled Alzheimer's risk. In the VITACOG trial, 168 people over 70 with mild cognitive impairment who completed MRI took 0.8 mg folic acid, 0.5 mg B12 and 20 mg B6 or placebo for 2 years; whole-brain atrophy ran at 0.76 versus 1.08 percent a year, and 53 percent slower in those starting above 13. But across 11 trials with cognitive data on 22,000 people, B vitamins lowered homocysteine 26 to 28 percent and had no effect on memory, speed, executive function or global cognition, an estimate that excluded a benefit of more than one month of cognitive aging per year of treatment. An expert consensus nonetheless names raised homocysteine a modifiable risk factor for dementia (relative risks 1.15 to 2.5), and asks for trials of conversion to dementia that have not been done.23,24,25,1Grade B

05 · What moves it

The levers with evidence behind them.

What is listed here has been tested. The size of each effect, and the size of the study, are in the sentence, so a small effect reads as a small effect.

  • Folic acid or dietary folate

    lowers it by about a quarter

    Across 12 randomized trials with individual data on 1,114 people, folic acid at 0.5 to 5 mg a day lowered homocysteine by 25 percent from a pre-treatment level of 12 µmol/L, with the same effect across that dose range and a larger effect when the starting level was higher or folate lower. Population fortification at a far smaller dose moved the Framingham mean from 10.1 to 9.4. Food folate counts: the fortification effect came from enriched grain, not pills.26,7Grade A

  • Vitamin B12

    lowers it a further 7 percent, far more when B12 is deficient

    Adding about 0.5 mg of B12 a day to folic acid produced an additional 7 percent reduction in the pooled trials; B6 at 16.5 mg a day added nothing measurable. When B12 is actually deficient the picture is different: in a metformin trial, people who ended with B12 deficiency had a mean homocysteine of 23.7 µmol/L against 14.9 in those with normal B12, and homocysteine was raised in 95.9 percent of confirmed deficiency episodes, so a high value is a reason to check B12 and methylmalonic acid before anything else.26,27,3Grade A

  • Riboflavin (B2), in people with the MTHFR 677TT genotype

    lowers it 22 to 40 percent in that genotype only

    In a 12-week randomized trial, 1.6 mg a day of riboflavin lowered homocysteine from 16.1 to 12.5 µmol/L (22 percent) in 32 people homozygous for the MTHFR 677T variant, and by 40 percent (22.0 to 13.2) in the 16 with the lowest riboflavin status, while people with one or no copy of the variant did not respond. A small trial in one genotype, but a specific, cheap lever when the genotype is known.28Grade C

  • Coffee

    raises it by about 1 µmol/L at 600 mL a day

    In 121 healthy non-smokers, three weeks without coffee lowered homocysteine by 1.04 µmol/L, and resuming 600 mL of filtered coffee a day raised it 1.26 on placebo; 200 µg of folic acid a day erased the rise (difference 1.43) while 40 mg of B6 did not. Caffeine intake tracked with homocysteine in the Framingham Offspring cohort as well.29,5Grade C

  • Smoking and alcohol

    raise it; moderate alcohol tracked lower in one cohort

    Homocysteine rose with the number of cigarettes smoked and with alcohol intake in the Framingham Offspring cohort. In the Hordaland study smoking raised it while moderate alcohol tracked with lower values, a difference that probably reflects beverage type and folate intake rather than a benefit of alcohol. Cross-sectional associations, not trials.5,6Grade C

  • Exercise

    a hard session raises it briefly; resistance training lowers it a little

    Pooling 22 studies and 520 participants, a single bout of exercise raised homocysteine by 1.18 µmol/L, so a sample drawn right after a workout reads high. Resistance training lowered it by 1.53 µmol/L across trials, aerobic training did not, and training overall (7 studies, 230 people) showed no significant change.30Grade C

  • Dietary protein and methionine

    ordinary intakes do not raise the fasting value

    Methionine is the source of homocysteine, which is why a methionine-loading test exists, but in a 10-week randomized trial in 29 older men, doubling protein intake from the recommended 0.8 g/kg, using animal-based protein, lowered fasting homocysteine rather than raising it, presumably because the protein brought its B vitamins with it. A small trial; the practical reading is that protein restriction is not a lever.31,2Grade C

  • Medications

    several common classes raise it

    Drugs that interfere with folate, B12 or B6 handling or with kidney function raise homocysteine: fibrates and niacin, metformin, methotrexate and sulfasalazine, anticonvulsants, levodopa and some diuretics are the documented classes. In a randomized trial of 390 people with type 2 diabetes, 4.3 years of metformin lowered B12 by 19 percent and raised the absolute risk of B12 deficiency by 7.2 percentage points. Whether a medication should change is a decision for the prescriber, never a reason to stop on one's own.32,27Grade B

06 · Reading it well

Caveats, and what belongs with a physician.

The sample matters. Red cells keep making homocysteine after the draw, so plasma has to be separated from cells within about an hour unless the tube is chilled or contains a stabilizer; in a 72-hour stability study only refrigerated tubes with the additive held steady. A surprisingly high value from a sample that sat on a bench is a reason to repeat it, drawn fasting and processed promptly.33,2Grade B

Week to week, a healthy person's homocysteine varies by about 7 percent, so two results need to differ by roughly 16 to 19 percent before the change is more than noise; between-person variation (24 percent) is far larger than within-person, which makes a person's own trend more informative than a population range.34Grade C

Kidney function is a major determinant. Homocysteine rises with serum creatinine in healthy cohorts and climbs steeply in renal failure, and in the B12 study the few folate-deficient patients with a raised methylmalonic acid owed it to renal insufficiency. A raised homocysteine in someone with a low estimated GFR is partly the kidney talking.5,3,2Grade B

Hypothyroidism raises it. Overt hypothyroidism is a recognized cause; a meta-analysis of 12 observational studies with 684 patients found even subclinical hypothyroidism carried a homocysteine 1.16 µmol/L higher than euthyroid controls. A TSH belongs beside an unexplained homocysteine.35Grade C

MTHFR genotype deserves context, not alarm. The 677TT genotype is common, raises homocysteine by about 1.9 µmol/L on average and by almost nothing (0.13) where grain is fortified, and carried no excess coronary risk in the largest unbiased dataset. Measuring homocysteine itself, with B12 and folate, captures what the genotype would predict, and riboflavin is the specific lever if the genotype is known; routine MTHFR testing is not needed to read the number.13,14,15,28Grade B

The cohort associations are real and the trial results are real, and they point different ways. The likeliest reconciliation is that homocysteine marks the B-vitamin status, kidney function, smoking and age that cause the harm, with only a modest causal share of its own, strongest for stroke in folate-poor populations. Lowering the number with pills is not the same as fixing what raised it.10,18,14Grade A

See a physician

  • A homocysteine above about 20 µmol/L on a properly handled sample, which usually has a cause worth finding: B12 or folate deficiency, kidney disease, thyroid disease or a medication.
  • A homocysteine above about 50 µmol/L at any age, the range in which an inherited disorder of homocysteine metabolism becomes a question; untreated cases typically run above 100.
  • Numbness or tingling, trouble with balance, memory change or anemia alongside a raised homocysteine, which can mean B12 deficiency that should not wait for more tests.
  • A blood clot in a vein or lung, especially at a young age or in a close relative, together with a raised homocysteine.
  • A raised homocysteine while taking metformin, methotrexate, an anticonvulsant or a fibrate, so the prescriber can weigh B12 or folate replacement.

This page is education, not individual medical advice, and reading it creates no physician-patient relationship.

07 · Open questions

What the literature does not settle.

  • No trial has treated healthy adults with normal B12 and folate to a homocysteine target below about 10 µmol/L and measured outcomes; everything below the laboratory limit is cohort association.
  • Why B vitamins prevented stroke but not heart attack is unresolved; candidate explanations are the folate status of the population, kidney function, and the form of B12 used in the early trials.
  • Whether B vitamins given early enough prevent dementia is untested: one trial slowed brain atrophy in mild cognitive impairment, eleven trials in 22,000 people found no effect on cognition, and no trial has measured conversion to dementia.
  • How much of the mortality association belongs to homocysteine itself and how much to the kidney function, B-vitamin status and smoking that travel with it has not been separated.
  • Reference ranges were set before and after folate fortification in different countries, and no body has published an outcome-based upper limit for a fortified population.

08 · In practice

How Dr. Tagge reads it in his own practice.

I like to see homocysteine under 10 µmol/L, and I read it as a report on B12, folate, riboflavin and B6 status, kidney function and methylation before I read it as a risk number. The cohorts put the lowest risk below about 9 to 11, and the trials taught me that a vitamin pill does not turn a high number into a lower heart-attack risk, so when it sits above 10 I go looking for the reason: B12 with methylmalonic acid, folate, creatinine, TSH, the medication list, coffee and smoking, and the MTHFR genotype when riboflavin might be the lever. Fixing the cause brings the number down. I do not chase the number for its own sake.

A practice judgment, labeled as one (Grade D): it is how one physician reads the number for the people he cares for, not a recommendation for you.

09

Questions

10 · Sources

35 sources, read in full.

Numbered in the order they appear. Each line says what this page relies on from the paper; the link opens the record at PubMed or the publisher.

  1. 1.

    Smith AD, Refsum H, Bottiglieri T, et al.. Homocysteine and dementia: an international consensus statement. Journal of Alzheimer's Disease. 2018. PMID 29480200. DOI 10.3233/JAD-171042.

    Consensus statement · Plasma total homocysteine reflects the functional status of folate, B12 and B6; relative risk of dementia 1.15 to 2.5 for moderately raised levels; above 11 µmol/L called moderately raised; trials of conversion to dementia still needed.

  2. 2.

    Refsum H, Smith AD, Ueland PM, et al.. Facts and recommendations about total homocysteine determinations: an expert opinion. Clinical Chemistry. 2004. PMID 14709635. DOI 10.1373/clinchem.2003.021634.

    Consensus statement · International expert opinion covering sample handling, biological determinants, reference intervals, within-person variability, the methionine loading test, renal failure and deficiency states.

  3. 3.

    Savage DG, Lindenbaum J, Stabler SP, Allen RH. Sensitivity of serum methylmalonic acid and total homocysteine determinations for diagnosing cobalamin and folate deficiencies. American Journal of Medicine. 1994. PMID 8154512. DOI 10.1016/0002-9343(94)90149-x.

    Cross-sectional study · Homocysteine raised in 95.9 percent of 434 B12-deficiency episodes and 91 percent of 123 folate-deficiency episodes; normal MMA and homocysteine together rule out B12 deficiency.

  4. 4.

    Devalia V, Hamilton MS, Molloy AM; British Committee for Standards in Haematology. Guidelines for the diagnosis and treatment of cobalamin and folate disorders. British Journal of Haematology. 2014. PMID 24942828. DOI 10.1111/bjh.12959.

    Guideline · Homocysteine is a second-line test for B12 status, less specific than methylmalonic acid; treatment should not wait when clinical features of deficiency are strong.

  5. 5.

    Jacques PF, Bostom AG, Wilson PW, Rich S, Rosenberg IH, Selhub J. Determinants of plasma total homocysteine concentration in the Framingham Offspring cohort. American Journal of Clinical Nutrition. 2001. PMID 11237940. DOI 10.1093/ajcn/73.3.613.

    Cross-sectional study · In 1,960 adults, homocysteine 11 percent higher in men and 23 percent higher at 65 and over; rose with creatinine, smoking, alcohol, caffeine and antihypertensive use; 18 percent lower in B-vitamin users.

  6. 6.

    Refsum H, Nurk E, Smith AD, et al.. The Hordaland Homocysteine Study: a community-based study of homocysteine, its determinants, and associations with disease. Journal of Nutrition. 2006. PMID 16702348. DOI 10.1093/jn/136.6.1731S.

    Prospective cohort · In more than 18,000 Norwegians, age, male sex, smoking, coffee, blood pressure, creatinine and MTHFR raise homocysteine; activity, moderate alcohol and folate or B12 status lower it; associations usually seen above 15 µmol/L with a continuous relation.

  7. 7.

    Jacques PF, Selhub J, Bostom AG, Wilson PW, Rosenberg IH. The effect of folic acid fortification on plasma folate and total homocysteine concentrations. New England Journal of Medicine. 1999. PMID 10320382. DOI 10.1056/NEJM199905133401901.

    Prospective cohort · After US folate fortification, mean homocysteine in non-supplement users fell from 10.1 to 9.4 µmol/L and the share above 13 from 18.7 to 9.8 percent.

  8. 8.

    Ganji V, Kafai MR. Population reference values for plasma total homocysteine concentrations in US adults after the fortification of cereals with folic acid. American Journal of Clinical Nutrition. 2006. PMID 17093148. DOI 10.1093/ajcn/84.5.989.

    Cross-sectional study · NHANES 1999 to 2002, 9,196 adults: age-adjusted means 8.39 (non-Hispanic white), 8.92 (non-Hispanic Black) and 8.12 µmol/L (Mexican American); higher in men and older adults.

  9. 9.

    Morris AAM, Kožich V, Santra S, et al.. Guidelines for the diagnosis and management of cystathionine beta-synthase deficiency. Journal of Inherited Metabolic Disease. 2017. PMID 27778219. DOI 10.1007/s10545-016-9979-0.

    Guideline · Upper reference limit generally 10 to 15 µmol/L; untreated homocystinuria typically above 100; mildly affected adults present with thromboembolism; treatment target below 50 in pyridoxine-responsive patients.

  10. 10.

    Homocysteine Studies Collaboration. Homocysteine and risk of ischemic heart disease and stroke: a meta-analysis. JAMA. 2002. PMID 12387654. DOI 10.1001/jama.288.16.2015.

    Systematic review and meta-analysis · 30 studies, 5,073 heart disease and 1,113 stroke events: 25 percent lower homocysteine (about 3 µmol/L) associated with 11 percent lower heart disease and 19 percent lower stroke risk; at most a modest independent predictor.

  11. 11.

    Wald DS, Law M, Morris JK. Homocysteine and cardiovascular disease: evidence on causality from a meta-analysis. BMJ. 2002. PMID 12446535. DOI 10.1136/bmj.325.7374.1202.

    Systematic review and meta-analysis · Per 5 µmol/L higher: ischemic heart disease odds 1.32 (prospective) and 1.42 (genetic); venous thrombosis 1.60 (genetic); stroke 1.59 (prospective).

  12. 12.

    Vollset SE, Refsum H, Tverdal A, et al.. Plasma total homocysteine and cardiovascular and noncardiovascular mortality: the Hordaland Homocysteine Study. American Journal of Clinical Nutrition. 2001. PMID 11451728. DOI 10.1093/ajcn/74.1.130.

    Prospective cohort · In 4,766 adults aged 65 to 67, mortality ratios versus below 9 µmol/L were 1.3, 2.1, 2.6 and 3.5 (cardiovascular) and 1.4, 1.9, 2.3 and 3.6 (non-cardiovascular) at 9 to 11.9, 12 to 14.9, 15 to 19.9 and 20 or more; 49 percent higher all-cause mortality per 5 µmol/L.

  13. 13.

    Casas JP, Bautista LE, Smeeth L, Sharma P, Hingorani AD. Homocysteine and stroke: evidence on a causal link from mendelian randomisation. Lancet. 2005. PMID 15652605. DOI 10.1016/S0140-6736(05)17742-3.

    Mendelian randomization · MTHFR TT versus CC: 1.93 µmol/L higher homocysteine in 15,635 people and stroke odds 1.26 in 13,928, matching the 1.20 predicted from cohorts.

  14. 14.

    Holmes MV, Newcombe P, Hubacek JA, et al.. Effect modification by population dietary folate on the association between MTHFR genotype, homocysteine, and stroke risk: a meta-analysis of genetic studies and randomised trials. Lancet. 2011. PMID 21803414. DOI 10.1016/S0140-6736(11)60872-6.

    Mendelian randomization · In 59,995 people, TT versus CC raised homocysteine 3.12 µmol/L in Asia and 0.13 in fortified regions, with stroke odds 1.68 versus 1.03; trials in high-folate regions matched the genetic prediction of no benefit.

  15. 15.

    Clarke R, Bennett DA, Parish S, et al.; MTHFR Studies Collaborative Group. Homocysteine and coronary heart disease: meta-analysis of MTHFR case-control studies, avoiding publication bias. PLoS Medicine. 2012. PMID 22363213. DOI 10.1371/journal.pmed.1001177.

    Mendelian randomization · In 19 unpublished datasets (48,175 cases), TT versus CC coronary odds 1.02 against 1.15 in 86 published studies; lifelong moderate homocysteine elevation has little or no effect on coronary disease.

  16. 16.

    Lonn E, Yusuf S, Arnold MJ, et al.; HOPE 2 Investigators. Homocysteine lowering with folic acid and B vitamins in vascular disease. New England Journal of Medicine. 2006. PMID 16531613. DOI 10.1056/NEJMoa060900.

    Randomized trial · 5,522 patients, 5 years: homocysteine down 2.4 µmol/L; primary outcome 18.8 versus 19.8 percent (RR 0.95); stroke RR 0.75; unstable angina admissions RR 1.24.

  17. 17.

    Bønaa KH, Njølstad I, Ueland PM, et al.; NORVIT Trial Investigators. Homocysteine lowering and cardiovascular events after acute myocardial infarction. New England Journal of Medicine. 2006. PMID 16531614. DOI 10.1056/NEJMoa055227.

    Randomized trial · 3,749 patients after myocardial infarction, 40 months: 27 percent homocysteine lowering, no effect on events (RR 1.08); trend to harm with the triple combination (RR 1.22).

  18. 18.

    Clarke R, Halsey J, Lewington S, et al.; B-Vitamin Treatment Trialists' Collaboration. Effects of lowering homocysteine levels with B vitamins on cardiovascular disease, cancer, and cause-specific mortality: meta-analysis of 8 randomized trials involving 37 485 individuals. Archives of Internal Medicine. 2010. PMID 20937919. DOI 10.1001/archinternmed.2010.348.

    Systematic review and meta-analysis · 25 percent homocysteine reduction over a median 5 years: rate ratios 1.01 major vascular events, 1.03 coronary, 0.96 stroke, 1.05 cancer, 1.02 all-cause death.

  19. 19.

    Martí-Carvajal AJ, Solà I, Lathyris D, Dayer M. Homocysteine-lowering interventions for preventing cardiovascular events. Cochrane Database of Systematic Reviews. 2017. PMID 28816346. DOI 10.1002/14651858.CD006612.pub5.

    Systematic review and meta-analysis · 15 trials, 71,422 people: myocardial infarction RR 1.02, death 1.01, stroke 0.90 (4.3 versus 5.1 percent), all high-quality evidence; about 143 treated for 5.4 years to prevent one stroke in the one mega-trial.

  20. 20.

    VITATOPS Trial Study Group. B vitamins in patients with recent transient ischaemic attack or stroke in the VITAmins TO Prevent Stroke (VITATOPS) trial: a randomised, double-blind, parallel, placebo-controlled trial. Lancet Neurology. 2010. PMID 20688574. DOI 10.1016/S1474-4422(10)70187-3.

    Randomized trial · 8,164 patients with recent stroke or TIA, median 3.4 years: composite endpoint 15 versus 17 percent (RR 0.91, p=0.05).

  21. 21.

    Huo Y, Li J, Qin X, et al.; CSPPT Investigators. Efficacy of folic acid therapy in primary prevention of stroke among adults with hypertension in China: the CSPPT randomized clinical trial. JAMA. 2015. PMID 25771069. DOI 10.1001/jama.2015.2274.

    Randomized trial · 20,702 adults with hypertension, 4.5 years: enalapril plus 0.8 mg folic acid reduced first stroke from 3.4 to 2.7 percent (HR 0.79); no effect on myocardial infarction (1.04) or death (0.94).

  22. 22.

    Zhang N, Zhou Z, Chi X, et al.. Folic acid supplementation for stroke prevention: a systematic review and meta-analysis of 21 randomized clinical trials worldwide. Clinical Nutrition. 2024. PMID 38824900. DOI 10.1016/j.clnu.2024.05.034.

    Systematic review and meta-analysis · 21 trials, 115,559 people: stroke RR 0.90 overall, 0.83 in unfortified or partially fortified regions, 1.04 with grain fortification; 0.77 in people without prior stroke or infarction in unfortified regions.

  23. 23.

    Seshadri S, Beiser A, Selhub J, et al.. Plasma homocysteine as a risk factor for dementia and Alzheimer's disease. New England Journal of Medicine. 2002. PMID 11844848. DOI 10.1056/NEJMoa011613.

    Prospective cohort · 1,092 Framingham adults, 8 years: relative risk 1.4 for dementia and 1.8 for Alzheimer's per standard deviation; above 14 µmol/L, Alzheimer's risk nearly doubled.

  24. 24.

    Smith AD, Smith SM, de Jager CA, et al.. Homocysteine-lowering by B vitamins slows the rate of accelerated brain atrophy in mild cognitive impairment: a randomized controlled trial. PLoS One. 2010. PMID 20838622. DOI 10.1371/journal.pone.0012244.

    Randomized trial · VITACOG, 168 people over 70 with MCI completing MRI: brain atrophy 0.76 versus 1.08 percent a year on B vitamins versus placebo; 53 percent slower in those with baseline homocysteine above 13 µmol/L.

  25. 25.

    Clarke R, Bennett D, Parish S, et al.; 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. American Journal of Clinical Nutrition. 2014. PMID 24965307. DOI 10.3945/ajcn.113.076349.

    Systematic review and meta-analysis · B vitamins lowered homocysteine 26 to 28 percent with no effect on any cognitive domain or global cognition; excluded a benefit of more than one month of cognitive aging per year of treatment.

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    Homocysteine Lowering Trialists' Collaboration. Lowering blood homocysteine with folic acid based supplements: meta-analysis of randomised trials. BMJ. 1998. PMID 9569395.

    Systematic review and meta-analysis · 12 trials, 1,114 people: folic acid 0.5 to 5 mg a day lowered homocysteine 25 percent from 12 µmol/L; B12 (0.5 mg) a further 7 percent; B6 (16.5 mg) no significant addition.

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    de Jager J, Kooy A, Lehert P, et al.. Long term treatment with metformin in patients with type 2 diabetes and risk of vitamin B-12 deficiency: randomised placebo controlled trial. BMJ. 2010. PMID 20488910. DOI 10.1136/bmj.c2181.

    Randomized trial · 390 patients, 4.3 years: metformin lowered B12 19 percent and raised absolute risk of B12 deficiency 7.2 points; mean homocysteine 23.7 µmol/L in those deficient versus 14.9 with normal B12.

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    McNulty H, Dowey le RC, Strain JJ, et al.. Riboflavin lowers homocysteine in individuals homozygous for the MTHFR 677C->T polymorphism. Circulation. 2006. PMID 16380544. DOI 10.1161/CIRCULATIONAHA.105.580332.

    Randomized trial · 1.6 mg/day riboflavin for 12 weeks lowered homocysteine 22 percent (16.1 to 12.5 µmol/L) in 32 TT homozygotes and 40 percent in those with low riboflavin status; no response in CT or CC.

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    Strandhagen E, Landaas S, Thelle DS. Folic acid supplement decreases the homocysteine increasing effect of filtered coffee. A randomised placebo-controlled study. European Journal of Clinical Nutrition. 2003. PMID 14576754. DOI 10.1038/sj.ejcn.1601703.

    Randomized trial · In 121 healthy non-smokers, coffee abstention lowered homocysteine 1.04 µmol/L; 600 mL filtered coffee a day raised it 1.26 on placebo; 200 µg folic acid offset it (difference 1.43); 40 mg B6 did not.

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    Deminice R, Ribeiro DF, Frajacomo FT. The effects of acute exercise and exercise training on plasma homocysteine: a meta-analysis. PLoS One. 2016. PMID 26986570. DOI 10.1371/journal.pone.0151653.

    Systematic review and meta-analysis · 22 studies, 520 participants: acute exercise raised homocysteine 1.18 µmol/L; resistance training lowered it 1.53; aerobic training did not; training overall (7 studies, 230 people) no significant change.

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    Gillies NA, Milan AM, Chia PHP, et al.. Responsiveness of one-carbon metabolites to a high-protein diet in older men: results from a 10-wk randomized controlled trial. Nutrition. 2021. PMID 33930787. DOI 10.1016/j.nut.2021.111231.

    Randomized trial · Older men (74 ± 3 years) randomized to the protein RDA (0.8 g/kg, n=14) or double (n=15) for 10 weeks: plasma homocysteine fell with both diets.

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    Dierkes J, Westphal S. Effect of drugs on homocysteine concentrations. Seminars in Vascular Medicine. 2005. PMID 16047265. DOI 10.1055/s-2005-872398.

    Review · Fibrates, niacin, metformin, methotrexate and sulfasalazine, anticonvulsants and levodopa raise homocysteine; N-acetylcysteine lowers it; clinical significance undetermined.

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    Hill DM, Johnson LJ, Burns PJ, Neale AM, Harmening DM, Kenney AC. Effects of temperature on stability of blood homocysteine in collection tubes containing 3-deazaadenosine. Clinical Chemistry. 2002. PMID 12406988.

    Laboratory method study · Plasma must normally be separated within 1 hour of collection; over 72 hours only EDTA tubes with 3-deazaadenosine kept refrigerated were stable.

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    Lindberg M, Borgstrøm Hager H, Brokner M. Week-to-week biological variation of methylmalonic acid and homocysteine in healthy women. Scandinavian Journal of Clinical and Laboratory Investigation. 2019. PMID 30957652. DOI 10.1080/00365513.2019.1590858.

    Laboratory method study · Within-subject variation 7.4 percent, between-subject 24.2 percent, index of individuality 0.31, reference change value -16.2 to +19.4 percent.

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    Zhang SF, Li LZ, Zhang W, et al.. Association between plasma homocysteine levels and subclinical hypothyroidism in adult subjects: a meta-analysis. Hormone and Metabolic Research. 2020. PMID 32629519. DOI 10.1055/a-1199-2633.

    Systematic review and meta-analysis · 12 observational studies, 684 patients: subclinical hypothyroidism carried homocysteine 1.16 µmol/L higher than euthyroid controls; overt hypothyroidism widely documented to raise it.

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