Homocysteine and Stroke and Dementia

Homocysteine and its relevance to arterial disease. Peter Wright

As a Neurologist with a long history of interest in Homocysteine and arterial diseases I have watched closely the accumulating evidence around this topic over the last 20 years. First the strong epidemiologic evidence suggesting that the higher the Homocysteine the greater the risk of stroke heart attack and dementia, then the evidence that it is fairly easy, safe, and cheap to lower Homocysteine with triple B-vitamins at mega-doses (vitamin B12, Folate and Pyridoxine), and most recently a series of large randomised controlled trials (RCT) from which it was generally concluded that lowering Homocysteine did not work for any of these diseases.

Looking closely at the stroke matter has helped me keep a candle burning for this treatment, as the VITATOPS study, lead author Graham Hankey, Neurologist in Perth, Australia, identified a strong trend to a benefit in reducing stroke+heart attack+ vascular death (the main endpoint of this international multicentre RCT). There was a 95% probability that it was effective (p=0.05 for the null hypothesis), and therefore by standard medical terminology it was a failed trial.

Within VITATOPS it was pre-planned that the subtypes of strokes were assessed as well. IN this it appeared that the two small vessel stroke types (intracerebral haemorrhage and lacunar infarcts) were highly benefitted. From the VITATOPS study; Those who benefit most in % reduction of the endpoint (ie stroke or heart attack or vascular cause of death) after an average of 3.4yrs followup were TIAs (14-->10%), milder strokes (more often small vessel stroke types) (22-->18%), small artery strokes (17-->14%), intracerebral haemorrhage (ie another small vessel stroke type) (18-->12%), and those with normal renal function (renal failure is often associated with large artery disease) (18-->15%).

Metanalysis of all stroke-related data (2010) showed that it is likely that this treatment benefits small vessel injury in the brain but not large artery or cardioembolic proceses. B-vitamins may reduce stroke in high risk vascular patients by 8% (p=0.05) but didn't reduce MI, nor combined (Stroke MI or vascular death) endpoints.

Since then we have seen


That in China, where folate levels are generally low, adding folate to the blood pressure (BP) treatment as a primary prevention of stroke, reduced stroke by 21% over just treating BP. The folate levels increased from 8 to 20. There was also at least a hint that the worst genetic makeup for folate/homocysteine was associated with both 1) lower folates at baseline, and 2) only the very highest folate level population managed to get benefit suggesting a resistance to showing benefits in such patients at lower doses of Folate 0.8mg/day. Those with a starting Folate pre-treatment in the top 1/5th of the population showed a 76% reduction in stroke once treated. The other 4/5ths with this gene makeup did not benefit.

JAMA. 2015;313(13):1325-1335


That in and MRI brain study, after adjusting for age, sex, follow-up time, and vascular risk factors, Homocysteinemia was associated with a 2.4 times increased risk of white matter brain lesion progression, and lower kidney function at follow-up. There was a clear trend in the data towards increased new lacunar infarcts being 1.8 times more common as well. This suggests that there is a role for homocysteine in the development of a generalized small-vessel disease in which both brain and kidney

Neurology 2014;82:777–783


Hyperhomocysteinemia is associated with small vessel diseases (SVD) of the brain and large vessel diseases (LVD) of cerebral arteries. The bad gene (MTHFR C677T) certainly was associated with higher Homocysteine (presumed through resistance to normal folate levels) but was not independently related to SVD and LVD.

Neurology 2014;83:695–701


The risk of Alzheimers disease may be increased by 16% for every 1mol/litre of plasma Homocysteine at baseline and reduced by 2% for every extra bit of VitaminB12 (using a novel and more accurate B12 marker than usual). The B12 status only partially accounted for the increased risk of Homocysteine. However addition of folate into the model did not change any of the results.

Neurology 2010;75:1408–1414

The main factors to reduce Homocysteine are B-vitamins. Vitamin B12 is very difficult for some patients to absorb from the stomach, so treatment either under the tongue, or by injection may be needed, and blood levels should rise to the upper end of the normal range. Treatments should not generally be used if kidney function has dropped below Creatinine Clearance of 50.

Folate 5mg tablet every 3 days (2mg daily was the researched dose) (prescribed or OTC)

Pyridoxine (B6) 100mg every 3 days (25-50mg/d = researched dose) (prescribed or OTC)

Vitamin B12 at 1000mcg oral or under tongue every 3 days. (500-1000mcg daily was researched). Find a dose which pushes their B12 level to upper range and corrects homocysteine. Oral formulations Methylcobalamin are not funded (obtain from "health food stores"). If B12 does not climb into high-normal range, lowering homocysteine, patients need…

  • Vitamin B12 injections by the GP
  • Gastric parietal cell antibodies for atrophic gastritis
  • Intrinsic factor antibodies
  • Remove proton pump inhibitors
  • Helicobacter serology (possible cause of impaired B12 absorption, treatable)
  • Upper GI endoscopy, especially if no reversible factor found or GPC Abs +ve
Food sources of the B-vitamins:

  • B12: Fish, poultry, meat, fortified cereals, yeast extracts (brewers' yeast, Marmite). Other good sources include: asparagus, broccoli, spinach, bananas, potatoes, dried apricots, dates and figs, milk, eggs, cheese, yoghurt, nuts and pulses, fish, brown rice, wheat germ, wholegrain cereals. B6 (pyridoxine) Fortified cereals, fortified soy products, organ meats, Vitamin B6 is found in most foods, so deficiency is rare. Sources also include avocado, herring, salmon, sunflower seeds and walnuts, Folate: Dark, leafy vegetables; enriched and whole grain breads; fortified cereals. Liver contains the greatest amount of folic acid, with lower levels found in beef, lamb and pork and a range of green vegetables and citrus fruits. Other sources of folate are dried beans, fresh orange juice, tomatoes, wheat germ (wholemeal bread and cereal) and wholegrain products (pasta and brown rice).

Please note: If Homocysteine does not respond to the above supplementation with the B-vitamins, it may indicate renal failure with accumulation, or else a deficit in Riboflavin (vitamin B2) and zinc, and only the latter may be assisted by supplementation of both +/- Trimethylglycine, and N-acetyl cysteine. This entire combination is unproven to help clinically, but convenient and not expensive.


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