Homocysteine

Homocysteine is an amino acid that builds up in the blood when vitamins B6, folate or B12 run low. High levels go with heart disease, stroke and brain shrinkage, but lowering them with B vitamins did not prevent heart attacks or deaths in large randomised trials. It behaves more like a marker of risk than a lever. The one real payoff is a small cut in stroke, seen mainly where food is not fortified with folic acid.

Treat a raised homocysteine as a reason to look for and correct low B12, folate or B6. Don't take B vitamins to push an already-normal value lower: no trial shows that improves health.

What it is

Homocysteine is a by-product of the body's handling of methionine, an amino acid from protein. At high levels it is toxic to neurons and blood vessels, and it is an independent risk factor for brain shrinkage and cognitive decline. Vitamins B6, B9 (folate) and B12 are the cofactors that clear it from the blood, so a high value can be a sign that one of them is short. Along with methylmalonic acid, it rises before blood B12 falls, which makes it a useful functional readout of B-vitamin status.

Lowering it did not prevent heart attacks

Because high homocysteine tracks with vascular disease, large trials set out to lower it with B vitamins. They succeeded in lowering it, and did not reduce heart attacks or cardiovascular death. In one trial of 5,522 people, homocysteine fell but the main cardiovascular outcome was unchanged.^[1] Trials in people after a heart attack, and in people who had had a stroke, were likewise null.

A 2017 Cochrane review of 15 trials, about 71,000 adults, found no effect on heart attacks or death, but a small reduction in stroke: 4.3% of people on B vitamins had a stroke against 5.1% on the comparison, about 10% lower in relative terms.^[2] Trials aimed at acutely reversing established arterial stiffness have been mixed at best.^[3]

The stroke exception: where food isn't fortified

The clearest positive trial randomised 20,702 adults with high blood pressure in China, a population with low folate and no food fortification, to a blood-pressure drug (enalapril) with or without folic acid. Over 4.5 years, the folic-acid group had 21% fewer first strokes (2.7% against 3.4%), with the benefit concentrated in those with the lowest folate.^[4]

Pooled across 21 trials, about 116,000 people, folic acid lowered stroke risk by about 10%. The benefit was seen in regions without grain fortification or with only partial fortification (about 17% lower risk); in regions with full fortification there was no reduction.^[5] That is a deficiency-correction effect, not a benefit for people who already get enough folate, which is why the null Western trials and the positive Chinese one are consistent.

Diet points the same way only weakly. In two large US cohorts, people with higher intake and blood levels of several B vitamins had a 10–20% lower stroke risk, but that is an observational association, not evidence that pills lower risk.^[6]

The brain

The strongest brain result comes from one trial in older adults with mild cognitive impairment, where B vitamins slowed brain shrinkage most in people whose homocysteine was above 13 µmol/L. It measured brain scans, not thinking; see VITACOG trial.

Testing: a readout, not a target

Homocysteine is worth measuring as a readout of B6, folate and B12 status, alongside the B12 tests in Midlife labs. A raised value is a reason to find and correct the shortfall. There is no trial-backed target: the trials lowered homocysteine without reducing heart attacks or death, and the stroke and brain benefits depended on people's starting status, not on reaching a particular number.

What to do

If your homocysteine is high, look for the cause: check B12 (with methylmalonic acid or holotranscobalamin, not blood B12 alone), folate and B6, and correct what is low.
Don't chase a lower number once it is normal.
Don't take B vitamins to prevent heart attacks. They don't.