Lowering homocysteine with B vitamins doesn't improve cognition

Clinical Question

Does supplementation to reduce homocysteine levels with folate, vitamin B12, and vitamin B6 have a beneficial effect on cognition in older adults?

Bottom Line

There is no evidence from this well-designed study that vitamin supplementation to lower homocysteine levels has any beneficial effect on cognition. Although cognition actually appeared to worsen with the use of vitamins in one of the tests, this may be a spurious finding given the large number of comparisons made by the researchers. (LOE = 1b)


McMahon JA, Green TJ, Skeaff CM, Knight RG, Mann JI, Williams SM. A controlled trial of homocysteine lowering and cognitive performance. N Engl J Med 2006;354:2764-2772.  [PMID:16807413]

Study Design

Randomized controlled trial (double-blinded)








Observational studies have found an association between higher levels of serum homocysteine and Alzheimer's disease and cognitive impairment. However, it is not clear whether this association is causal, or whether lowering homocysteine levels improves cognition. In this trial, community-dwelling healthy adults older than 65 years with a plasma homocysteine level of at least 13 micromoles per liter were recruited. The authors excluded those with impaired renal function, with known cognitive impairment, who were taking folate or B vitamins, or who were taking medications that might interfere with folate metabolism. After an extensive battery of baseline cognitive tests, patients were randomly assigned to receive either 1000 mcg folate, 500 mcg vitamin B12 (cobalamin), and 10 mg vitamin B6 (pyridoxine) daily or matching placebo. The 276 patients underwent cognitive testing after 1 and 2 years; of 138 who began the study in each group, 126 in the placebo group and 127 in the treatment group had data available for analysis. The mean age of participants was 73 years and 44% were female (37% in the vitamin group, 52% in the placebo group; P = .02). The vitamins had the expected effect on homocysteine levels, reducing them approximately 16 to 12 micromoles per liter in the treatment group during the 2-year study. The homocysteine levels did not change in the placebo group. There was no improvement on cognition. In fact, the average score on the Wechsler Paragraph Recall test was worse in the vitamin group, although this difference disappeared after adjustment for sex and education. The vitamin group also did worse on the Reitan Trail Making Test, a difference that persisted after adjustment for sex and education.