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Am Fam Physician. 2011;84(3):320

Background: Observational studies have consistently linked high plasma homocysteine levels with cognitive impairment. Homocysteine is a potentially modifiable risk factor because levels can be lowered by about 20 percent with vitamin B supplementation. However, most randomized trials have not been able to demonstrate that lowering homocysteine levels improves cognitive function or dementia. Ford and colleagues studied the long-term effectiveness of homocysteine-lowering treatment to decrease cognitive decline in older men.

The Study: The authors randomized 299 men 75 years or older with hypertension to receive daily placebo or vitamin B supplementation at doses known to reduce homocysteine levels (25 mg of B6, 2 mg of B9 [folic acid], and 400 mcg of B12). The primary outcome was assessment of cognitive function, which was monitored over two years using the cognitive subscale of the Alzheimer's Disease Assessment Scale. The study was powered to detect a two-point difference from baseline, which is similar to the demonstrated effect of donepezil (Aricept) in patients with Alzheimer disease. Secondary outcomes were the rates of cognitive impairment and dementia eight years after study initiation. Exclusion criteria included a baseline Mini-Mental State Examination score of 24 or less, a Beck Depression Inventory score of 18 or more, current use of vitamin B supplements, and living in a residential care facility.

Results: The treatment group experienced a mean decrease in plasma homocysteine levels of 22.5 percent, compared with a 10.7 percent increase in the placebo group. However, no differences in cognition were noted between groups after two years of vitamin B supplementation, even after adjusting for age, harmful alcohol use, education, or depression scores (P = .705). Among the 73 patients who were reevaluated eight years after study initiation, the vitamin B group had a lower risk of cognitive impairment (odds ratio = 0.72) and of dementia (hazard ratio = 0.72), but neither finding was statistically significant.

Conclusion: The authors conclude that two years of supplementation with folic acid and vitamins B6 and B12 does not change the rate of cognitive decline in older men with hypertension. In addition, it did not reduce mortality rates in this study or the incidence of dementia in the intervention group. The authors suggest that an elevated plasma homocysteine level is not a risk factor for cognitive decline, but rather a marker reflecting an underlying common process for dementia and cognitive deterioration.

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