Editorials: Homocysteine, B vitamins, and the risk of dementia

INTRODUCTION The "homocysteine hypothesis" of Alzheimer disease was prompted by the observation in a case-control study that patients with Alzheimer disease had significantly higher serum concentrations of homocysteine, a sulfur-containing amino acid previously linked to the risk of cardiovascular disease (CVD), than did control subjects (1). More recently, however, some prospective cohort studies also reported that persons with elevated serum homocysteine concentrations have a significantly greater risk of developing dementia than do persons without elevated homocysteine (2, 3), but the results have not been entirely consistent (4). It is unclear whether low vitamin B-12 or folate status was responsible for the greater risk of dementia or cognitive decline associated with elevated serum homocysteine concentrations in those studies. In this issue of the Journal, Haan et al (5) report significant associations of dementia or cognitive impairment with elevated plasma homocysteine concentrations in a 4.5-y follow-up of a cohort study, conducted after the introduction of mandatory folic acid fortification in the United States, of 1779 Mexican Americans aged 60 y. The study by Haan et al found twice the risk of dementia or cognitive impairment associated with elevated homocysteine (hazard ratio: 2.39; 95% CI: 1.11, 5.16). The report also suggested a U-shaped association of dementia or cognitive impairment with plasma concentrations of vitamin B-12, but no association with red blood cell folate concentrations was found. The results of this study are important for 3 reasons. First, Haan et al provide evidence that the associations of dementia or cognitive impairment with elevated homocysteine may be explained by reduced vitamin B-12 status rather than by reduced folate status. Second, the U-shaped association of dementia and cognitive impairment with vitamin B-12 may be an artifact, but, if real, it may add to previously reported concerns about the safety of mandatory folic acid fortification in older people with vitamin B-12 deficiency. A population survey of older persons carried out in the United States after the introduction of folic acid fortification in North America found that persons with low vitamin B-12 status appeared to have a significantly more rapid deterioration in cognitive function in a setting of very high intakes of folic acid (6). Third, if Haan et al had measured plasma holotranscobalamin (the active fraction of vitamin B-12) or methylmalonic acid (specific metabolite of vitamin B-12), rather than total vitamin B-12, they may have found stronger associations of dementia or cognitive impairment with impaired vitamin B-12 status than those reported in the current study. A recent study of 1000 older persons living in the United Kingdom reported strong, independent associations of cognitive impairment with low serum concentrations of holotranscobalamin and with high concentrations of methylmalonic acid or homocysteine-associations all of which were significantly stronger than those with standard serum measurements of vitamin B-12 (7). ..