To the Editor: The randomized controlled trial by Dr Aisen and colleagues1 provided evidence that treatment with high-dose B vitamin supplements for 18 months does not slow cognitive decline in individuals with mild to moderate Alzheimer disease (AD). The rationale behind the study was that hyperhomocysteinemia (levels of homocysteine >15 μmol/L) is associated with a higher risk of dementia and AD2 - 3 and that homocysteine levels can be reduced by use of high-dose B vitamins and folate. Thus, the study was designed to determine in patients with AD whether a regimen of high-dose B vitamins and folate would slow their cognitive decline by reducing homocysteine levels. However, despite a 20% to 25% reduction in homocysteine level and an increase in B vitamin and folate levels associated with the active treatment, the trial found no effect.
While the reasons for these findings remain unclear, there are 2 important considerations that need to be taken into account. First, homocysteine is an important amino acid whose normal levels influence the cellular levels of S-adenosylmethionine and S-adenosylhomocysteine, which in turn regulate the activity of transferases involved in posttranslational modification of protein.4 For this reason, there could be a risk of harm associated with lowering homocysteine levels if they are not elevated.
Second, most of the data in the literature agree on one concept: homocysteine is not per se a risk factor for dementia, but it becomes one when its levels are above the normal range (>15 μmol/L). Since in the study by Aisen et al the mean (SD) homocysteine level was 9.2 (3.4) μmol/L, the overall negative results regarding the effect of lowering these levels and cognitive decline are not surprising. In this respect, it would be interesting to have more details on the subgroup of individuals in the highest homocysteine quartile who also did not benefit from the therapy. In particular, it would be important to know how many of these participants qualified for a diagnosis of hyperhomocysteinemia and, of these, how many were in the active treatment group.
The important message of this study is that if homocysteine levels are in the normal range, there is no indication to reduce them. However, this is probably a more general concept that applies not only to homocysteine but to any biologic measure.
Financial Disclosure: None reported.
Country-Specific Mortality and Growth Failure in Infancy and Yound Children and Association With Material Stature
Use interactive graphics and maps to view and sort country-specific infant and early dhildhood mortality and growth failure data and their association with maternal
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