B Vitamin Supplements and Alzheimer Disease

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The randomized trial by Dr Aisen and colleagues1 evaluating the use of high-dose B vitamins in patients with AD suggested that there is no cognitive benefit from such a treatment approach. Although this study provides some assistance in selection of potential combination therapies, several questions arise.

Prior studies have shown a relationship between low cerebrospinal fluid folate levels in patients with AD compared with normal controls. Low levels of L-methyl folate and methyl B12 have correlated with increased risk of cognitive impairment. It is possible that the patients in the study by Aisen et al were too advanced beyond a potential time window for benefit from B vitamin intervention to see a beneficial result.

The article suggests studying efficacy for mild cognitive impairment. Alternatively, consider the deleterious effect of high-dose oral folate (5 mg daily) on cerebrospinal fluid folate levels. At doses of 400 µg and above, there is unmetabolized folic acid in the serum. The unmetabolized folic acid does not cross the blood-brain barrier and has been shown to bind to the folate binding receptors and compromise the passage of bioactive L-methyl folate across the blood-brain barrier, especially in the group of patients possessing the methylene tetrahydrofolate reductase (MTHFR) polymorphism. If so, this could explain the finding of increased depression in the active treatment group, as the pathway to S-adenosylmethionine may have been adversely affected by such a process.

Since patients with low central nervous system folate and B12 levels (which act as cofactors in the methylation of homocysteine) do not adequately synthesize several neurotransmitters, it is possible that the active treatment group was ultimately biochemically similar to the controls. I wonder how these patients might have fared if L-methyl folate had been provided instead of folate, as the biologically active form is able to cross the blood-brain barrier and can lower homocysteine levels more effectively than folic acid. ...JAMA. 2009 Mar 11;301(10):1021

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