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1 From the Jean Mayer US Department of Agriculture Human Nutrition Research Center on Aging at Tufts University, Boston, MA.
2 Presented at the symposium "Is It Time for Mandatory Vitamin B-12 Fortification in Flour?" held at Experimental Biology 2008, San Diego, CA, 8 April 2008. 3 Any opinions, findings, conclusions, or recommendations expressed in this publication are those of the authors and do not necessarily reflect the view of the US Department of Agriculture. 4 Supported by the USDA (agreements 1950-51520-008-00D and 58-1950-9-001 and grant 2006-35200-17198) and by the NIH (R03 AG021536-01). 5 Reprints not available. Address correspondence to J Selhub, Jean Mayer USDA Human Nutrition Research Center on Aging, Tufts University, 711 Washington Street, 8th Floor, Boston, MA 02111. E-mail jacob.selhub{at}tufts.edu.
ABSTRACT
Previous reports on pernicious anemia treatment suggested that high folic acid intake adversely influences the natural history of vitamin B-12 deficiency, which affects many elderly individuals. However, experimental investigation of this hypothesis is unethical, and the few existing observational data are inconclusive. With the use of data from the 1999–2002 National Health and Nutrition Examination Survey (NHANES), we evaluated the interaction between high serum folate and low vitamin B-12 status [ie, plasma vitamin B-12 < 148 pmol/L or methylmalonic acid (MMA) > 210 nmol/L] with respect to anemia and cognitive impairment. With subjects having both plasma folate 
59 nmol/L and normal vitamin B-12 status as the referent category, odds ratios for the prevalence of anemia compared with normal hemoglobin concentration and impaired compared with unimpaired cognitive function were 2.1 (95% CI: 1.1, 3.7) and 1.7 (95% CI: 1.01, 2.9), respectively, for those with low vitamin B-12 status but normal serum folate and 4.9 (95% CI: 2.3, 10.6) and 5.0 (95% CI: 2.7, 9.5), respectively, for those with low vitamin B-12 status and plasma folate >59 nmol/L. Among subjects with low vitamin B-12 status, mean circulating vitamin B-12 was 228 pmol/L for the normal-folate subgroup and 354 pmol/L for the high-folate subgroup. We subsequently showed increases in circulating homocysteine and MMA concentrations with increasing serum folate among NHANES participants with serum vitamin B-12 < 148 pmol/L, whereas the opposite trends occurred among subjects with serum vitamin B-12 
148 pmol/L. These interactions, which were not seen in NHANES III before fortification, imply that, in vitamin B-12 deficiency, high folate status is associated with impaired activity of the 2 vitamin B-12–dependent enzymes, methionine synthase and MMA–coenzyme A mutase.
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