Submitted to: American Journal of Clinical Nutrition
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 3/3/2010
Publication Date: 3/31/2010
Citation: Morris, M.S., Jacques, P.F., Rosenberg, I.H., Selhub, J. 2010. Circulating unmetabolized folic acid and 5-methyltetrahydrofolate in relation to anemia, macrocytosis, and cognitive test performance among American seniors. American Journal of Clinical Nutrition. 91(6):1733-1744. Interpretive Summary: The B-group vitamin folate is important for the development and functioning of the central nervous system. Many studies have suggested that higher folate status is beneficial for cognitive performance in older people. Furthermore, some birth defects affecting the nervous system, like spina bifida, can be prevented if pregnant women take folic acid supplements. However, there has been some skepticism about the elderly, because many older people are vitamin B-12 deficient, and folic acid has long been considered harmful to people whose vitamin B-12 status is low. Precisely what should be expected if people with low vitamin B-12 status consume large amounts of folic acid is unclear. A previous study by our group linked high blood levels of total folate to poorer cognitive test performance and more cases of anemia among seniors with low vitamin B-12 status. In the current study, we analyzed blood samples obtained from senior participants in the National Health and Nutrition Examination Survey for folic acid as well as methyl-folate, the form of folate found in the body when no folic acid is consumed. We then determined whether each folate form was related to three consequences of vitamin B-12 deficiency; namely, macrocytosis (i.e., enlarged red blood cells), anemia, and poor cognitive test performance. We conducted these analyses in two subgroups of subjects. One subgroup had normal vitamin B-12 status, and the other had low vitamin B-12 status. Among the seniors with low vitamin B-12 status, we found that both folic acid and methyl folate were associated with less macrocytosis. Since macrocytosis is an important diagnostic feature for vitamin B-12 deficiency, this result supported the idea that the diagnosis of vitamin B-12 deficiency might be delayed if folate intake were high. Also among seniors with low vitamin B-12 status, we found that folic acid was related to poorer cognitive test performance, but that methyl-folate was not. Folic acid was not related to cognitive test performance in the subgroup with normal vitamin B-12 status, but in that group, a high methyl-folate level was associated with better cognitive test performance. These findings raise the hypothesis that consuming the synthetic form of folate might make the cognitive consequences of vitamin B-12 deficiency worse, but that high folate intake can benefit cognition in the elderly, as long a vitamin B-12 status is not low. Folic acid was related to a higher prevalence of anemia regardless of vitamin B-12 status. However, upon further investigation, we found that association was restricted to alcohol users. However, this finding requires corroboration by other studies. Finally, a higher methyl-folate level was associated with more cases of anemia only among the seniors with low vitamin B-12 status. The results were consistent with some fears for the elderly about high folate intakes. Specifically, the results tend to support the idea that high folate status might remove an important diagnostic feature of vitamin B-12 deficiency at the same time that it makes some consequences of vitamin B-12 deficiency worse. The results were also consistent with the idea that high folate status might benefit cognitive function in the absence of vitamin B-12 deficiency. Finally, the results raise the concern that having the synthetic form of folic acid in the body might result in harm to people with conditions or exposures other than vitamin B-12 deficiency.
Technical Abstract: Folate deficiency has serious consequences for the fetus. Folic acid fortification of food addresses this problem. However, clinical consequences of vitamin B-12 deficiency may be worsened by high folic acid intakes, perhaps as a direct result of unmetabolized folic acid, which does not occur naturally in body tissues. We attempted to attribute associations we previously found between higher folate status and anemia and cognitive test performance to circulating unmetabolized folic acid or 5-methyltetrahydrofolate (5MeTHF). The subjects (n=1858) were senior participants in the US National Health and Nutrition Examination Survey (1999-2002) who had normal renal function and reported no history of stroke, recent anemia therapy, or diseases of the liver, thyroid, or coronary arteries. Subjects had undergone phlebotomy, a complete blood count, and cognitive and dietary assessment. Circulating unmetabolized folic acid was detected in about 1/3 of the subjects and was related to increased odds of anemia in alcohol users. In seniors with serum vitamin B-12 <148 pmol/L or plasma methylmalonic acid >/= 210 nmol/L, the presence versus absence of detectable circulating unmetabolized folic acid was related to lower cognitive test scores and lower mean cell volume. In the same subgroup, higher serum 5MeTHF was related to increased odds of anemia and marginally significantly decreased odds of macrocytosis. In seniors with normal vitamin B-12 status, higher serum 5MeTHF was related to higher cognitive test scores. Results of this epidemiologic study were somewhat consistent with reports on the folic acid treatment of pernicious anemia patients, but some findings were unexpected.