Advanced Age as a Risk Factor for Folate‐Associated Functional Cobalamin Deficiency

Abstract

To determine whether high serum folate levels contribute to metabolite changes in elderly subjects with normal cobalamin levels. Case series. Outpatient clinic at a university-based staff model health maintenance organization. Two hundred thirty-three ambulatory individuals without diabetes mellitus with normal renal function and normal cobalamin levels evaluated for cobalamin deficiency. Cobalamin, serum folate, methylmalonic acid (MMA), and homocysteine. Older individuals (≥60) with low-normal cobalamin levels (201-300pg/mL) had higher MMA and lower homocysteine levels when serum folate levels were high (>20ng/mL) than when serum folate levels were normal (P<.02), but serum folate levels within the normal range were not a determinant of either metabolite. In younger subjects with low-normal cobalamin levels, high serum folate levels were not associated with significant differences in either metabolite. At mid-normal cobalamin levels (301-600pg/mL), high serum folate levels were associated with lower homocysteine levels in older adults (P<.001) but not with differences in MMA in either age group. Cobalamin therapy decreased or normalized MMA and homocysteine in 89% or more of participants even at pretherapy cobalamin levels greater than 600pg/mL. High serum folate levels are associated with higher MMA levels when cobalamin levels are low-normal, and this effect is age dependent, not progressive within the normal serum folate range (suggesting a threshold effect), and reversed by cobalamin therapy. Because MMA may be neurotoxic, these findings suggest caution in the use of folic acid supplements in elderly adults.