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


  • Lawrence R. Solomon MD

    Corresponding author
    • Section of Palliative Care, Department of Medicine, School of Medicine, Yale University, New Haven, Connecticut
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Address Correspondence to Lawrence R. Solomon, Section of Palliative Care, Department of Medicine, School of Medicine, Yale University, 403 www, 333 Cedar Street, P.O. Box 208021, New Haven, CT 06520. E-mail:



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 (201–300 pg/mL) had higher MMA and lower homocysteine levels when serum folate levels were high (>20 ng/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 (301–600 pg/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 600 pg/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.