High folic acid or folate combined with low vitamin B-12 status: potential but inconsistent association with cognitive function in a nationally representative cross-sectional sample of US older adults participating in the NHANES

Am J Clin Nutr. 2020 Dec 10;112(6):1547-1557. doi: 10.1093/ajcn/nqaa239.


Background: Potential safety concerns relative to impaired cognitive function may exist when high folic acid exposures are combined with low vitamin B-12 status.

Objectives: We aimed to examine the relation of the coexistence of high folate and low vitamin B-12 status with cognitive function, utilizing various definitions of "high" folate status.

Methods: Cross-sectional data from older adults (≥60 y; n = 2420) from the 2011-2014 NHANES were analyzed. High folate status was defined as unmetabolized serum folic acid (UMFA) > 1 nmol/L or serum total folate > 74.1 nmol/L, and low vitamin B-12 status as methylmalonic acid > 271 nmol/L or serum vitamin B-12 < 150 pmol/L. Logistic regression models estimated ORs of scoring low on 1 of 4 cognitive tests: the Digit Symbol Substitution Test (DSST), the Consortium to Establish a Registry for Alzheimer's Disease Delayed Recall (CERAD-DR) and Word Learning tests, and the Animal Fluency test (AF).

Results: A significant interaction was observed relative to scoring low on the DSST (<34; UMFA; P-interaction = 0.0071) and AF (serum folate; P-interaction = 0.0078) for low vitamin B-12 and high folate status. Among those with low vitamin B-12, high UMFA or high serum total folate was associated with higher risk of scoring low on the DSST (OR: 2.16; 95% CI: 1.05, 4.47) and the AF (OR: 1.93; 95% CI: 1.08, 3.45). Among those with "normal" vitamin B-12, higher UMFA or serum total folate was protective on the CERAD-DR. In noninteraction models, when high folate and normal vitamin B-12 status was the reference group, low vitamin B-12 combined with high UMFA was associated with greater risk based on the DSST (<34, OR: 2.87; 95% CI: 1.85, 4.45; <40, OR: 2.22; 95% CI: 1.31, 3.75) and AF (OR: 1.97; 95% CI: 1.30, 2.97); but low vitamin B-12 and lower UMFA (OR: 1.69; 95% CI: 1.16, 2.47) was also significantly associated for DSST < 40 risk.

Conclusions: Low vitamin B-12 was associated with cognitive impairment both independently and in an interactive manner with high folate for certain cognitive performance tests among older adults.

Keywords: NHANES; cognitive function; folate; interaction; older adults; unmetabolized folic acid; vitamin B-12.

MeSH terms

  • Aged
  • Cognition*
  • Cross-Sectional Studies
  • Dose-Response Relationship, Drug
  • Female
  • Folic Acid / administration & dosage*
  • Humans
  • Male
  • Middle Aged
  • Nutrition Surveys
  • United States
  • Vitamin B 12
  • Vitamin B 12 Deficiency*


  • Folic Acid
  • Vitamin B 12