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

Abstract

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