Assessment of the Dose–Response Relationship Between Folate Exposure and Cognitive Impairment: Synthesizing Data from Documented Studies

Abstract

The dose–response relationship between folate levels and cognitive impairment among individuals with vitamin B12 deficiency is an essential component of a risk‐benefit analysis approach to regulatory and policy recommendations regarding folic acid fortification. Epidemiological studies provide data that are potentially useful for addressing this research question, but the lack of analysis and reporting of data in a manner suitable for dose–response purposes hinders the application of the traditional evidence synthesis process. This study aimed to estimate a quantitative dose–response relationship between folate exposure and the risk of cognitive impairment among older adults with vitamin B12 deficiency using “probabilistic meta‐analysis,” a novel approach for synthesizing data from observational studies. Second‐order multistage regression was identified as the best‐fit model for the association between the probability of cognitive impairment and serum folate levels based on data generated by randomly sampling probabilistic distributions with parameters estimated based on summarized information reported in relevant publications. The findings indicate a “J‐shape” effect of serum folate levels on the occurrence of cognitive impairment. In particular, an excessive level of folate exposure is predicted to be associated with a higher risk of cognitive impairment, albeit with greater uncertainty than the association between low folate exposure and cognitive impairment. This study directly contributes to the development of a practical solution to synthesize observational evidence for dose–response assessment purposes, which will help strengthen future nutritional risk assessments for the purpose of informing decisions on nutrient fortification in food.

Vitamin B12 and Folate Status in Cognitively Healthy Older Adults and Associations with Cognitive Performance

“…We found a trend for better memory performance with higher folate, but worse attention with elevated folate in both men and women. These results are similar to the previously reported finding of a J-shaped dose-response relationship between folate exposure and risk of cognitive impairment for those with vitamin B12 deficiency (26). This may reflect the fact that high folate levels can mask B12 deficiency due to their shared metabolic reactions.…”

Intended and Unintended Benefits of Folic Acid Fortification—A Narrative Review

“…Similar results have been found in another meta-analysis, which indicated a dose-response relationship between folic acid and the risk of cognitive impairment in older adults with vitamin B-12 deficiency. The study suggested a “J shape” relationship between serum folate concentration and cognitive impairment [ 48 ]. The suggested mechanism behind this relationship is that elevated folate might mask vitamin B-12 deficiency.…”

“…The suggested mechanism behind this relationship is that elevated folate might mask vitamin B-12 deficiency. Epidemiological studies have shown that individuals with low serum vitamin B-12 in combination with high folate present a higher risk of cognitive impairment compared to those with normal serum folate, especially in the elderly population due to lower absorption of vitamin B-12 [ 29 , 48 ]. It has been estimated that folic acid fortification might be associated with an increase in the risk of cognitive impairment in up to 4% of older adults in the US [ 29 ].…”