Low folate status has been associated with cognitive decline. We investigated the association of folate status and the 5,10-methylenetetrahydrofolate reductase (MTHFR) 677C-->T polymorphism with performance on a battery of neuropsychological tests. Furthermore, we investigated whether the association of folate with cognitive performance was mediated by plasma homocysteine or risk of vascular disease. We used cross-sectional data from 818 individuals aged 50-70 years old. Low concentrations of erythrocyte folate but not serum folate were associated with poor performance on complex speed and memory tasks, independent of educational level and conventional risk factors of vascular disease. These associations were not mediated by homocysteine concentrations or carotid intima-media thickness. Subjects with the MTHFR 677TT genotype tended to perform better on cognitive tasks than CC/CT subjects, although this was significant for sensorimotor speed only (differences in Z-scores between MTHFR 677TT homozygotes and CC homozygotes -0.15, 95% CI: -0.30 to 0.00). Low concentrations of erythrocyte folate are associated with decreased cognitive performance, possibly through a homocysteine-independent mechanism such as DNA infidelity and mitochondrial decay.
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