Background: In some prospective studies, associations of serum vitamin B₁₂ and homocysteine concentrations with cognitive decline have been reported but few have examined the role of methylmalonic acid, a more specific marker of vitamin B₁₂ deficiency than homocysteine.

Objective: The aim of the study was to determine whether serum concentrations of vitamin B₁₂ or selected metabolites are related to cognitive decline.

Methods: A total of 516 subjects were selected in a stratified random sampling design from among Chicago Health and Aging Project participants for clinical evaluation. We used linear mixed models to examine the association of blood markers of vitamin B₁₂ status to change in cognitive scores over 6 years. Cognitive function was assessed every 3 years and measured as the sum of standardized scores on four tests.

Results: Probable vitamin B₁₂ deficiency was observed in 14.2% of the sample. Elevated serum concentrations of homocysteine were present in 19.2% of subjects, and of methylmalonic acid, in 36.4%. Higher serum methylmalonic acid concentrations were predictive of faster rates of cognitive decline (β = –0.00016, SE = 0.0001, p = 0.004) and higher serum vitamin B₁₂ concentrations were associated with slower rates of cognitive decline (β = +0.00013, SE < 0.0001, p = 0.005) in multivariable adjusted mixed models. Serum concentrations of homocysteine had no relationship to cognitive decline.

Conclusions: Serum methylmalonic acid and vitamin B₁₂ concentrations may be the more important risk factors for cognitive decline when compared to serum homocysteine concentrations, particularly in older populations exposed to food fortification and possible supplements containing folic acid.