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Biochemical indicators of vitamin B₁₂ and folate insufficiency and cognitive decline

From the Department of Clinical Nutrition (C.C.T.), Rush Institute for Healthy Aging (Y.T., D.A.E., M.C.M.), Department of Internal Medicine (M.C.M.), Department of Preventive Medicine (D.A.E., M.C.M.), Rush Alzheimer's Disease Center (D.A.E.), Rush University Medical Center, Chicago, IL is currently affiliated with the Program for Appropriate Technology in Health (PATH), Seattle, WA.

Address correspondence to Dr. Christine C. Tangney, Department of Clinical Nutrition 425 TOB, 1700 West Van Buren St., Chicago, IL 60612 ctangney{at}rush.edu

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.

CHAP = Chicago Health and Aging Project; CI = confidence interval; FFQ = food frequency questionnaire; NHANES = National Health and Nutrition Examination Survey; OR = odds ratio.

Supplemental data at www.neurology.org

Supported by grants (AG11101 and AG13170) from the National Institute on Aging.

Disclosure: The authors report no disclosures.

Received July 11, 2008. Accepted in final form October 15, 2008.