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A Randomized Controlled Trial

Paul S. Aisen, MD; Lon S. Schneider, MD, MS; Mary Sano, PhD; Ramon Diaz-Arrastia, MD, PhD; Christopher H. van Dyck, MD; Myron F. Weiner, MD; Teodoro Bottiglieri, PhD; Shelia Jin, MD, MPH; Karen T. Stokes, BA, BS; Ronald G. Thomas, PhD; Leon J. Thal, MD; for the Alzheimer Disease Cooperative Study

JAMA. 2008;300(15):1774-1783.

Context  Blood levels of homocysteine may be increased in Alzheimer disease (AD) and hyperhomocysteinemia may contribute to disease pathophysiology by vascular and direct neurotoxic mechanisms. Even in the absence of vitamin deficiency, homocysteine levels can be reduced by administration of high-dose supplements of folic acid and vitamins B₆ and B₁₂. Prior studies of B vitamins to reduce homocysteine in AD have not had sufficient size or duration to assess their effect on cognitive decline.

Objective  To determine the efficacy and safety of B vitamin supplementation in the treatment of AD.

Design, Setting, and Patients  A multicenter, randomized, double-blind controlled clinical trial of high-dose folate, vitamin B₆, and vitamin B₁₂ supplementation in 409 (of 601 screened) individuals with mild to moderate AD (Mini-Mental State Examination scores between 14 and 26, inclusive) and normal folic acid, vitamin B₁₂, and homocysteine levels. The study was conducted between February 20, 2003, and December 15, 2006, at clinical research sites of the Alzheimer Disease Cooperative Study located throughout the United States.

Intervention  Participants were randomly assigned to 2 groups of unequal size to increase enrollment (60% treated with high-dose supplements [5 mg/d of folate, 25 mg/d of vitamin B₆, 1 mg/d of vitamin B₁₂] and 40% treated with identical placebo); duration of treatment was 18 months.

Main Outcome Measure  Change in the cognitive subscale of the Alzheimer Disease Assessment Scale (ADAS-cog).

Results  A total of 340 participants (202 in active treatment group and 138 in placebo group) completed the trial while taking study medication. Although the vitamin supplement regimen was effective in reducing homocysteine levels (mean [SD], –2.42 [3.35] in active treatment group vs –0.86 [2.59] in placebo group; P < .001), it had no beneficial effect on the primary cognitive measure, rate of change in ADAS-cog score during 18 months (0.372 points per month for placebo group vs 0.401 points per month for active treatment group, P = .52; 95% confidence interval of rate difference, –0.06 to 0.12; based on the intention-to-treat generalized estimating equations model), or on any secondary measures. A higher quantity of adverse events involving depression was observed in the group treated with vitamin supplements.

Conclusion  This regimen of high-dose B vitamin supplements does not slow cognitive decline in individuals with mild to moderate AD.

Trial Registration  clinicaltrials.gov Identifier: NCT00056225

Author Affiliations: Departments of Neurosciences (Drs Aisen, Thomas, and Thal, and Ms Stokes) and Family and Preventive Medicine (Drs Jin, Thomas, and Thal), University of California, San Diego; Keck School of Medicine, University of Southern California, Los Angeles (Dr Schneider); School of Medicine, Mount Sinai, Bronx, New York (Dr Sano); Department of Neurology, University of Texas Southwestern Medical Center, Dallas (Drs Diaz-Arrastia and Weiner); Department of Psychiatry, Yale University, New Haven, Connecticut (Dr van Dyck); and Institute of Metabolic Disease, Baylor University Medical Center, Dallas, Texas (Dr Bottiglieri).
Deceased.

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