Vitamin E and Donepezil for the Treatment of Mild Cognitive Impairment
Ronald C. Petersen, Ph.D., M.D., Ronald G. Thomas, Ph.D., Michael Grundman, M.D., M.P.H., David Bennett, M.D., Rachelle Doody, M.D., Ph.D., Steven Ferris, Ph.D., Douglas Galasko, M.D., Shelia Jin, M.D., M.P.H., Jeffrey Kaye, M.D., Allan Levey, M.D., Ph.D., Eric Pfeiffer, M.D., Mary Sano, Ph.D., Christopher H. van Dyck, M.D., Leon J. Thal, M.D., for the Alzheimer's Disease Cooperative Study Group
Background Mild cognitive impairment is a transitional statebetween the cognitive changes of normal aging and early Alzheimer'sdisease.
Methods In a double-blind study, we evaluated subjects withthe amnestic subtype of mild cognitive impairment. Subjectswere randomly assigned to receive 2000 IU of vitamin E daily,10 mg of donepezil daily, or placebo for three years. The primaryoutcome was clinically possible or probable Alzheimer's disease;secondary outcomes were cognition and function.
Results A total of 769 subjects were enrolled, and possibleor probable Alzheimer's disease developed in 212. The overallrate of progression from mild cognitive impairment to Alzheimer'sdisease was 16 percent per year. As compared with the placebogroup, there were no significant differences in the probabilityof progression to Alzheimer's disease in the vitamin E group(hazard ratio, 1.02; 95 percent confidence interval, 0.74 to1.41; P=0.91) or the donepezil group (hazard ratio, 0.80; 95percent confidence interval, 0.57 to 1.13; P=0.42) during thethree years of treatment. Prespecified analyses of the treatmenteffects at 6-month intervals showed that as compared with theplacebo group, the donepezil group had a reduced likelihoodof progression to Alzheimer's disease during the first 12 monthsof the study (P=0.04), a finding supported by the secondaryoutcome measures. Among carriers of one or more apolipoproteinE 4 alleles, the benefit of donepezil was evident throughoutthe three-year follow-up. There were no significant differencesin the rate of progression to Alzheimer's disease between thevitamin E and placebo groups at any point, either among allpatients or among apolipoprotein E 4 carriers.
Conclusions Vitamin E had no benefit in patients with mild cognitiveimpairment. Although donepezil therapy was associated with alower rate of progression to Alzheimer's disease during thefirst 12 months of treatment, the rate of progression to Alzheimer'sdisease after three years was not lower among patients treatedwith donepezil than among those given placebo.
Source Information
From the Mayo Clinic College of Medicine, Rochester, Minn. (R.C.P.); University of California, San Diego, San Diego (R.G.T., D.G., S.J., L.J.T.); Elan Pharmaceuticals, San Diego (M.G.); Rush University Medical School, Chicago (D.B.); Baylor College of Medicine, Houston (R.D.); New York University, New York (S.F.); Oregon Health and Science University, Portland (J.K.); Emory University, Atlanta (A.L.); University of South Florida, Tampa (E.P.); Mt. Sinai School of Medicine, New York (M.S.); and Yale University, New Haven, Conn. (C.H.D.). This article was published at www.nejm.org on April 13, 2005.
Address reprint requests to Dr. Petersen at the Alzheimer's Disease Research Center, Mayo Clinic College of Medicine, 200 First St. SW, Rochester, MN 55905, or at peter8{at}mayo.edu.
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