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Previous Volume 352:2379-2388 June 9, 2005 Number 23 Next

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ABSTRACT

Background Mild cognitive impairment is a transitional state between the cognitive changes of normal aging and early Alzheimer's disease.

Methods In a double-blind study, we evaluated subjects with the amnestic subtype of mild cognitive impairment. Subjects were randomly assigned to receive 2000 IU of vitamin E daily, 10 mg of donepezil daily, or placebo for three years. The primary outcome was clinically possible or probable Alzheimer's disease; secondary outcomes were cognition and function.

Results A total of 769 subjects were enrolled, and possible or probable Alzheimer's disease developed in 212. The overall rate of progression from mild cognitive impairment to Alzheimer's disease was 16 percent per year. As compared with the placebo group, there were no significant differences in the probability of progression to Alzheimer's disease in the vitamin E group (hazard ratio, 1.02; 95 percent confidence interval, 0.74 to 1.41; P=0.91) or the donepezil group (hazard ratio, 0.80; 95 percent confidence interval, 0.57 to 1.13; P=0.42) during the three years of treatment. Prespecified analyses of the treatment effects at 6-month intervals showed that as compared with the placebo group, the donepezil group had a reduced likelihood of progression to Alzheimer's disease during the first 12 months of the study (P=0.04), a finding supported by the secondary outcome measures. Among carriers of one or more apolipoprotein E 4 alleles, the benefit of donepezil was evident throughout the three-year follow-up. There were no significant differences in the rate of progression to Alzheimer's disease between the vitamin E and placebo groups at any point, either among all patients or among apolipoprotein E 4 carriers.

Conclusions Vitamin E had no benefit in patients with mild cognitive impairment. Although donepezil therapy was associated with a lower rate of progression to Alzheimer's disease during the first 12 months of treatment, the rate of progression to Alzheimer's disease after three years was not lower among patients treated with 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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