This study evaluated the effectiveness of vitamin E and donepezil in treating mild cognitive impairment (MCI). A total of 769 participants with amnestic MCI were randomly assigned to receive either 2000 IU of vitamin E daily, 10 mg of donepezil daily, or a placebo for three years. The primary outcome was the development of possible or probable Alzheimer's disease, while secondary outcomes included cognition and function. The study found that the overall rate of progression from MCI to Alzheimer's disease was 16% per year. There were no significant differences in the probability of progression to Alzheimer's disease between the vitamin E group and the placebo group, or between the donepezil group and the placebo group, during the three-year treatment period. However, the donepezil group showed a reduced likelihood of progression to Alzheimer's disease during the first 12 months of the study, a finding supported by secondary outcome measures. This benefit was particularly evident among carriers of one or more APOE ε4 alleles. Vitamin E had no significant effect on the progression to Alzheimer's disease. Donepezil therapy was associated with a lower rate of progression to Alzheimer's disease during the first 12 months of treatment, but the rate of progression after three years was not lower among patients treated with donepezil than among those given placebo. The study found that adverse events in the donepezil group included muscle cramps, gastrointestinal symptoms, and sleep disturbances. 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 APOE ε4 carriers. The study concluded that 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. The results suggest that donepezil may delay clinical progression to Alzheimer's disease, but do not address the question of the underlying mechanism. The study also found that amnestic MCI and the presence of one or more APOE ε4 alleles were highly predictive of progression to Alzheimer's disease.This study evaluated the effectiveness of vitamin E and donepezil in treating mild cognitive impairment (MCI). A total of 769 participants with amnestic MCI were randomly assigned to receive either 2000 IU of vitamin E daily, 10 mg of donepezil daily, or a placebo for three years. The primary outcome was the development of possible or probable Alzheimer's disease, while secondary outcomes included cognition and function. The study found that the overall rate of progression from MCI to Alzheimer's disease was 16% per year. There were no significant differences in the probability of progression to Alzheimer's disease between the vitamin E group and the placebo group, or between the donepezil group and the placebo group, during the three-year treatment period. However, the donepezil group showed a reduced likelihood of progression to Alzheimer's disease during the first 12 months of the study, a finding supported by secondary outcome measures. This benefit was particularly evident among carriers of one or more APOE ε4 alleles. Vitamin E had no significant effect on the progression to Alzheimer's disease. Donepezil therapy was associated with a lower rate of progression to Alzheimer's disease during the first 12 months of treatment, but the rate of progression after three years was not lower among patients treated with donepezil than among those given placebo. The study found that adverse events in the donepezil group included muscle cramps, gastrointestinal symptoms, and sleep disturbances. 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 APOE ε4 carriers. The study concluded that 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. The results suggest that donepezil may delay clinical progression to Alzheimer's disease, but do not address the question of the underlying mechanism. The study also found that amnestic MCI and the presence of one or more APOE ε4 alleles were highly predictive of progression to Alzheimer's disease.