Wednesday, April 13, 2005

Donepezil, Vitamin E, and Mild Cognitive Impairment in Aging

The New England Journal of Medicine has made available on its website prepublication versions of the results of a large study relevant to aging, neuropsychological changes in aging, and the onset of dementia. It has also made available in the same format an editorial on this research study. The full-text versions of both articles can be found at: Original Article and at Editorial.

The editorial, by Blacker, concludes by bringing emphasis to three primary findings in the study:

[1] Symptoms of memory loss in older persons need to be taken with seriousness, as they may herald the onset of Alzheimer disease.
[2] Donepezil may have some benefit, but this benefit is "quite limited and apparently transient."
[3] Vitamin E has no impact.

As a neuropsychologist, I can say that the clearest way to examine symptoms of memory problems is through a thorough neuropsychology examination.

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. Published at April 13, 2005 (10.1056/NEJMoa050151)


Background. Mild cognitive impairment is a transitional state between the cognitive changes of normal aging and very 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 after three years, the rate of progression to Alzheimer's disease was not lower among patients treated with donepezil than among those given placebo, donepezil therapy was associated with a lower rate of progression to Alzheimer's disease during the first 12 months of treatment.

Notice: To coincide with a presentation at the annual meeting of the American Academy of Neurology, this article was published at on April 13, 2005. It will appear in the June 9 issue of the Journal.


Deborah Blacker, M.D., Sc.D. Mild Cognitive Impairment -- No Benefit from Vitamin E, Little from Donepezil. Published at April 13, 2005 (10.1056/NEJMe058086).

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