Is the glass half empty or half full? Alzheimer disease (AD) clinicians might be asking themselves that question after seeing the long-awaited results of a large, prospective clinical study weighing the ability of vitamin E or the cholinesterase inhibitor donepezil to delay the onset of AD in people just beginning to show signs of memory loss. The glass came up half empty with the finding that vitamin E had no effect on disease progression after three years of treatment. The half full bit was the result that treatment with donepezil (Aricept) did significantly reduce the rate of onset of AD in the first year of the study, although the effect wore off by the third year. The modest and transient effect of donepezil is consistent with its clinical performance in more advanced AD (see ARF related news story).
The results were unveiled by Ronald Peterson from the Mayo Clinic in Rochester, Minnesota, and Leon Thal of the University of California, San Diego, on April 13 at the American Academy of Neurology meeting in Miami, the same day their paper appeared online in the New England Journal of Medicine.
The multicenter study, carried out by the Alzheimer Disease Study Group, enrolled 768 subjects who fit carefully defined criteria of amnestic mild cognitive impairment (MCI), a subtype of MCI with memory defects that shows an increased risk of progression to AD over time. Previous work indicated that about 10-15 percent of people with amnestic MCI progress to AD each year, compared to less than 2 percent of the general population, and 80 percent progress to AD within 6 years. The enrollees were randomized to receive placebo or one of two standard treatments for AD, namely, vitamin E (2,000 IU per day) or donepezil (10 mg per day) for three years. Patients were followed until diagnosis of possible or probable AD, and their performance measured with a battery of cognitive tests.
Over the course of the study, 212 participants developed AD, a rate of 16 percent per year. There was no difference between placebo and either treatment in risk of progression after three years. But when a secondary analysis was done for each 6-month treatment period, the donepezil group had reduced likelihood of progression during the first year. After three years, however, the donepezil group appeared to be doing as badly as placebo, and the difference was gone. Results of the cognitive tests generally followed the same pattern.
Among carriers of ApoE4 alleles, the results were different. Overall, about half the participants carried one or more ApoE4 alleles, and as a group, the carriers showed a faster progression to AD than noncarriers—ApoE4 is a well-known risk factor for AD (see ARF related news story). ApoE4 carriers treated with donepezil showed a significant reduction in progression to AD at three years compared to carriers who received placebo. However, the researchers conclude that the data, while intriguing, are insufficient to make a case for genotyping of MCI patients. A larger study designed expressly to compare ApoE4 carriers and noncarriers would be needed to address that question.
The clear-cut failure of the antioxidant vitamin E, which had no effect versus placebo at any time point, whether the patient was or wasn’t ApoE4-positive, stands in contrast to its positive effects in moderately severe AD (Sano et al., 1997). Vitamin E is taken by many healthy people who view it as a harmless supplement that may ward off brain aging and cardiovascular disease. The demonstration of no benefit in this study, coupled with new data that suggest harmful cardiovascular effects of daily dosing, should have physicians and the public rethinking this practice.
A recommendation for donepezil is less clear-cut. While the authors indicate the reduction in progression to AD with the drug is likely to be clinically significant in some people, they stop short of recommending its general use. “Although our findings do not provide support for a clear recommendation for the use of donepezil in persons with mild cognitive impairment, they could prompt a discussion between the clinician and the patient about this possibility,” the investigators write.
Despite the somewhat cloudy conclusion, the trial is a major step forward in testing potential treatments for MCI, a critical point for early intervention in AD, writes Deborah Blacker of Harvard Medical School in an accompanying editorial. The authors have shown that “this difficult-to-define diagnostic category can be measured and studied, which is no small feat,” Blacker writes. The effect of donepezil, although small, is a hopeful sign that should pave the way for successful clinical trials of treatments for both MCI and early AD that are just now working their way through the development pipeline. (See related news on WebMD and HealthDay.)—Pat McCaffrey
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- Sano M, Ernesto C, Thomas RG, Klauber MR, Schafer K, Grundman M, Woodbury P, Growdon J, Cotman CW, Pfeiffer E, Schneider LS, Thal LJ. A controlled trial of selegiline, alpha-tocopherol, or both as treatment for Alzheimer's disease. The Alzheimer's Disease Cooperative Study. N Engl J Med. 1997 Apr 24;336(17):1216-22. PubMed.
No Available Further Reading
- Petersen RC, Thomas RG, Grundman M, Bennett D, Doody R, Ferris S, Galasko D, Jin S, Kaye J, Levey A, Pfeiffer E, Sano M, van Dyck CH, Thal LJ, . Vitamin E and donepezil for the treatment of mild cognitive impairment. N Engl J Med. 2005 Jun 9;352(23):2379-88. Epub 2005 Apr 13 PubMed.
- Blacker D. Mild cognitive impairment--no benefit from vitamin E, little from donepezil. N Engl J Med. 2005 Jun 9;352(23):2439-41. PubMed.