Abstract & Commentary
By Norman R. Relkin, MD, PhD, Associate Professor of Clinical Neurology and Neuroscience at New York Presbyterian Hospital-Cornell Campus, Assistant Editor, Neurology Alert. Dr. Relkin is on the speaker’s bureau of Pfizer, Eisai, and Athena Diagnostics and does research for Pfizer and Merck.
Synopsis: The rate of development of dementia in patients with MCI can be altered by a medical intervention, in this case by administration of an acetylcholinesterase inhibitor.
Source: Petersen RC, et al. Vitamin E and Donepezil for the Treatment of Mild Cognitive Impairment. N Engl J Med. 2005;352(23):2379-2388.
Mild cognitive impairment (MCI) is a recognized prodrome to dementia and amnestic forms of MCI progress most commonly to Alzheimer’s disease (AD). The Alzheimer’s Disease Cooperative Study (ADCS) Group investigated the effects of alpha-tocopheral (Vit E) and donepezil (Aricept ®) on progression of amnestic MCI to AD. In a 3-year multicenter study involving 769 MCI patients, they randomly assigned subjects to receive either placebo, 2000 IU Vit E or 10 mg donepezil daily in a double-blind treatment protocol. Approximately 28% of subjects progressed to frank Alzheimer’s during the course of the trial, representing an annual conversion rate of 16%. Vitamin E had no impact on the rate of conversion, whereas donepezil significantly reduced the likelihood of progression to AD in the first 12 months. Donepezil did not alter the 3-year conversion rate except among persons carrying the APOE-e4 allele, for whom the benefits were maintained over the full 3 years of the trial. APOE carrier status had no impact on results with vitamin E. The occurrence of adverse events with donepezil and vitamin E was generally comparable to that previously reported with these agents in Alzheimer patients, as was mortality during the period of treatment. This study is among the first to suggest that rate of development of dementia in patients with MCI can be altered by a medical intervention, in this case by administration of an acetylcholinesterase inhibitor.
Commentary
There are several noteworthy findings in this ADCS study. The observed 16% annual conversion rate from MCI to AD validates predictions for patients meeting Petersen’s criteria for amnestic MCI. This illustrates that it is possible to identify persons with a relatively high likelihood of developing Alzheimer’s in the next 3-5 years by careful patient selection. While this may make amnestic MCI a good construct for future AD prevention trials, patients meeting these criteria represent only a very small percentage of the total population, and it is likely to be challenging for physicians to identify such individuals in routine clinical practice.
Vitamin has been used in the treatment of AD since a previous ADCS study suggested that high doses (2000 I.U./day) could forestall the development of major impairments in patients with symptomatic AD. This reported benefit of Vitamin E has not been subsequently confirmed, and the failure of Vitamin E to slow progression of MCI to AD is a blow to those who advocate anti-oxidant treatment for AD. A recent meta-analysis found that vitamin E doses in excess of 400 IU per day were associated with increased morbidity, bringing into question the wisdom of administering 5x higher doses to elderly AD patients.
The effects of donepezil on progression of AD in the study cohort as a whole reached statistical significance in the first year only, which is comparable to the period of time in which AD patients responding to this agent experience improvement of their cognitive decline above baseline. It is, therefore, not possible to say on the basis of this trial whether donepezil exerts a true protective effect against AD or simply delays a formal AD diagnosis by virtue of symptomatic benefits that maintain cognitive status above the cutoff for dementia. The possibility that donepezil and other acetylcholinesterase inhibitors exert neuroprotective effects is currently under study in light of recent findings that rate of hippocampal and cortical atrophy may be slowed by these agents.
The results were more dramatic among MCI patients with the APOE-4 allele, who were a third less likely to develop AD over 3 years with donepezil treatment than those receiving placebo. The rate of progression to AD was considerably higher among 4 carriers, with 76% of those who converted to AD during the trial possessing at least one APOE-4 allele. While the possibility of an interaction between APOE and cholinesterase treatment cannot be ruled out, the more likely explanation for the observed risk reduction is that MCI patients who are APOE-4 carriers are more likely to progress to AD in the time span of the trial, providing a better signal for observing the benefits of cholinesterase inhibition.
Since the primary outcome measure of this trial was negative, further studies will be needed before evidenced-based treatment of MCI can be carried out. However, this trial demonstrates that progression from mild impairment to frank dementia need not be considered inexorable, and its rate may be altered by available treatments.
The rate of development of dementia in patients with MCI can be altered by a medical intervention, in this case by administration of an acetylcholinesterase inhibitor.
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