Correspondence

Vitamin E and Donepezil for the Treatment of Mild Cognitive Impairment

N Engl J Med 2005; 353:951-952September 1, 2005

Article

To the Editor:

Petersen et al. (June 9 issue)1 report in their randomized, controlled trial of vitamin E, donepezil, and placebo in subjects with amnestic mild cognitive impairment that apolipoprotein E (APOE) ε4 status had “a major modifying effect” and that “the benefit of donepezil was evident throughout the three-year follow-up” among carriers of APOE ε4 alleles. This finding differs from those of prior studies in patients with Alzheimer's disease, which suggest that there is either no difference in the effect of cholinesterase inhibitors according to APOE ε4 status2,3 or that there is a stronger treatment effect among noncarriers of APOE ε4 alleles than among carriers.4,5 To determine whether APOE ε4 status truly modified the effect in this study, it would be useful to know whether the APOE ε4 subgroup analysis was prespecified or exploratory, what the hazard ratio was for donepezil among APOE ε4 noncarriers, and the P value for the interaction between APOE ε4 status and treatment group. We also commend the authors' sensitivity analysis and are curious to know the results of a more conservative, worst-case-scenario approach, in which all of the excess dropouts are assumed to have had progression to dementia.

Deborah E. Barnes, Ph.D., M.P.H.
Kristine Yaffe, M.D.
University of California, San Francisco, San Francisco, CA 94121
barnes@medicine.ucsf.edu

Dr. Yaffe reports having received research support from Pfizer.

5 References

1. 1

   Petersen RC, Thomas RG, Grundman M, et al. Vitamin E and donepezil for the treatment of mild cognitive impairment. N Engl J Med 2005;352:2379-2388
   Full Text | Web of Science | Medline

2. 2

   Rigaud AS, Traykov L, Latour F, Couderc R, Moulin F, Forette F. Presence or absence of at least one epsilon 4 allele and gender are not predictive for the response to donepezil treatment in Alzheimer's disease. Pharmacogenetics 2002;12:415-420
   CrossRef | Medline

3. 3

   Rigaud AS, Traykov L, Caputo L, et al. The apolipoprotein E epsilon4 allele and the response to tacrine therapy in Alzheimer's disease. Eur J Neurol 2000;7:255-258
   CrossRef | Web of Science | Medline

4. 4

   Poirier J, Delisle M-C, Quirion R, et al. Apolipoprotein E4 allele as a predictor of cholinergic deficits and treatment outcome in Alzheimer disease. Proc Natl Acad Sci U S A 1995;92:12260-12264
   CrossRef | Web of Science | Medline

5. 5

   Farlow MR, Lahiri DK, Poirier J, Davignon J, Schneider L, Hui SL. Treatment outcome of tacrine therapy depends on apolipoprotein genotype and gender of the subjects with Alzheimer's disease. Neurology 1998;50:669-677
   Web of Science | Medline

Author/Editor Response

We believe that our data do not necessarily imply that donepezil is effective for mild cognitive impairment only in APOE ε4 carriers. The APOE ε4 subset analysis over 36 months of follow-up was prespecified in the statistical-analysis plan. The additional 12-month and 24-month analyses were exploratory. The hazard ratios for the APOE ε4 noncarriers were as follows: at 12 months, 0.66 (P=0.44); at 24 months, 1.02 (P=0.97); and at 36 months, 1.37 (P=0.37).

As stated in the article, in the sensitivity analysis, we used a very conservative assumption that the rate of progression to Alzheimer's disease among the 24 excess dropouts was approximately 25 percent per year (6 of 24), which is quite high. Therefore, it is not surprising that an analysis of the worst-case scenario, in which the rate of progression would be 100 percent (24 of 24), would not demonstrate a statistically significant difference between the two groups. In summary, although no effect would be found under this set of circumstances, the likelihood of this scenario is extremely low.

Ronald C. Petersen, Ph.D., M.D.
Mayo Clinic College of Medicine, Rochester, MN 55905
peter8@mayo.edu

Ronald G. Thomas, Ph.D.
Leon J. Thal, M.D.
University of California, San Diego, La Jolla, CA 92093

Citing Articles (3)

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2. 2

   Rukhsana Sultana, D. Allan Butterfield. 2007. Redox Proteomics Analysis of Oxidative Modified Brain Proteins in Alzheimer's Disease and Mild Cognitive Impairment: Insights into the Progression of This Dementing Disorder. , 379-401.
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