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n engl j med 352;23 www.nejm.org june 9, 2005
2379
The
new england
journal
of
medicine
established in 1812
june 9
,
2005
vol. 352 no. 23
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., and Leon J. Thal, M.D., for the Alzheimer’s Disease Cooperative Study Group*
abstract
From the Mayo Clinic College of Medicine,
Rochester, Minn. (R.C.P.); University of Cal-
ifornia, San Diego, San Diego (R.G.T., D.G.,
S.J., L.J.T.); Elan Pharmaceuticals, San Diego
(M.G.); Rush University Medical School,
Chicago (D.B.); Baylor College of Medi-
cine, Houston (R.D.); New York Univer-
sity, New York (S.F.); Oregon Health and
Science University, Portland (J.K.); Emory
University, Atlanta (A.L.); University of South
Florida, Tampa (E.P.); Mt. Sinai School of
Medicine, New York (M.S.); and Yale Univer-
sity, New Haven, Conn. (C.H.D.). Address
reprint requests to Dr. Petersen at the Alz-
heimer’s Disease Research Center, Mayo
Clinic College of Medicine, 200 First St. SW,
Rochester, MN 55905, or at [email protected]
edu.
*Members of the Alzheimer’s Disease Co-
operative Study (ADCS) Group are listed
in the Appendix.
This article was published at www.nejm.
org on April 13, 2005.
N Engl J Med 2005;352:2379-88.
Copyright © 2005 Massachusetts Medical Society.
background
Mild cognitive impairment is a transitional state between the cognitive changes of nor-
mal aging and 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 possi-
ble 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 de-
veloped in 212. The overall rate of progression from mild cognitive impairment to Alz-
heimer’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 treat-
ment 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 dur-
ing the first 12 months of the study (P=0.04), a finding supported by the secondary out-
come measures. Among carriers of one or more apolipoprotein E e 4 alleles, the benefit
of donepezil was evident throughout the three-year follow-up. There were no signifi-
cant differences in the rate of progression to Alzheimer’s disease between the vitamin