Vitamin E and Donepezil for the Treatment of Mild Cognitive Impairment

Baylor College of Medicine, Houston, Texas, United States
New England Journal of Medicine (Impact Factor: 55.87). 07/2005; 352(23):2379-88. DOI: 10.1056/NEJMoa050151
Source: PubMed


Mild cognitive impairment is a transitional state between the cognitive changes of normal aging and early Alzheimer's disease.
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.
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 epsilon4 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 epsilon4 carriers.
Vitamin E had no benefit in patients with mild cognitive impairment. Although donepezil therapy was associated with a lower rate of progression to Alzheimer's disease during the first 12 months of treatment, the rate of progression to Alzheimer's disease after three years was not lower among patients treated with donepezil than among those given placebo.

Full-text preview

Available from:
  • Source
    • "" The ADAS-Cog test has been widely used to assess the severity of dysfunction in adults [Rosen, Mohs and Davis (1984)]. The genetic variables include the APOE genetic covariates, since it is well known that mutations in APOE raise the risk of progression from amnestic MCI to AD [Petersen et al. (2005)]. The Apolipoprotein E (APOE) SNPs, rs429358 and rs7412 were, separately, genotyped in ADNI-1. "

    Full-text · Article · Dec 2015 · The Annals of Applied Statistics
  • Source
    • "In contrast, a smaller study of tacrine and galantamine (also an acetylcholinesterase-inhibitor) found the opposite, that APOE4 women carriers were more likely to benefit from acetylcholinesterase-inhibitor therapy (MacGowan et al. 1998). Despite these intriguing early finding, most subsequent studies of AD or MCI treatments did not explore the possible effect of the APOE by gender interaction on treatment response (Petersen et al. 2005; Raskind et al. 2000) (Rogers et al. 1998; Rosler et al. 1999; Wilcock et al. 2000). One subsequent study of donepezil's efficacy in AD did formally explore the interaction and though it did not reach significance, it reported a p-value of 0.09 (with an N of only 117), although tantalizingly that study did not report in which direction their results were trending (Rigaud et al. 2002). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Alzheimer’s disease (AD) is an increasingly prevalent, fatal neurodegenerative disease that has proven resistant, thus far, to all attempts to prevent it, forestall it, or slow its progression. The ε4 allele of the Apolipoprotein E gene (APOE4) is a potent genetic risk factor for sporadic and late-onset familial AD. While the link between APOE4 and AD is strong, many expected effects, like increasing the risk of conversion from MCI to AD, have not been widely replicable. One critical, and commonly overlooked, feature of the APOE4 link to AD is that several lines of evidence suggest it is far more pronounced in women than in men. Here we review previous literature on the APOE4 by gender interaction with a particular focus on imaging-related studies.
    Full-text · Article · Jun 2014 · Brain Imaging and Behavior
  • Source
    • "As far as treatment strategies for this neurodegenerative disease, vitamin E seems to be a promising candidate since it acts as a “chain-breaking” antioxidant that can terminate the propagation steps of lipid peroxidation. However, Petersen et al.(62) reported that vitamin E given to 769 patients with mild cognitive impairment did nothing to improve their symptoms. Moreover, significant effects of vitamin E have also not been observed in treatment for AD.(63,64) "
    [Show abstract] [Hide abstract]
    ABSTRACT: There has been much evidence demonstrating the involvement of oxidative stress in the pathology of neurological disorders. Moreover, the vulnerability of the central nervous system to reactive oxygen species mediated injury is well established since neurons consume large amounts of oxygen, the brain has many areas containing high iron content, and neuronal mitochondria generate large amounts of hydrogen peroxide. Furthermore, neuronal membranes are rich in polyunsaturated fatty acids, which are particularly susceptible to oxidative stress. Recently, the biological roles of products produced by lipid peroxidation have received much attention, not only for their pathological mechanisms associated with neurological disorders, but also for their practical clinical applications as biomarkers. Here, we discuss the production mechanisms of reactive oxygen species in some neurological disorders, including Alzheimer's disease, Down syndrome, Parkinson's disease, and stroke. We also describe lipid peroxidation biomarkers for evaluating oxidative stress.
    Preview · Article · May 2014 · Journal of Clinical Biochemistry and Nutrition
Show more