Vitamin E and Donepezil for the Treatment of Mild Cognitive Impairment
Open accessAbstract
BACKGROUND: Mild cognitive impairment is a transitional state between the cognitive changes of normal 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 possible 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 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. CONCLUSIONS: 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.
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Trials of antioxidants like vitamin E in aMCI and AD have mostly been disappointing.
“It is therefore surprising that the results of clinical trials in aMCI and AD involving antioxidant therapies (such as vitamin E) have been largely disappointing2,8,70,78,80.”
From Oxidative stress, dysfunctional glucose metabolism and Alzheimer disease (2019) · cites this paper as [80]
In the ‘No Progression to AD’ discussion, this trial reports that vitamin E did not significantly reduce progression from amnestic mild cognitive impairment to Alzheimer’s disease and had only minimal effects on secondary measures. That supports disappointment for the aMCI trial, but this paper does not establish that antioxidant trials in aMCI and AD were largely disappointing overall; its Abstract also reports an earlier positive vitamin E result in moderately severe AD. (LLM, conf=0.86)
Experimental — accuracy not yet measuredThe donepezil study found a tiny degree of cognitive improvement during the first 12 months of a 36-month study, but the effect was not sustained.
“Among them, donepezil study found a tiny degree of cognitive improvement during the first 12 months of a 36-month study, but the effect was not sustained.16”
From A 2025 update on treatment strategies for the Alzheimer’s disease spectrum (2025) · cites this paper as [16]
The secondary outcome measures section reports cognitive differences favoring donepezil that, with one exception, were confined to the first 18 months—not specifically the first 12. The discussion also says the donepezil–placebo difference on the MMSE was about 0.5 point throughout the 36-month trial, so the claim that the cognitive effect was not sustained is too absolute. The 12-month finding primarily concerns progression to Alzheimer’s disease. (LLM, conf=0.86)
Experimental — accuracy not yet measuredNone of the tested antioxidant compounds have proven effective for treating Alzheimer's disease to date.
“To date, none of the tested compounds have proven effective (Sano et al., 1997; Petersen et al., 2005; Pham and Plakogiannis, 2005; DeKosky et al., 2008).”
From The mitochondria-targeted antioxidant MitoQ prevents loss of spatial memory retention and early neuropathology in a transgenic mouse model of Alzheimer’s disease (2011) · cites this paper as Petersen et al., 2005
The primary outcome measures report that vitamin E did not significantly reduce progression from mild cognitive impairment to Alzheimer’s disease. That supports a narrower claim about one antioxidant in a prevention trial, not a claim about all tested antioxidants treating Alzheimer’s disease. The paper’s introductory passage also reports evidence that vitamin E could delay important milestones in patients with moderately severe Alzheimer’s disease. (LLM, conf=0.86)
Experimental — accuracy not yet measuredOne report found high-dose vitamin E delayed nursing-home placement in late-stage AD compared with placebo, but later vitamin E studies were less positive.
“Following a report of success of high-dose vitamin E in keeping late-stage AD patients out of long-term care facilities longer than patients on a placebo81, other studies with vitamin E have been less impressive70,78,80.”
From Oxidative stress, dysfunctional glucose metabolism and Alzheimer disease (2019) · cites this paper as [80]
Two drug studies (AHEAD and TRAILBRAZER-ALZ 3) employing lecanemab and donanemab have completed recruitment for preventive treatment of stage 1 and 2 Alzheimer's disease.
“Two drug studies (AHEAD study and TRAILBRAZER-ALZ 3 study), employing recently FDA-approved anti-amyloid drugs (lecanemab and donanemab), have completed the recruitment phase of preventive treatment for stage 1 and 2 AD.15,16”
From A 2025 update on treatment strategies for the Alzheimer’s disease spectrum (2025) · cites this paper as [16]
The study design and primary outcome measures sections describe a trial of vitamin E and donepezil in people with mild cognitive impairment. Searches for AHEAD, TRAILBLAZER-ALZ 3, lecanemab, donanemab, and preventive-treatment recruitment found no passage addressing those studies or their recruitment status. (LLM, conf=0.78)
Experimental — accuracy not yet measured
Level II or equivocal level I evidence suggest donepezil treatment may be beneficial in very mild stage AD or for subgroups with MCI due to AD (carriers of APOE-ε4 allele, those with depression or depressive symptoms).
“Level II or equivocal level I evidence suggest donepezil treatment may be beneficial in very mild stage AD or for subgroups with MCI due to AD (ie, carriers of APOE-ε4 allele, 96 those with depression or depressive symptoms 97 ).”
From The Alzheimer’s Disease Clinical Spectrum (2019) · cites this paper as [96]
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References 23 · Cited by 1,844
Research works printed but not linked: 1
- Doody RS, Stevens JC, Beck C, et al. Management of dementia (an evidence-based review): report of the Quality Standards Sub- committee of the American Academy of Neu- rology. Neurology 2001;56:1154-66.
- Authors
- Petersen, R. C., Thomas, R. G., Grundman, M., Bennett, D., Doody, R., Ferris, S., Galasko, D., Jin, S., Kaye, J., Levey, A., Pfeiffer, E., Sano, M., van Dyck, C. H., & Thal, L. J.
- Affiliations
- Mayo Clinic (US)
- University of California San Diego (US)
- Rush University Medical Center (US)
- Baylor College of Medicine (US)
- New York University (US)
- Oregon Health & Science University (US)
- Emory University (US)
- University of South Florida (US)
- Icahn School of Medicine at Mount Sinai (US)
- ORCID
- Venue
- New England Journal of Medicine
- Publisher
- Massachusetts Medical Society
- Published
- 2005-06-09
- Volume
- 352
- Issue
- 23
- Pages
- 2379-2388
- ISSN
- 0028-4793 (ISSN-L)
- 1533-4406
- OpenAlex
- W2107820540
- Cited by
- 1,844
- References
- 23
- Citations by year
- 2026: 22 · 2025: 36 · 2024: 49 · 2023: 49 · 2022: 63 · 2021: 69 · 2020: 63 · 2019: 72 · 2018: 70 · 2017: 72 · 2016: 71 · 2015: 94 · 2014: 85 · 2013: 86 · 2012: 101
- FWCI
- 95.24
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- New England Journal of Medicine (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Pfizer
- Eisai
- University of California, San Diego
- DSM Nutritional Products
- National Institute on Aging (AG 10483, U01AG010483, UO1 AG10483, U19AG010483)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Pharmacology › Cholinesterase and Neurodegenerative Diseases
- Keywords
- vitamin E, donepezil, mild cognitive impairment, Alzheimer's disease, amnestic mild cognitive impairment, cholinesterase inhibitors, cognitive function
- MeSH terms
- Donepezil, Alzheimer Disease, Apolipoproteins E, Cholinesterase Inhibitors, Cognition Disorders, Double-Blind Method, Humans, Indans, Piperidines, Vitamin E, Proportional Hazards Models, Treatment Failure, Disease Progression, Nootropic Agents, Apolipoprotein E4
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