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Cited by 2,380Dementia and Cognitive Impairment ResearchAlzheimer's disease research and treatmentsCholinesterase and Neurodegenerative Diseases

A Controlled Trial of Selegiline, Alpha-Tocopherol, or Both as Treatment for Alzheimer's Disease

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Sano, Mary, Ernesto, Christopher, Thomas, Ronald G., Klauber, Melville R., Schafer, Kimberly, Grundman, Michael, Woodbury, Peter, Growdon, John +4 more·1997·New England Journal of Medicine
DOI 10.1056/nejm199704243361704
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Abstract

BACKGROUND: There is evidence that medications or vitamins that increase the levels of brain catecholamines and protect against oxidative damage may reduce the neuronal damage and slow the progression of Alzheimer's disease. METHODS: We conducted a double-blind, placebo-controlled, randomized, multicenter trial in patients with Alzheimer's disease of moderate severity. A total of 341 patients received the selective monoamine oxidase inhibitor selegiline (10 mg a day), alpha-tocopherol (vitamin E, 2000 IU a day), both selegiline and alpha-tocopherol, or placebo for two years. The primary outcome was the time to the occurrence of any of the following: death, institutionalization, loss of the ability to perform basic activities of daily living, or severe dementia (defined as a Clinical Dementia Rating of 3). RESULTS: Despite random assignment, the baseline score on the Mini-Mental State Examination was higher in the placebo group than in the other three groups, and this variable was highly predictive of the primary outcome (P<0.001). In the unadjusted analyses, there was no statistically significant difference in the outcomes among the four groups. In analyses that included the base-line score on the Mini-Mental State Examination as a covariate, there were significant delays in the time to the primary outcome for the patients treated with selegiline (median time, 655 days; P=0.012), alpha-tocopherol (670 days, P=0.001) or combination therapy (585 days, P=0.049), as compared with the placebo group (440 days). CONCLUSIONS: In patients with moderately severe impairment from Alzheimer's disease, treatment with selegiline or alpha-tocopherol slows the progression of disease.

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  • None 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 Sano et al., 1997

    The Discussion reports that selegiline and alpha-tocopherol were beneficial in delaying the primary outcome of disease progression in patients with Alzheimer's disease. The paper does not report improved cognition, and the unadjusted analysis found no significant difference, but its adjusted analysis found significant delays. Its conclusion therefore runs contrary to the claim that none of the tested compounds had proven effective. (LLM, conf=0.88)

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  • One 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 [81]

    The Discussion reports a significant delay in institutionalization with alpha-tocopherol (vitamin E), and the Methods specify a high dose of 2,000 IU daily in a placebo-controlled trial. The participants had moderately severe Alzheimer’s disease (Clinical Dementia Rating 2), not late-stage disease; severe dementia was a possible study outcome. The statement about later studies is cited to other sources, not this paper. (LLM, conf=0.88)

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  • There were no concerning safety signals or increased mortality with high-dose vitamin E.

    “there were no concerning safely signals or increased mortality with high-dose vitamin E. 127,128”

    From The Alzheimer’s Disease Clinical Spectrum (2019) · cites this paper as [127]

  • Two randomized controlled trials supported approximately 20% lower rate of activities of daily living decline over approximately 2 to 3 years with high-dose vitamin E (1000 IU twice daily).

    “high-dose vitamin E (1000 IU twice daily was the regimen tested) may be considered based on results of 2 RCTs that supported approximately 20% lower rate of ADL decline over approximately 2 to 3 years; there were no concerning safely signals or increased mortality with high-dose vitamin E. 127,128”

    From The Alzheimer’s Disease Clinical Spectrum (2019) · cites this paper as [127]

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Research works printed but not linked: 1

  1. Piccinin GL, Finali G, Piccirilli M. Neuropsychological effects of L-dep- renyl in Alzheimer's type dementia. Clin Neuropharmacol 1990;13:147-63.

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Authors
Sano, M., Ernesto, C., Thomas, R. G., Klauber, M. R., Schafer, K., Grundman, M., Woodbury, P., Growdon, J., Cotman, C. W., Pfeiffer, E., Schneider, L. S., & Thal, L. J.
Affiliations
  • University of California San Diego (US)
  • Harvard University (US)
  • University of California, Irvine (US)
  • University of South Florida (US)
  • University of Southern California (US)
ORCID
Venue
New England Journal of Medicine
Publisher
Massachusetts Medical Society
Published
1997-04-24
Volume
336
Issue
17
Pages
1216-1222
ISSN
  • 0028-4793 (ISSN-L)
  • 1533-4406
DOI
10.1056/nejm199704243361704
OpenAlex
W2326200998
Cited by
2,380
References
36
Citations by year
2026: 19 · 2025: 23 · 2024: 39 · 2023: 39 · 2022: 41 · 2021: 38 · 2020: 44 · 2019: 43 · 2018: 44 · 2017: 47 · 2016: 55 · 2015: 54 · 2014: 72 · 2013: 62 · 2012: 82
FWCI
118.07
Type
journal article
Language
en
Open access
Locations
  • New England Journal of Medicine (publishedVersion)
  • PubMed (publishedVersion)
Funders
National Institute on Aging (U01‐AG10483, U01AG010483, 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
Alzheimer's disease, selegiline, alpha-tocopherol, vitamin E, monoamine oxidase inhibitors, combination therapy, disease progression, dementia, activities of daily living, Mini-Mental State Examination, oxidative stress, catecholamines
MeSH terms
Activities of Daily Living, Aged, Alzheimer Disease, Cognition, Double-Blind Method, Drug Combinations, Female, Humans, Institutionalization, Male, Mental Status Schedule, Monoamine Oxidase Inhibitors, Selegiline, Vitamin E, Proportional Hazards Models, Treatment Outcome, Disease Progression

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