Effect of Vitamin E and Memantine on Functional Decline in Alzheimer Disease: The TEAM-AD VA Cooperative Randomized Trial
Open accessAbstract
IMPORTANCE: Although vitamin E and memantine have been shown to have beneficial effects in moderately severe Alzheimer disease (AD), evidence is limited in mild to moderate AD. OBJECTIVE: To determine if vitamin E (alpha tocopherol), memantine, or both slow progression of mild to moderate AD in patients taking an acetylcholinesterase inhibitor. DESIGN, SETTING, AND PARTICIPANTS: Double-blind, placebo-controlled, parallel-group, randomized clinical trial involving 613 patients with mild to moderate AD initiated in August 2007 and concluded in September 2012 at 14 Veterans Affairs medical centers. INTERVENTIONS: Participants received either 2000 IU/d of alpha tocopherol (n = 152), 20 mg/d of memantine (n = 155), the combination (n = 154), or placebo (n = 152). MAIN OUTCOMES AND MEASURES: Alzheimer's Disease Cooperative Study/Activities of Daily Living (ADCS-ADL) Inventory score (range, 0-78). Secondary outcomes included cognitive, neuropsychiatric, functional, and caregiver measures. RESULTS: Data from 561 participants were analyzed (alpha tocopherol = 140, memantine = 142, combination = 139, placebo = 140), with 52 excluded because of a lack of any follow-up data. Over the mean (SD) follow-up of 2.27 (1.22) years, ADCS-ADL Inventory scores declined by 3.15 units (95% CI, 0.92 to 5.39; adjusted P = .03) less in the alpha tocopherol group compared with the placebo group. In the memantine group, these scores declined 1.98 units less (95% CI, -0.24 to 4.20; adjusted P = .40) than the placebo group's decline. This change in the alpha tocopherol group translates into a delay in clinical progression of 19% per year compared with placebo or a delay of approximately 6.2 months over the follow-up period. Caregiver time increased least in the alpha tocopherol group. All-cause mortality and safety analyses showed a difference only on the serious adverse event of "infections or infestations," with greater frequencies in the memantine (31 events in 23 participants) and combination groups (44 events in 31 participants) compared with placebo (13 events in 11 participants). CONCLUSIONS AND RELEVANCE: Among patients with mild to moderate AD, 2000 IU/d of alpha tocopherol compared with placebo resulted in slower functional decline. There were no significant differences in the groups receiving memantine alone or memantine plus alpha tocopherol. These findings suggest benefit of alpha tocopherol in mild to moderate AD by slowing functional decline and decreasing caregiver burden. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00235716.
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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 [128]
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- Authors
- Dysken, M. W., Sano, M., Asthana, S., Vertrees, J. E., Pallaki, M., Llorente, M., Love, S., Schellenberg, G. D., McCarten, J. R., Malphurs, J., Prieto, S., Chen, P., Loreck, D. J., Trapp, G., Bakshi, R. S., Mintzer, J. E., Heidebrink, J. L., Vidal-Cardona, A., Arroyo, L. M., Cruz, A. R., Zachariah, S., Kowall, N. W., Chopra, M. P., Craft, S., Thielke, S., Turvey, C. L., Woodman, C., Monnell, K. A., Gordon, K., Tomaska, J., Segal, Y., Peduzzi, P. N., & Guarino, P. D.
- Affiliations
- Minneapolis VA Health Care System (US)
- James J. Peters VA Medical Center (US)
- William S. Middleton Memorial Veterans Hospital (US)
- Cooperative Studies Program Clinical Research Pharmacy Coordinating Center, Albuquerque, New Mexico
- Louis Stokes Cleveland VA Medical Center (US)
- Washington DC VA Medical Center (US)
- University of Pennsylvania (US)
- Miami VA Healthcare System (US)
- VA Maryland Health Care System (US)
- VA North Texas Health Care System (US)
- Medical University of South Carolina (US)
- VA Ann Arbor Healthcare System (US)
- VA Caribbean Healthcare System, San Juan, Puerto Rico
- VA Caribbean Healthcare System (PR)
- Bay Pines VA Healthcare System (US)
- VA Boston Healthcare System (US)
- University of Washington (US)
- University of Iowa (US)
- W. G. (Bill) Hefner VA Medical Center (US)
- Yale University (US)
- ORCID
- Venue
- JAMA
- Publisher
- American Medical Association (AMA)
- Published
- 2014-01-01
- Volume
- 311
- Issue
- 1
- Pages
- 33
- ISSN
- 0002-9955 (ISSN-L)
- 0098-7484
- PMC
- PMC4109898
- OpenAlex
- W2128047032
- Cited by
- 628
- References
- 40
- Citations by year
- 2026: 34 · 2025: 41 · 2024: 36 · 2023: 54 · 2022: 56 · 2021: 53 · 2020: 47 · 2019: 47 · 2018: 61 · 2017: 48 · 2016: 50 · 2015: 55 · 2014: 44 · 2013: 1 · 2012: 1
- FWCI
- 35.66
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- JAMA (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute on Aging (P50AG005138, P30AG013846, P50AG005136)
- 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, vitamin E, alpha-tocopherol, memantine, functional decline, activities of daily living, acetylcholinesterase inhibitors, disease progression, caregiver burden, neuropsychiatric symptoms, adverse events, infections and infestations, combination therapy, veterans, older adults, cognitive decline, mortality, quality of life, cost-effectiveness
- MeSH terms
- Activities of Daily Living, Aged, Aged, 80 and over, Alzheimer Disease, Antioxidants, Cholinesterase Inhibitors, Double-Blind Method, Drug Therapy, Combination, Female, Humans, Male, Memantine, Middle Aged, Severity of Illness Index, Vitamin E, Dopamine Agents, Treatment Outcome, Caregivers, Disease Progression
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