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JAMA. 2014 Jan 1;311(1):33-44. doi: 10.1001/jama.2013.282834.

Effect of vitamin E and memantine on functional decline in Alzheimer disease: the TEAM-AD VA cooperative randomized trial.

Author information

  • 1Minneapolis VA Health Care System, Minneapolis, Minnesota.
  • 2James J. Peters VA Medical Research Center, New York, New York.
  • 3William S. Middleton Memorial Veterans Hospital, Madison, Wisconsin.
  • 4Cooperative Studies Program Clinical Research Pharmacy Coordinating Center, Albuquerque, New Mexico.
  • 5Louis Stokes Cleveland VA Medical Center, Cleveland, Ohio6Case Western Reserve University School of Medicine, Cleveland, Ohio.
  • 6Washington DC VA Medical Center, Washington, DC.
  • 7University of Pennsylvania School of Medicine, Philadelphia.
  • 8Miami VA Healthcare System, Miami, Florida.
  • 9VA Maryland Healthcare System, Baltimore11University of Maryland Medical School, Department of Psychiatry, Baltimore.
  • 10VA North Texas Health Care System, Dallas.
  • 11Ralph H. Johnson VA Medical Center, Charleston, South Carolina14Department of Health Studies, Medical University of South Carolina, Charleston15Roper St Francis Healthcare, Charleston, South Carolina.
  • 12VA Ann Arbor Healthcare System, Ann Arbor, Michigan.
  • 13VA Caribbean Healthcare System, San Juan, Puerto Rico.
  • 14Bay Pines VA Healthcare System, Bay Pines, Florida.
  • 15VA Boston Healthcare System, Boston, Massachusetts.
  • 16VA Puget Sound Health Care System, Seattle, Washington21Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle.
  • 17Iowa City VA Medical Center, Iowa City, Iowa23University of Iowa, Iowa City.
  • 18W. G. (Bill) Hefner VA Medical Center, Salisbury, North Carolina.
  • 19Cooperative Studies Program Coordinating Center, VA Connecticut Healthcare System, West Haven26Yale University School of Public Health, New Haven, Connecticut.

Erratum in

  • JAMA. 2014 Mar 19;311(11):1161.



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.


To determine if vitamin E (alpha tocopherol), memantine, or both slow progression of mild to moderate AD in patients taking an acetylcholinesterase inhibitor.


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.


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).


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.


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).


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: Identifier: NCT00235716.

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