title: Effect of vitamin E and memantine on functional decline in Alzheimer disease: the TEAM-AD VA cooperative randomized trial.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  METHODS
  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).
  
  
  METHODS
  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
  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.
  
  
  BACKGROUND
  clinicaltrials.gov Identifier: NCT00235716.
authors.affiliation: Minneapolis VA Health Care System, Minneapolis, Minnesota.
authors.forename: Maurice W
authors.initials: MW
authors.lastname: Dysken
authors.affiliation: James J. Peters VA Medical Research Center, New York, New York.
authors.forename: Mary
authors.initials: M
authors.lastname: Sano
authors.affiliation: William S. Middleton Memorial Veterans Hospital, Madison, Wisconsin.
authors.forename: Sanjay
authors.initials: S
authors.lastname: Asthana
authors.affiliation: Cooperative Studies Program Clinical Research Pharmacy Coordinating Center, Albuquerque, New Mexico.
authors.forename: Julia E
authors.initials: JE
authors.lastname: Vertrees
authors.affiliation: Louis Stokes Cleveland VA Medical Center, Cleveland, Ohio6Case Western Reserve University School of Medicine, Cleveland, Ohio.
authors.forename: Muralidhar
authors.initials: M
authors.lastname: Pallaki
authors.affiliation: Washington DC VA Medical Center, Washington, DC.
authors.forename: Maria
authors.initials: M
authors.lastname: Llorente
authors.affiliation: Minneapolis VA Health Care System, Minneapolis, Minnesota.
authors.forename: Susan
authors.initials: S
authors.lastname: Love
authors.affiliation: University of Pennsylvania School of Medicine, Philadelphia.
authors.forename: Gerard D
authors.initials: GD
authors.lastname: Schellenberg
authors.affiliation: Minneapolis VA Health Care System, Minneapolis, Minnesota.
authors.forename: J Riley
authors.initials: JR
authors.lastname: McCarten
authors.affiliation: Miami VA Healthcare System, Miami, Florida.
authors.forename: Julie
authors.initials: J
authors.lastname: Malphurs
authors.affiliation: Miami VA Healthcare System, Miami, Florida.
authors.forename: Susana
authors.initials: S
authors.lastname: Prieto
authors.affiliation: Louis Stokes Cleveland VA Medical Center, Cleveland, Ohio6Case Western Reserve University School of Medicine, Cleveland, Ohio.
authors.forename: Peijun
authors.initials: P
authors.lastname: Chen
authors.affiliation: VA Maryland Healthcare System, Baltimore11University of Maryland Medical School, Department of Psychiatry, Baltimore.
authors.forename: David J
authors.initials: DJ
authors.lastname: Loreck
authors.affiliation: VA North Texas Health Care System, Dallas.
authors.forename: George
authors.initials: G
authors.lastname: Trapp
authors.affiliation: VA North Texas Health Care System, Dallas.
authors.forename: Rajbir S
authors.initials: RS
authors.lastname: Bakshi
authors.affiliation: Ralph H. Johnson VA Medical Center, Charleston, South Carolina14Department of Health Studies, Medical University of South Carolina, Charleston15Roper St Francis Healthcare, Charleston, South Carolina.
authors.forename: Jacobo E
authors.initials: JE
authors.lastname: Mintzer
authors.affiliation: VA Ann Arbor Healthcare System, Ann Arbor, Michigan.
authors.forename: Judith L
authors.initials: JL
authors.lastname: Heidebrink
authors.affiliation: VA Caribbean Healthcare System, San Juan, Puerto Rico.
authors.forename: Ana
authors.initials: A
authors.lastname: Vidal-Cardona
authors.affiliation: VA Caribbean Healthcare System, San Juan, Puerto Rico.
authors.forename: Lillian M
authors.initials: LM
authors.lastname: Arroyo
authors.affiliation: Bay Pines VA Healthcare System, Bay Pines, Florida.
authors.forename: Angel R
authors.initials: AR
authors.lastname: Cruz
authors.affiliation: Bay Pines VA Healthcare System, Bay Pines, Florida.
authors.forename: Sally
authors.initials: S
authors.lastname: Zachariah
authors.affiliation: VA Boston Healthcare System, Boston, Massachusetts.
authors.forename: Neil W
authors.initials: NW
authors.lastname: Kowall
authors.affiliation: VA Boston Healthcare System, Boston, Massachusetts.
authors.forename: Mohit P
authors.initials: MP
authors.lastname: Chopra
authors.affiliation: VA Puget Sound Health Care System, Seattle, Washington21Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle.
authors.forename: Suzanne
authors.initials: S
authors.lastname: Craft
authors.affiliation: VA Puget Sound Health Care System, Seattle, Washington21Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle.
authors.forename: Stephen
authors.initials: S
authors.lastname: Thielke
authors.affiliation: Iowa City VA Medical Center, Iowa City, Iowa23University of Iowa, Iowa City.
authors.forename: Carolyn L
authors.initials: CL
authors.lastname: Turvey
authors.affiliation: Iowa City VA Medical Center, Iowa City, Iowa23University of Iowa, Iowa City.
authors.forename: Catherine
authors.initials: C
authors.lastname: Woodman
authors.affiliation: W. G. (Bill) Hefner VA Medical Center, Salisbury, North Carolina.
authors.forename: Kimberly A
authors.initials: KA
authors.lastname: Monnell
authors.affiliation: W. G. (Bill) Hefner VA Medical Center, Salisbury, North Carolina.
authors.forename: Kimberly
authors.initials: K
authors.lastname: Gordon
authors.affiliation: Minneapolis VA Health Care System, Minneapolis, Minnesota.
authors.forename: Julie
authors.initials: J
authors.lastname: Tomaska
authors.affiliation: Minneapolis VA Health Care System, Minneapolis, Minnesota.
authors.forename: Yoav
authors.initials: Y
authors.lastname: Segal
authors.affiliation: Cooperative Studies Program Coordinating Center, VA Connecticut Healthcare System, West Haven26Yale University School of Public Health, New Haven, Connecticut.
authors.forename: Peter N
authors.initials: PN
authors.lastname: Peduzzi
authors.affiliation: Cooperative Studies Program Coordinating Center, VA Connecticut Healthcare System, West Haven26Yale University School of Public Health, New Haven, Connecticut.
authors.forename: Peter D
authors.initials: PD
authors.lastname: Guarino
mesh_terms: D000203:Activities of Daily Living; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000188:drug therapy* / Q000451:nursing / Q000503:physiopathology*; D000975:Antioxidants / Q000009:adverse effects / Q000627:therapeutic use*; D017028:Caregivers; D002800:Cholinesterase Inhibitors / Q000627:therapeutic use; D018450:Disease Progression; D015259:Dopamine Agents / Q000009:adverse effects / Q000627:therapeutic use*; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D008297:Male; D008559:Memantine / Q000009:adverse effects / Q000627:therapeutic use*; D008875:Middle Aged; D012720:Severity of Illness Index; D016896:Treatment Outcome; D014810:Vitamin E / Q000009:adverse effects / Q000627:therapeutic use*
chemical_list: D000975:Antioxidants; D002800:Cholinesterase Inhibitors; D015259:Dopamine Agents; D014810:Vitamin E; D008559:Memantine