1. 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.

Dysken MW(1), Sano M(2), Asthana S(3), Vertrees JE(4), Pallaki M(5), Llorente
M(6), Love S(1), Schellenberg GD(7), McCarten JR(1), Malphurs J(8), Prieto S(8), 
Chen P(5), Loreck DJ(9), Trapp G(10), Bakshi RS(10), Mintzer JE(11), Heidebrink
JL(12), Vidal-Cardona A(13), Arroyo LM(13), Cruz AR(14), Zachariah S(14), Kowall 
NW(15), Chopra MP(15), Craft S(16), Thielke S(16), Turvey CL(17), Woodman C(17), 
Monnell KA(18), Gordon K(18), Tomaska J(1), Segal Y(1), Peduzzi PN(19), Guarino
PD(19).

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

Comment in
    JAMA. 2014 Jan 1;311(1):29-30.
    Evid Based Med. 2014 Aug;19(4):140.

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.

DOI: 10.1001/jama.2013.282834 
PMCID: PMC4109898
PMID: 24381967  [Indexed for MEDLINE]