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

Abstract

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.

Figure 1. Flow of Participants in the Study

Figure 2. Changes in Primary Outcome (ADCS-ADL Inventory Score) During the 4-Year Study Period, Compared With Baseline

In this between-group comparison, lower scores indicate worse functioning. Data are least squares means at each time point. Values have been adjusted for baseline scores as a fixed effect and the study site as a random effect. ADCS-ADL indicates Alzheimer's Disease Cooperative Study/Activities of Daily Living; error bars, 95% CIs.

Figure 3. Changes in 4 Secondary Outcomes During the 4-Year Study Period, Compared With Baseline

Data are least squares means at each time point. Values have been adjusted for baseline scores as a fixed effect and the study site as a random effect. For between-group comparisons of scores on the the Mini-Mental State Examination (MMSE) (A), lower scores indicate worse functioning. For comparisons of the Alzheimer Disease Assessment Scale–Cognitive portion (ADAS-cog) (B), Neuropsychiatric Inventory (C), and the Caregiver Activity Survey (D), higher scores indicate worse functioning. Error bars indicate 95% CIs.

Figure 4. Dependence Scale Score Time-to-Event Analysis

The Dependence Scale assesses 6 levels of functional dependence. Time to event is the time to loss of 1 dependence level (increase in dependence). We used an interval-censored model assuming a Weibull distribution because the time of the event was known only at the end of a discrete interval of time (every 6 months).