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Dysken MW, Sano M, Asthana S, Vertrees JE, Pallaki M, Llorente M, Love S, Schellenberg GD, McCarten JR, Malphurs J, Prieto S, Chen P, Loreck DJ, Trapp G, Bakshi RS, Mintzer JE, Heidebrink JL, Vidal-Cardona A, Arroyo LM, Cruz AR, Zachariah S, Kowall NW, Chopra MP, Craft S, Thielke S, Turvey CL, Woodman C, Monnell KA, Gordon K, Tomaska J, Segal Y, Peduzzi PN, Guarino PD. Effect of vitamin E and memantine on functional decline in Alzheimer disease: the TEAM-AD VA cooperative randomized trial. JAMA. 2014 Jan 1;311(1):33-44. PubMed.
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University of California, San Diego
The TEAM-AD study revives interest in two areas: treatment with antioxidants such as vitamin E, and carrying out clinical trials in patients with mild to moderate AD to evaluate effects on disease progression.
The findings of a benefit in the vitamin E treatment arm of slowing of functional decline are encouraging—as the authors note, caregivers would appreciate this type of benefit. However, they need to be tempered by the nonsignificant effects in the memantine plus vitamin E treatment arm. Secondary analyses of this trial will be interesting, in particular, the comparison between everyone on vitamin E versus everyone not on vitamin E, and whether baseline dementia severity influenced the findings.
The safety profile of the high dose of vitamin E that was used was good in this population. Unfortunately we do not know whether vitamin E may be influencing CNS oxidative or other pathways in the patients in this study. The lack of this knowledge complicates questions such as dose selection (would 1000 units/day, or a lower dose, work as effectively as 2000, and would an antioxidant cocktail show greater benefits?) and interpretation of findings (does vitamin E improve peripheral function, with a small benefit on maintaining ADL performance, rather than acting on AD pathological pathways?).
The primary outcome measure of functional abilities (ADCS-ADL) was clearly explained by the authors as having unambiguous face value. It also appeared to show two useful characteristics in this long trial: relatively linear change over as long as four years of follow-up, and a significant degree of change to allow a potential treatment effect to be detected. The failure to detect a cognitive effect of treatment is concerning. However, the cognitive outcome measures (MMSE and ADAS-cog) showed relatively little decline during this trial —e.g., the ADAS-cog changed by < 6 points over 24 months, and the MMSE by about 3 points at 24 months and 6 points at 48 months. For comparison, in an 18-month simvastatin clinical trial (Sano et al, 2011), the ADAS-cog declined by 8 – 9.5 points over 18 months. Both of these cognitive tests may be susceptible to floor effects and practice effects in trials in symptomatic AD and efforts are still ongoing to standardize their administration and scoring within trials.
The study population in this trial had a mean age of about 78, which is slightly older than the typical mean age of many AD clinical trials (typically 70-75). This may have influenced the high dropout rate – 7.8 percent every six months. The adherence rate was reported as 65 percent. These factors raise questions about interpreting the statistical significance of this study. Nevertheless, given the absence of effective treatment for AD, these results are likely to encourage further trials of vitamin E or other antioxidant or neuroprotective strategies.
References:
Sano M, Bell KL, Galasko D, Galvin JE, Thomas RG, van Dyck CH, Aisen PS. A randomized, double-blind, placebo-controlled trial of simvastatin to treat Alzheimer disease. Neurology. 2011 Aug 9;77(6):556-63. PubMed.
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