07 Jan 2014

Offering a renewed glimmer of hope that vitamin E could benefit people with dementia, results from the Trial of Vitamin E and Memantine in Alzheimer’s Disease (TEAM-AD) study suggest that the supplement modestly delays functional impairment in people with mild to moderate AD when taken for an average of 2.3 years. Tempering the findings were the absence of cognitive benefits, and the fact that any perks from vitamin E disappeared in combination with memantine, an NMDA receptor antagonist approved for patients with moderate to severe AD. Scientists led by Maurice Dysken of the Minneapolis Veteran Affairs Health Care System published their results in the January 1 Journal of the American Medical Association. While scientists expressed differing opinions on the study's significance, most agreed that the effects were small and more research was warranted. The findings made the popular press, including The New York Times. 

"In reality, the magnitude of the benefit is modest," said Ron Petersen, Mayo Clinic, Rochester, Minnesota, who was not involved with the new study but has tested vitamin E in patients with mild cognitive impairment before. "This is not a major game-changer for AD." He said that Alzheimer's patients considering taking vitamin E should do so under a physician's advice, as risks such as hemorrhage accompany high doses of this food supplement. 

Vitamin E’s history with Alzheimer's goes back more than a decade. Researchers led by Mary Sano at the James J. Peters VA Medical Center, New York, a co-author on the new study, previously reported the antioxidant slowed functional decline in people with severe AD (see Apr 1997 news story on Sano et al., 1997). Vitamin E did not appear to stall progression from mild cognitive impairment to AD, however, and a controversial meta-analysis suggesting higher mortality rates in vitamin E users discouraged physicians from prescribing it (see Apr 2005 news story; Miller et al., 2005). On top of that, a study questioned the rationale behind the treatment when it found that while vitamin E modestly improved a biomarker of oxidative stress, it had no effect on the two key AD markers Aβ and tau and failed to halt cognitive decline (see Mar 2012 news story). Still, no one had examined whether the antioxidant prevented deterioration in early stages of established disease. 

In 2007, Dysken and colleagues set out to do that. They enrolled 613 patients with mild to moderate AD who were taking acetylcholinesterase inhibitors. Participants were randomized to one of four groups: those who received 2,000 international units of vitamin E per day, vitamin E plus 20 milligrams of memantine, memantine alone, or placebo. Each group was matched for average baseline cognitive and functional scores, though individual scores varied within groups. The researchers then monitored function and cognition every six months for up to four years. Fifty-two participants died or withdrew consent before the researchers could collect follow-up data, including three who dropped out because of adverse events that could have been related to the treatments. Data from 561 patients made the final analysis. The authors noted equal dropout rates between groups, and no indication of a higher mortality rate in vitamin E users.

Compared with placebo, the average 2.3-year vitamin E treatment led to a 19 percent drop in annual rate of decline on the Alzheimer’s Disease Cooperative Study/Activities of Daily Living Inventory, which measures ability to perform daily functions such as bathing. That roughly equals a 6.2-month delay in clinical progression. Furthermore, the amount of time caregivers spent with patients rose more slowly in this group compared with those on memantine alone. While patients in the vitamin E group performed slightly better on cognitive tests than those on placebo, the trends fell below statistical significance. Curiously, volunteers taking both vitamin E and memantine showed no functional benefit, and memantine alone proved just as ineffective. 

The functional improvement echoes that from the earlier study on people with severe AD, but Dysken said he is unsure why either occurred in the absence of cognitive changes. High dropout rates could have masked positive cognitive results, he suggested. Martha Clare Morris, Rush University, Chicago, who co-authored an accompanying JAMA editorial, suggested the gains could be unrelated to AD progression, and could simply reflect mitigation of age-related decline in function. Alternatively, she suggested that function may be a more sensitive way to track disease than cognition. Regardless, because this is the second randomized trial to suggest a functional benefit of vitamin E in AD and the supplement is cheap and seems relatively safe, more physicians may now prescribe the vitamin, she wrote. However, Morris and co-authors point out in the editorial that the study highlights the challenges inherent in combining treatments. While vitamin E worked with acetylcholinesterase inhibitors, it did not work with memantine.

Some saw this as an indication the vitamin simply does not work. Lon Schneider, University of Southern California, Los Angeles, said that given the high dropout rate and baseline heterogeneity in each group, any benefit in the vitamin E group may have arisen by chance, especially since it disappeared in combination with memantine and went unsupported by secondary outcomes. No proposed mechanism explains why memantine would interfere with vitamin E, so any benefits should have emerged in the memantine/vitamin E group as well, he said. However, this study does provide a hypothesis for vitamin E that could be tested in a larger study, he told Alzforum.

The authors do not plan to follow these patients any further. However, Dysken said they will re-analyze the data to look for effects of ApoE4 status and blood levels of vitamin E and memantine, to see if they better predict outcomes.—Gwyneth Dickey Zakaib

Comments

1. • Douglas Galasko
     University of California, San Diego
   • Posted: 10 Jan 2014
   • Paper: Effect of vitamin E and memantine on functional decline in Alzheimer disease: the TEAM-AD VA cooperative randomized trial.

   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.

   View all comments by Douglas Galasko

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References

News Citations

1. Vitamin E, Antioxidants and Alzheimer's Disease 22 Nov 2002
2. Early Intervention Trial Bears Little Fruit, but Sows Hope 15 Apr 2005
3. Antioxidants No Help for Alzheimer’s, Biomarker Trial Says 23 Mar 2012

Paper Citations

1. Sano M, Ernesto C, Thomas RG, Klauber MR, Schafer K, Grundman M, Woodbury P, Growdon J, Cotman CW, Pfeiffer E, Schneider LS, Thal LJ. A controlled trial of selegiline, alpha-tocopherol, or both as treatment for Alzheimer's disease. The Alzheimer's Disease Cooperative Study. N Engl J Med. 1997 Apr 24;336(17):1216-22. PubMed.
2. Miller ER, Pastor-Barriuso R, Dalal D, Riemersma RA, Appel LJ, Guallar E. Meta-analysis: high-dosage vitamin E supplementation may increase all-cause mortality. Ann Intern Med. 2005 Jan 4;142(1):37-46. PubMed.

External Citations

1. The New York Times

Further Reading

News

1. In Mice, Oxidative Changes Come Early and Antioxidants Work 27 Apr 2012
2. Antioxidants No Help for Alzheimer’s, Biomarker Trial Says 23 Mar 2012