Recently you may have seen headlines like “Vitamin E slows decline in patients with mild Alzheimer’s” or “There’s still no cure for Alzheimer’s disease, but the latest hope for slowing its progression is already on drugstore shelves.” They were referring to an article in the January 1, 2014 issue of the Journal of the American Medical Association (JAMA) announcing the results of the TEAM-AD VA Cooperative Randomized Trial of vitamin E and memantine (Namenda) for Alzheimer’s disease (AD).
The study attracted a lot of media attention. Most of the news reports I have seen were accurate and cautious, explaining the nuances of the study rather than suggesting that everyone should run out and buy vitamin E; but I wouldn’t be surprised to learn that a lot of readers ignored the fine print and did just that. It would be interesting to track sales of vitamin E and see if there was a bump following the publicity.
We know of no treatment that will delay, prevent or cure Alzheimer’s disease, or that affects the underlying disease process. It’s a tragic, frustrating disease that takes away the very things that make us who we are: memory and personality. It is affecting more and more people as the numbers of elderly increase. Available prescription medications are only modestly effective in slowing functional decline and delaying the need for institutionalization. They are expensive, they don’t help everyone, and when they do help, they only help for a limited time. It is very exciting to think an inexpensive vitamin could help patients with mild to moderate AD, but we must resist the temptation to read too much into this study.
The study was a large, rigorous, multicenter randomized placebo-controlled trial with 33 authors, carried out at 14 Veterans Affairs (VA) medical centers. It enrolled 613 patients age 53 to 96 with a diagnosis of possible or probable AD of mild to moderate severity who were already taking an acetylcholinesterase inhibitor (AChEI). 65% were on Donepezil, 32% on Galantamine, and 3% on Rivastigmine); 97% were male, 86% were white, 13% black, and 11% Hispanic. (Note: these were classified as possible or probable cases, since definitive diagnosis of AD is only possible at autopsy.)
Participants were randomized to one of four groups:
- Alpha tocopherol (vitamin E) 1,000 IU twice a day + memantine-matching placebo
- Memantine 10 mg twice a day + vitamin E-matching placebo
- Both vitamin E and memantine
- Two placebos
Primary outcome measure was the Alzheimer’s Disease Cooperative Study/Activities of Daily Living Inventory (ADCS-ADL), a validated questionnaire that assesses functional abilities to perform activities of daily living. A difference of 2 points on this scale is generally considered significant because it potentially represents, for example, a loss of dressing or bathing independently. Secondary outcome measures included tests of cognitive function and dementia severity, memory, language and praxis functions, assessment of psychological and behavioral problems, the time required for caregivers to assist patients in major areas of daily activities, and a measure of functional dependence.
Annual assessments included physical exams, review of concomitant medications, blood concentrations of the study drugs to assess adherence, and careful questioning about adverse experiences. 42% of subjects failed to complete the trial, most commonly due to death (50%), withdrawal of consent (30%) and adverse events possibly related to the study medication (1%). Mean follow-up time was 2.27 years.
All participants got worse over the period of the study. Subjects in the vitamin E group had a significantly slower decline than those in the placebo group (3.15 units less on the ADCS-ADL Inventory, annual rate of decline 19% less, delay in progression of 6.2 months). There was no significant difference between the placebo group and the memantine or memantine + vitamin E groups. The group taking both vitamin E and memantine did significantly worse than the group taking vitamin E alone.
Adherence was estimated at 65-68%, which isn’t all that bad considering the age of patients and the effects of Alzheimer’s.
Secondary outcomes showed no significant differences between the four groups except that caregiver hours increased less in the vitamin E group than in the memantine group.
Safety: there were no significant differences between groups for serious adverse events. The annual mortality rate was 7.3% for vitamin E, 11.3% for memantine, 9% for vitamin E + memantine, and 9.4% for placebo.
They concluded that 2,000 IU of vitamin E significantly delayed clinical progression in activities of daily living in patients with mild to moderate AD who were also taking AChEI. Paradoxically, the combination of memantine and vitamin E had less effect than either drug alone; the authors could not think of a plausible mechanism for this finding. No significant changes were seen in cognition or memory, but the researchers considered the 6.2-month delay in progression of functional loss to be of more practical importance. Mortality rate was reduced with vitamin E, in contrast to a previous meta-analysis of vitamin E studies that had showed an increase in all-cause mortality with doses typically lower than the 2,000 IU used in this study. Interestingly, only one study in that meta-analysis involved Alzheimer’s patients, and that one also showed a decrease in mortality.
An accompanying editorial praised the study as reflecting the best in trials of AD therapy, especially because of its size, duration, and separation from commercial motivation; but it characterized the therapeutic effect as “modest” and more relevant to functional disability than to any effect on the disease process itself. They pointed out that functional ability is non-specific (decreasing with age as well as with disease), that the primary outcome was not confirmed by any of the secondary outcomes, and that the mechanism of vitamin E in AD is uncertain. Memantine is only approved for moderate to severe AD, and this study confirms that it is not indicated for milder disease. The results for vitamin E are encouraging, but can’t be extrapolated to situations other than the specific ones in the study.
An ND quoted on one website said “This new study demonstrates that scientists seeking to slam the door on vitamins, and new vitamin research, is the antithesis of what science is all about.” He is responding to a straw man. Several recent studies and editorials have discouraged indiscriminate use of multivitamins in healthy populations, especially as a substitute for a nutritious diet. But no one has recommended we stop studying individual vitamins for new indications where there is preliminary evidence that they might be helpful in specific populations or diseases.
This study is encouraging, but it doesn’t mean everyone should start taking high doses of vitamin E to ward off Alzheimer’s. And it would be premature to incorporate vitamin E into routine treatment of Alzheimer’s patients on the basis of this one study. There are too many unanswered questions. Women and minority groups were underrepresented, the interaction with memantine is puzzling, the secondary outcomes didn’t support the primary outcome, the beneficial effect on mortality may not be generalizable to all AD patients, and interactions with other medications or illnesses have not been studied.
I agree with the Alzheimer’s Association’s call for caution:
No one should take vitamin E to treat Alzheimer’s disease except under the supervision of a physician. Vitamin E — especially at the high doses used in the ADCS study — can negatively interact with other medications, including those prescribed to keep blood from clotting or to lower cholesterol.
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