Dysken MW, Sano M, Asthana S, et al. Effect of vitamin E and memantine on functional decline in Alzheimer disease: the TEAM-AD VA cooperative randomized trial. JAMA. 2014;311(1):33-44.
Double-blind, placebo-controlled, parallel-group, randomized clinical trial. Duration was 6 months to 4 years, with a mean follow-up of 2.27 years.
Study included 613 patients with mild to moderate Alzheimer’s disease who were concurrently taking an acetyl-cholinesterase inhibitor (AChEI).
Participants were divided into 4 groups to receive 1 of the following: alpha tocopherol (2,000 IU/d), memantine (20 mg/d), both alpha tocopherol and memantine, or placebo. The alpha tocopherol (as DL-alpha-tocopherol acetate) was delivered in gelatin, liquid-filled capsules.
Primary Outcome Measures
The primary outcome measurement was the Alzheimer’s Disease Cooperative Study/Activities of Daily Living (ADCS-ADL) Inventory Score. This score ranges from 0 to 78, and a lower score reflects lower function. Secondary outcome measurements included cognitive, neuropsychiatric, functional, and caregiver measures.
The slowest decline in mental function was seen in the group assigned to alpha tocopherol alone. The results observed in this group were significant and said to “translate into a delay in clinical progression of 19% per year compared to placebo.” Treatment with memantine alone or in combination with vitamin E did not yield statistically significant benefit.
Vitamin E is of interest in the treatment of Alzheimer's disease (AD) because of its antioxidant properties. It has been proposed that oxidative stress underlies cognitive decline,1,2 and it is well established that vitamin E is a lipid-soluble antioxidant particularly effective at protecting cell membranes and nerve tissue.3
There have, however, been few clinical trials on the effect of vitamin E on Alzheimer's disease. A 2012 Cochrane review4 identified only 3 studies on vitamin E and AD or mild cognitive impairment (MCI). The first showed that alpha tocopherol delayed the progression of AD, but the results were not statistically significant.5 The second showed no benefit of alpha tocopherol in those with MCI.6 The third showed that alpha tocopherol actually promoted progression of AD in some patients.7 The conclusion of the Cochrane review was that “vitamin E should not be used for the treatment of mild cognitive impairment (MCI) and Alzheimer’s dementia (AD).”
In contrast to these previous trials, the current study published in the January 2014 issue of the Journal of the American Medical Association (JAMA) yielded not only statistically significant—but also clinically relevant—therapeutic results of vitamin E for Alzheimer disease.8 The primary outcome measurement (ADCS-ADL Inventory scores) differed by 3.15 units between the alpha tocopherol group and placebo. Authors explain that a difference of only 2 units can shift a person from the ability to perform basic self-care activities, such as dressing or bathing, to reliance on a caregiver to perform these tasks. Further evidence of real-life significance was the finding that those receiving alpha tocopherol required approximately 2 hours less attention from a caregiver per day. What’s more, positive results of vitamin E treatment persisted for the full 4 years of the study.
But before committing to prescribe 2,000 IU/day of alpha tocopherol to all of our patients with cognitive impairment, we should first be clear that all participants in this study continued to experience mental decline throughout its duration. Vitamin E did not halt or reverse disease progression, but rather slowed its progression. We also must review the documented risks associated with high-dose vitamin E and consider the best form of supplemental vitamin E if we choose to prescribe it.
Vitamin E supplementation is not without risk and has, in fact, been associated with an increase in all-cause mortality. A meta-analysis performed as part of a 2012 Cochrane review found that “vitamin E used singly or in combination with other antioxidants significantly increased mortality in 46 trials.”9 This was consistent with a previous meta-analysis of 19 clinical trials that concluded vitamin E (≥400 IU/day) increases all-cause mortality.10 The authors of the latter review suggest that the isolated form of vitamin E (alpha tocopherol) might “displace other fat-soluble antioxidants…disrupting the natural balance of antioxidant systems and increasing vulnerability to oxidative damage.”
Evidence suggests that vitamin E from foods may be safer and more effective than alpha tocopherol provided in supplement form. Two studies of similar design, both reported in JAMA in 2002, found that a higher intake of dietary vitamin E was associated with a lower risk of Alzheimer's disease.11,12 The same result was found in a study reported in 2005 in the Journal of Clinical Nutrition,13 in which authors conclude that “various tocopherol forms rather than alpha-tocopherol alone may be important in the vitamin E protective association with Alzheimer disease.” A more recent publication actually assessed the relationship between all forms of vitamin E (4 tocopherols and 4 tocotrienols) to MCI and AD.14 This study found that mild cognitive impairment and Alzheimer's disease were associated with low plasma levels of all forms of vitamin E—total tocopherols, total tocotrienols, and total vitamin E.
The study under current review had success with 2,000 IU/day of alpha tocopherol for the treatment of Alzheimer's disease with no significant adverse events.15 But given past safety concerns of supplemental alpha tocopherol and the clear evidence of the importance of all forms of naturally occurring vitamin E, I strongly recommend that we do the following: treat our patients with mild cognitive impairment or Alzheimer's disease with foods, food-sourced vitamin E supplements, or supplements that provide the full complement of mixed tocopherols and tocotrienols. With the current study in our toolbox, we can reliably choose an effective dose of 2,000 IU/day.
1. Aliev G, Priyadarshini M, Reddy VP, et al. Oxidative Stress Mediated Mitochondrial and Vascular Lesions as Markers in the Pathogenesis of Alzheimer Disease. Curr Med Chem. 2013
2. Nunomura A. Oxidative stress hypothesis for Alzheimer’s disease and its potential therapeutic implications. Rinsho Shinkeigaku. 2013;53(11):1043-1045.
3. Traber MG, Stevens JF. Vitamins C and E: beneficial effects from a mechanistic perspective. Free Radic Biol Med. 2011;51(5):1000-1013.
4. Farina N, Isaac MG, Clark AR, Rusted J, Tabet N. Vitamin E for Alzheimer’s dementia and mild cognitive impairment. Cochrane Database Syst Rev. 2012;11CD002854.
5. Sano M, Ernesto C, Thomas RG et al. 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;336(17):1216-1222.
6. Petersen RC, Thomas RG, Grundman M et al. Vitamin E and donepezil for the treatment of mild cognitive impairment. N Engl J Med. 2005;352(23):2379-2388.
7. Lloret A, Badia MC, Mora NJ, Pallardo FV, Alonso MD, Vina J. Vitamin E paradox in Alzheimer’s disease: it does not prevent loss of cognition and may even be detrimental. J Alzheimers Dis. 2009;17(1):143-149.
8. Dysken MW, Sano M, Asthana S et al. Effect of vitamin E and memantine on functional decline in Alzheimer disease: the TEAM-AD VA cooperative randomized trial. JAMA. 2014;311(1):33-44.
9. Bjelakovic G, Nikolova D, Gluud LL, Simonetti RG, Gluud C. Antioxidant supplements for prevention of mortality in healthy participants and patients with various diseases. Cochrane Database Syst Rev. 2012;3CD007176.
10. 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;142(1):37-46.
11. Engelhart MJ, Geerlings MI, Ruitenberg A et al. Dietary intake of antioxidants and risk of Alzheimer disease. JAMA. 2002;287 (24):3223-3229.
12. Morris MC, Evans DA, Bienias JL et al. Dietary intake of antioxidant nutrients and the risk of incident Alzheimer disease in a biracial community study. JAMA. 2002;287(24):3230-3237.
13. Morris MC, Evans DA, Tangney CC et al. Relation of the tocopherol forms to incident Alzheimer disease and to cognitive change. Am J Clin Nutr. 2005;81(2):508-514.
14. Mangialasche F, Xu W, Kivipelto M et al. Tocopherols and tocotrienols plasma levels are associated with cognitive impairment. Neurobiol Aging. 2012;33(10):2282-2290.
15. Dysken MW, Sano M, Asthana S et al. Effect of vitamin E and memantine on functional decline in Alzheimer disease: the TEAM-AD VA cooperative randomized trial. JAMA. 2014;311(1):33-44.