Does Vitamin E have a role in the treatment of Alzheimer’s Disease? (Mary Sano) May 2014
Does Vitamin E have a role in the treatment of Alzheimer’s disease?
Mary Sano, Director and ADRC Professor, Department of Psychiatry, Mount Sinai School of Medicine, New York, United States
A new report in the Journal of the American Medical Association (JAMA) provides evidence that vitamin E (alpha tocopherol) may reduce functional decline in patients with mild to moderate Alzheimer’s disease (AD) (Dysken et al., 2014). A randomized clinical trial of vitamin E and memantine compared these agents alone and in combination to placebo in a trial with treatment exposures up to four years with a mean follow-up time of 2.27 years. A significant benefit was seen in the primary outcome, the Alzheimer Disease Cooperative Study Activities of Daily Living (ADCS-ADL) Inventory.
This outcome, developed specifically for measuring functional abilities in those with Alzheimer’s disease, focuses on the amount and type of supervision an individual needs to accomplish instrumental and basic activities of daily living. Participants were taking approved treatments for AD, specifically cholinesterase inhibitors. The study was conducted across the United States in 14 hospitals in the U.S. Veterans Affairs Health Care System and recruited more than 600 participants. A daily dose of 2000 IU of vitamin E and 20 mg of memantine were used alone and in combination. Those receiving vitamin E had a slower decline than those receiving placebo with a three-point difference in the rate of decline, which was described as a 19% per year delay in clinical progression. The effect size was characterized as a six-month delay in progression. Secondary outcomes, which included cognitive and psychiatric measures as well as measure of caregiver time, did not differ between treatment groups. However, the ADAS-cog and the Caregiver Activity Inventory both demonstrated trends in the direction of benefit for the vitamin E group. There were no positive effects for memantine on any outcome.
Of note, vitamin E demonstrated excellent safety with no increased risk of any adverse event except for an increased risk of infection. Annual mortality was lowest in the vitamin E group (7.3%), highest in the memantine groups (11.3%) and intermediate in the placebo group (9.0%; these differences were not significant.
This safety profile is particularly encouraging especially in this population with high rates of cardiovascular disease and multiple comorbidities. It is in contrast to the concerns raised by a meta-analysis by Miller et al., (2005), which suggested increased mortality with high dose vitamin E among individuals with other diseases, particularly when it was taken in combination with other anti-oxidant vitamins.
The motivation for this study arose from findings from a 1997 paper that demonstrated a delay in clinical progression among those with moderate AD of approximately 6 months—there was also no cognitive benefit observed in that trial. Additionally, the earlier study was conducted prior to the availability of approved treatments. Thus, the new results extend the population with an observed benefit to those with milder disease who are currently receiving standard of care treatments. Of note, previous trials with memantine have also been unable to demonstrate efficacy in mildly impaired AD participants.
There are several limitations in this study. For example, the population was primarily male as is common in many veteran studies, though it was ethnically diverse with a 14% non-white population. There was also minimal collection of biomarkers that might assist in defining the mechanisms of action.
It has been assumed that vitamin E action was via its antioxidant properties; however, a trial that used vitamin E in combination with other antioxidants was unable to show this association (Galasko et al., 2012). Specifically, an antioxidant cocktail of 800 IU/d of vitamin E (α-tocopherol) plus 500 mg/d of vitamin C plus 900 mg/d of α-lipoic acid (E/C/ALA) administered over a 16-week period was able to lower cerebrospinal fluid levels of isoprostanes, an oxidative stress biomarker, but was associated with worsening of cognition. While such a result is difficult to attribute to vitamin E it does raise doubt about its potential mechanism of action.
This report provides strength to the use of vitamin E as a treatment in AD, though other data tempers this enthusiasm. In a trial using a similar dose of vitamin E in those with Mild Cognitive Impairment (MCI), no benefit was seen on the primary endpoint, time to transition to dementia, nor was there a benefit on functional or cognitive outcomes (Peterson et al., 2005).
There remains a challenge of applying these findings in clinical practice. A growing evidence base supports the use of vitamin E in AD to achieve the functional benefit of delaying decline, though not in prodromal conditions such as MCI. Further, the safety profile of vitamin E in neurologic conditions may be acceptable. The results are positive enough to warrant independent review to determine if changes in current practice should be considered.
- Dysken, M.W., 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.
- Galasko, D.R., Peskind, E., Clark, C.M., et al. Antioxidants for Alzheimer disease: a randomized clinical trial with cerebrospinal fluid biomarker measures. Archives of Neurology. 2012; 69: 836-41.
- Miller, III, E.R., Pastor-Barriuso, R., Dalal, D., Riemersma, R.A., Appel, L.J., Guallar, E. Meta-analysis: high-dosage vitamin E supplementation may increase all-cause mortality. Annals of Internal Medicine. 2005; 142(1): 37-46.
- Petersen, R.C., Thomas, R.G., Grundman, M., et al. Alzheimer’s Disease Cooperative Study Group. Vitamin E and donepezil for the treatment of mild cognitive impairment. New England Journal of Medicine. 2005; 352(23): 2379-2388.
- Sano, M., Ernesto, C., Thomas, R.G., et al. A controlled trial of selegiline, alpha-tocopherol, or both as treatment for Alzheimer’s disease: the Alzheimer’s Disease Cooperative Study. New England Journal of Medicine. 1997; 336(17): 1216-1222.