Effect of Vitamin E and Memantine in Alzheimer's Disease
Abstract & Commentary
By Harold L. Karpman, MD, FACC, FACP
Clinical Professor of Medicine, UCLA School of Medicine
Dr. Karpman reports no financial relationships relevant to this field of study.
Synopsis: Among patients with mild-to-moderate Alzheimer's
disease, 2000 IU/d of vitamin E resulted in a slower functional decline and a decrease in the caregiver burden.
Source: Dysken MW, et al. Effect of vitamin E and memantine on functional decline in Alzheimer disease: The TEAM-AD VA cooperative randomized trial. JAMA 2014;311:33-44.
The effects of vitamin e (alpha tocopherol) have previously been studied in patients with moderately severe Alzheimer's disease (AD)1 and in patients with mild cognitive impairment (MCI)2 but not in patients with mild-to-moderate AD. In patients with moderately severe MCI, 2000 IU/d of vitamin E has been demonstrated to be effective in slowing clinical progression, but it has had no benefit in reducing the rate of conversion to AD. Memantine had previously been demonstrated to be effective in patients with AD and moderately severe dementia.3,4,5
The Department of Veterans Affairs (VA) Cooperative Studies Program designed the TEAM-AD trial as a double-blind, placebo-controlled, parallel group study to assess the effectiveness of 2000 IU/d of vitamin E, 20 mg/d of memantine, or the combination in delaying clinical progression of AD in patients who were already taking a background acetylcholinesterase inhibitor. The original sample size of 840 participants resulted in 613 being randomized with the diagnosis of possible or probable AD of mild-to-moderate severity who were then followed from 6 months to 4 years. The primary outcome measurement was the Alzheimer's Disease Cooperative Study/Activities of Daily Living (ADCS-ADL) Inventory6 and the secondary outcome measures included the Mini Mental State Examination7 used to assess cognitive function and dementia severity as well as the Alzheimer Disease Assessment Scale Cognitive Subscale, the Neuropsychiatric Inventory, the Caregiver Activity Survey, and the Dependence Scale, which measured six levels of functional dependence.8 All randomized participants were scheduled for assessments every 6 months for a minimum of 6 months to a maximum of 4 years. A total of 956 participants did not complete the trial because of death or withdrawal of consent, and only a small percentage discontinued because of an adverse event possibly related to the study medications. Withdrawal rates were comparable across treatment groups. Study results determined that a dosage of 2000 IU/d of vitamin E was effective in slowing the functional decline of mild-to-moderate AD and was also effective in reducing caregiver time required in assisting patients. Neither memantine nor the combination of vitamin E and memantine demonstrated clinical benefit in patients with mild-to-moderate AD. The findings suggested that vitamin E is beneficial in mild-to-moderate AD by slowing functional decline and decreasing caregiver burden.
The important finding in the study by Dysken and his colleagues9 was that 2000 IU/d of vitamin E significantly delayed clinical progression in activities of daily living in patients with mild-to-moderate AD who were also taking an acetylcholinesterase inhibitor. The same effect was not found to be present in the memantine or in the memantine plus vitamin E groups. In addition, the caregiver time required increased the least in the vitamin E group compared with the other three groups. It should be noted that the original target sample size could not be achieved because of a lower than expected number of eligible patients. It should also be noted that the follow-up of the enrolled patients proved to be for less time than expected, primarily because of a greater withdrawal and mortality rate than initially had been estimated and also because of the non-uniform enrollment rate over time associated with a larger number of missed final visits than expected. Major limitations of the study were that the withdrawal rates were higher than anticipated, although the withdrawal rates were nearly equivalent across all treatment groups, and because it was a VA study, the percentage of women in the study was relatively small. However, based on the results of previous studies, there is no evidence that the effectiveness of vitamin E and/or memantine differs in males compared to females.1-5
In summary, a dose of 2000 IU/d of vitamin E was effective in slowing the functional decline of mild-to-moderate AD and was also effective in reducing caregiver time required in assisting patients. Neither memantine nor the combination of vitamin E and memantine demonstrated clinical benefits in patients with mild-to-moderate AD. These findings suggested that vitamin E is beneficial in mild-to-moderate AD by slowing functional decline and decreasing caregiver burden.
- Sano M, 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;336:1216-1222.
- Peterson RC, et al. The Alzheimer's Disease Cooperative Study Group. Vitamin E and donepezil for the treatment of mild cognitive impairment. N Engl J Med 2005;352:2379-2388.
- Reisberg B, et al; Memantine Study Group. Memantine in moderate-to-severe Alzheimer's disease. N Engl J Med 2003;348:1333-1341.
- Tariot PN, et al. Memantine Study Group. Memantine treatment in patients with moderate to severe Alzheimer's disease already receiving donepezil: A randomized controlled trial. JAMA 2004;291:317-324.
- Schneider LS, et al. Lack of evidence for the efficacy of the memantine in mild Alzheimer's disease. Arch Neurol 2011;68:991-998.
- Galasko D, et al. An inventory to assess activities of daily living for clinical trials in Alzheimer's disease: The Alzheimer's Disease Cooperative Study. Alzheimer Dis Assoc Disord 1997;11(suppl 2):533-539.
- Folstein MF, et al. "Mini-mental state." A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 1975;12:189-198.
- Stern Y, et al. Assessing patient dependence in Alzheimer's disease. J Gerontol 1994;49:M216-M222.
- Dysken MW, et al. Effect of vitamin E and memantine on functional decline in Alzheimer disease: The TEAM-AD VA cooperative randomized trial. JAMA 2014;311: 33-44.