Vitamin E for Mild-to-Moderate Alzheimer Dementia – Is the Evidence Strong Enough?

Alzheimer Dementia (AD) is devastating and we need to start thinking outside the box with regard to treatment options. Currently available medications have only modest symptomatic benefits.¹ Could something as widely available as vitamin E significantly alter the course of cognitive and functional decline invariable caused by AD?

Acheylcholinesterase inhibitors (AChEIs) are approved for use in patients in all stages of AD, while the NMDA-receptor antagonist memantine is approved for treatment in moderate-severe AD.² Vitamin E, also known as alpha tocopherol (AT), is a fat-soluble vitamin with anti-oxidant properties that has been previously studied in patients with moderate-severe AD at a dose of 2000 international units (IU)/day. Patients in that study displayed slower time to progression of disease when compared to placebo.³ AT was not associated with a significant increase in adverse effects.^3,4 Current guidelines do not recommend the use of AT in the treatment of AD as there is insufficient evidence to support its use.²  The recently published Trial of Vitamin E and Memantine in Alzheimer Disease (TEAM-AD) trial contributes to our understanding regarding the efficacy of vitamin E in patients with mild-moderate AD, defined as a mini-mental status exam (MMSE) score between 12-26 at baseline.⁵

The TEAM-AD trial (n=613) was a double-blind, placebo-controlled, parallel-group, randomized-controlled trial to assess the effectiveness of high-dose vitamin E (2000 IU/d), memantine (20mg/d), or the combination of both in delaying clinical progression of AD as measured by changes in the Alzheimer’s Disease Cooperative Study/Activities of Daily Living (ADCS-ADL) inventory in participants concurrently taking a AChEI.⁵ The ADCS-ADL inventory is a 45-item questionnaire (delivered in person or via telephone to participants or caregivers) and it has been used in numerous AD trials designed to assess patient functioning.⁶  The TEAM-AD study was conducted at 14 Veterans Affairs (VA) medical centers.  Most participants were Caucasian men (96%) with a mean age was 78.8 years at baseline and had been treated with either donepezil or galantamine  for a mean of 53 weeks prior to enrollment.  At baseline, the mean score  on ADCS-ADL inventory was 56.8 and the mean MMSE score was 21.⁷ Follow-up was conducted every 6 months for a maximum of 4 years. Secondary outcomes included the MMSE, the Caregiver Activity Survey (CAS), and other scales that assess cognitive and behavioral symptoms.

The planned sample size was 840 participants.  Due to challenges in recruitment, retention, and study staff workload, the data monitoring committee approved a reduction in the sample size to 600 participants with a longer mean follow-up period in order to maintain 90% power. The investigators did not meet their pre-specified power due to a high rate of loss to follow-up.  About 40% of participants did not complete the trial (including 20% who died during the study), illustrating the inherent difficulty in conducting trials in elderly patients with AD.  Of the 613 randomized participants, data from 561 were analyzed with intention-to-treat. The TEAM-AD sample size is comparable to other AD treatment studies, but the duration is one of the longest. Unfortunately adherence to therapy was sub-optimal and study medications were taken only 65-68% of the time. These limitations likely resulted in an underestimation of the potential benefits of AT and memantine.

The results of the TEAM-AD study are a bit of a head scratcher. Participants taking AT experienced a significantly slower decline on the ADCS-ADL inventory when compared to placebo-treated patients. The least squares mean change from baseline was 3.15 units less than the decline observed in the placebo group (95% CI, 0.92-5.39; adjusted p=0.03). The authors suggest that this difference roughly correlates to 6 months in disease progression over the 4 year clinical trial.   AT was not associated with any significant improvements (relative to placebo) in cognitive function, behavioral symptoms, or caregiver burden.  Notably memantine alone or in combination with AT was no more effective than placebo for both the primary and secondary outcomes. The lack of effect associated with memantine use is consistent with previous studies. However, the lack of benefit  from the combination of memantine with AT raises some puzzling questions.^8,9 Type 2 error due to the small sample size may be one explanation but a possible interaction between AT and memantine cannot be ruled out.

The effect of AT on caregiver time and burden as measured by the CAS was another interesting finding. At baseline, caregivers spent 2.7-3.2 hours per day caring for participants.  At study completion AT was associated with a significantly lower increase in the hours per day spent caregiving compared to memantine alone with a mean difference of 2.17 fewer hours (AT = 7.3 to 10.6 hours vs. memantine = 6.7 to 12.2 hours; 95% CI, 0.63-3.71; p=0.03).  But, oddly, there was no significant difference in the CAS between AT and placebo after adjustment for multiple comparisons.  Take note that the caregivers in this study received “extra-attention,” including phone calls from investigators, patient and caregiver education, and access to AD support groups which may have contributed to the observed differences in CAS.⁷

High-dose AT use was not associated with a significant increase in adverse effects or increased mortality in the TEAM-AD study. This contrasts with meta-analyses that suggest an increase in the risk of heart failure, coagulation disturbances, and all-cause mortality when AT doses exceed 400 IU/day in patients with cardiovascular disease or cancer.^2,10,11 The TEAM-AD study wasn’t powered to detect a difference in adverse events or mortality, but perhaps the adverse effect profile is somewhat different in AD.

The TEAM-AD authors conclude that AT is effective at slowing functional decline in mild to moderate AD when used in combination with an AChEI. While these conclusions are enticing, the lack of improvement in cognitive function is worrisome.  The ADCS-ADL inventory is not commonly used in the clinic setting.  Most practitioners typically rely on MMSE and caregiver reports when monitoring patients.  Additionally, functional impairment may be the consequence of other co-morbidities.  Therefore, while the ADCS-ADL findings are intriguing, there may be other explanations why patients in the AT group declined less rapidly.

Should clinicians recommend high-dose AT treatment in combination with AChE inhibitor therapy for patients with mild to moderate AD?  Clearly patients should continue to receive standard of care treatments for AD as recommended in current guidelines, but this does not preclude the use of AT.  Although the evidence to date for AT use isn’t compelling, given the devastating consequence of AD, I believe every patient should be offered AT as add-on therapy.  What do you think?  Do you recommend AT therapy in your patients with Alzheimer’s Disease?