Skip to main content

Does vitamin E and/or memantine help in mild to moderate Alzheimer's disease?

Alpha-tocopherol (vitamin E) and dementia have had a long and confusing history. For the prevention of dementia, Vitamin E has generally been shown to be ineffective over follow-up periods that ranged from 7 to 10 years. Even more concerning, higher doses (more than 400mg a day) have actually been shown to increase mortality (in one meta-analysis the all-cause mortality risk difference in high-dosage vitamin E trials was 39 per 10,000 persons).

For the treatment of dementia, Vitamin E’s story is even a little murkier. There was an Alzheimer's Disease Cooperative Study (ADCS) randomized control trial of Vitamin E (alpha-tocopherol) , selegiline (a monoamine oxidase inhibitor), both, or placebo in adults with moderately severe Alzhiemers disease. There was no significant differences in the primary outcomes, however the authors argued that they needed to make statistical adjustments since the placebo group had higher MMSE score at baseline. After adjustment, the authors found a delayed progression to outcome in the vitamin E group. This trial left a lot of uncertainty on what to do with Vitamin E, especially given the mortality concern.  This confusion is somewhat cleared up by the TEAM-AD VA Cooperative Randomized Trial published this week in JAMA.

TEAM-AD VA Cooperative Randomized Trial

This was a randomized clinical trial in older veterans with Alzheimers disease with MMSE scores ranging from 12 to 26, all of who were receiving acetylcholinesterase inhibitors.  The participants were randomized to 4 treatment groups:

  1. Vitamin E (alpha tocopherol) at 2000 IU/day 
  2. Memantine 20 mg/day 
  3. Vitamin E and memantine 
  4. Placebo

The primary trial outcome was about function using a score on the Alzheimer’s Disease Cooperative Study/Activities of Daily Living (ADCS-ADL) Inventory. This s a 78 point score, so a 1 point improvement may be statistically significant but also may have no clinical significance. The authors suggest that a 2 point change may be meaningful as “it potentially represents, for example, a loss of dressing or bathing”. Secondary outcomes included two cognitive measures: the MMSE and the Alzheimer’s Disease Assessment Scale–Cognitive subscale (ADAS-cog), one measure of psychological and behavioral problems (the Neuropsychiatric Inventory), and a measure of time caregivers spend assisting patients with Alzheimers (Caregiver Activity Survey) (CAS), and the Dependence Scale,which assesses 6 levels of functional dependence.


613 veterans (mostly male) were randomized to the four groups and followed for a mean of 2.27 years. 256 participants didn’t complete the trial, mainly because 128 died during the follow up period, however withdrawal rates were similar among all treatment groups.

Primary Functional Outcome (ADCS-ADL Inventory)
Compared with individuals assigned to placebo, those assigned to vitamin E alone experienced 3.15 units less functional decline on the ADCS-ADL Inventory (95% CI, 0.92-5.39; adjusted P = .03).

There was no statistically significant difference in ADCS-ADL score for memantine or the combination group versus placebo (I must say the graphs looked pretty much the same to me for most of the treatments).

Secondary Outcomes
None of the groups differed on the ADAS-cog or the MMSE. Vitamin E did have a statistically significant improvement over memantine on the time caregivers needed to spend assisting patients with ADLs (2.17 hours less in the Vitamin E group).

There was no significant increase in mortality with vitamin E compared to placebo. “Infections or infestations” occurred more frequently in the memantine and the combination group compared with placebo (although I can’t say I’m sure though what the authrs mean by an infestation).

What to do with this information

1) Vitamin E may have some very modest benefit on daily function, but it is unlikely to improve cognition based on this study. Like cholinesterase-inhibitors for dementia, vitamin E gives at best a statistically significant but modest clinical benefit in individuals with mild to moderate disease.    However, this shouldn't be generalized to others as evidence suggests that Vitamin E does not prevent dementia in cognitively normal adults or those with mild cognitive impairment (MCI).

2) Don’t prescribe memantine for mild to moderate dementia. This is just one of several studies showing memantine doesn't really do anything for those with mild to moderate dementia (despite previous attempts by authors to paint some of these articles in a very positive light despite negative results).  Also, in this study the combination of vitamin E and memantine was less effective than vitamin E alone.  For a good review you can read this meta-analysis (

3. The need for Advance Care Planning. Why? 1 out of 5 particants die within a median follow-up time of 2 years. I’ll leave it at that.

by: Eric Widera (@ewidera)

Note: for a great review on this article check out Pam Belluck's article published in the NY Times the New Old Age Blog


Jeanne Lahaie said…
Thank you for another wonderful blog post. Can you advise on what to do if the patient has a history of breast cancer and comorbid mild dementia? Where studies have found vitamin E to increase rates of breast cancer, do the risks outweigh the benefits in taking vitamin E to optimize function?
Eric Widera said…
Vitamin E is has only very modest benefits in mild to moderate AD (a 3 point improvement in a 78 point scale) so I wouldn't say it is a slam dunk for Vitamin E's clinical effectiveness.

I'm also not sure I know of the increased risk for breast cancer (there is some concern for prostate cancer though). There was a large RTC showing that Vitamin E doesn't work for prevention of breast cancer (JAMA. 2005;294(1):56)
Bruce Scott said…
"2) Don’t prescribe memantine for mild to moderate dementia."

I can shorten that:

"2) Don't prescribe memantine."

Be careful Eric. You keep this up and you won't be getting your Big Pharma Shill check this year. :)
Joshua Uy said…
If you do 20 trials in Dementia with Vitamin E measure 3-4 scales/outcomes per trial, eventually one will have a p value <.05 by sheer chance. My guess is that the null hypothesis is still true for Vitamin E.

Popular posts from this blog

The Future of Palliative Care: A Podcast with Diane Meier

There are few names more closely associated with palliative care than Diane Meier.  She is an international leader of palliative care, a MacArthur "genius" awardee, and amongst many other leadership roles, the CEO of the Center to Advance Palliative Care (CAPC).  We were lucky enough to snag Diane for our podcast to talk about everything we always wanted to ask her, including:
What keeps her up at night?Does palliative care need a national strategy and if so why and what would it look like?The history of CAPC and the leadership centersAdvice that she has for graduating fellows who want to continue to move palliative care forward as they start their new careersWhat she imagines palliative care will look like in 10 or 15 years?What is the biggest threat facing palliative care? So take a listen and if you want to dive a little deeper, here are two articles that we discussed during the podcast:
A National Strategy For Palliative Care. Health Affairs 2017Palliative Care Leadership…

Elderhood: Podcast with Louise Aronson

In this week's podcast we talk with Louise Aronson MD, MFA, Professor of Geriatrics at UCSF about her new book Elderhood, available for purchase now for delivery on the release date June 11th.

We are one of the first to interview Louise, as she has interviews scheduled with other lesser media outlets to follow (CBS This Morning and Fresh Air with Terry...somebody).

This book is tremendously rich, covering a history of aging/geriatrics, Louise's own journey as a geriatrician facing burnout, aging and death of family of Louise's members, insightful stories of patients, and more.

We focus therefore on the 3 main things we think our listeners and readers will be interested in.

First - why the word "Elder" and "Elderhood" when JAGS/AGS and others recently decided that the preferred terminology was "older adult"?

Second - Robert Butler coined the term ageism in 1969 - where do we see ageism in contemporary writing/thinking?  We focus on Louise's…

Psychedelics: Podcast with Ira Byock

In this week's podcast, we talk with Dr. Ira Byock, a leading palliative care physician, author, and public advocate for improving care through the end of life.

Ira Byock wrote a provocative and compelling paper in the Journal of Pain and Symptom Management titled, "Taking Psychedelics Seriously."

In this podcast we challenge Ira Byock about the use of psychedelics for patients with serious and life-limiting illness.   Guest host Josh Biddle (UCSF Palliative care fellow) asks, "Should clinicians who prescribe psychedelics try them first to understand what their patient's are going through?" The answer is "yes" -- read or listen on for more!

While you're reading, I'll just go over and lick this toad.


You can also find us on Youtube!

Listen to GeriPal Podcasts on:
iTunes Google Play MusicSoundcloudStitcher
Eric: Welcome to the GeriPal Podcast. This is Eric Widera.

Alex: This is Alex Smith.

Eric: Alex, I spy someone in our …