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 Dangers of Fleet Enemas

The dangers of oral sodium phosphate preparations are fairly well known in the medical community. In 2006 the FDA issued it’s first warning that patients taking oral sodium phosphate preparations are at risk for potential for acute kidney injury. Two years later, over-the-counter preparations of these drugs were voluntarily withdrawn by the manufacturers.  Those agents still available by prescription were given black box warnings mainly due to acute phosphate nephropathy that can result in renal failure, especially in older adults. Despite all this talk of oral preparations, little was mentioned about a sodium phosphate preparation that is still available over-the-counter – the Fleet enema.

Why Oral Sodium Phosphate Preparations Are Dangerous 

Before we go into the risks of Fleet enemas, lets spend just a couple sentences on why oral sodium phosphate preparations carry significant risks. First, oral sodium phosphate preparations can cause significant fluid shifts within the colon …

Length of Stay in Nursing Homes at the End of Life

One out of every four of us will die while residing in a nursing home. For most of us, that stay in a nursing home will be brief, although this may depend upon social and demographic variables like our gender, net worth, and marital status. These are the conclusions of an important new study published in JAGS by Kelly and colleagues (many of whom are geripal contributors, including Alex Smith and Ken Covinsky).

The study authors used data from the Health and Retirement Study (HRS) to describe the lengths of stay of older adults who resided in nursing homes at the end of life. What they found was that out of the 8,433 study participants who died between 1992 and 2006, 27.3% of resided in a nursing home prior to their death. Most of these patients (70%) actually died in the nursing home without being transferred to another setting like a hospital.

 The length of stay data were striking:

the median length of stay in a nursing home before death was 5 months the average length of stay was l…

Palliative Care in Nursing Homes: Discussion of a Multinational Trial with Lieve Van den Block

Nursing homes are a tough place to do palliative care.  There is extremely high staff turnover, physicians are often not present except for the occasional monthly visit, many residents die with untreated symptoms usually after multiple hospitalizations and burdensome life-prolonging treatments, and specialty palliative care - well that is nowhere to be found in most nursing homes outside of hospice.  So what can we do to improve the palliative care outlook in nursing homes?

On todays podcast we talk with Lieve Van den Block about her recent palliative care intervention that was published in JAMA IM this week.  Lieve led a multicomponent intervention to integrate basic nonspecialist palliative care in in 78 nursing homes located in 7 different European countries.  Just take a moment to grasp the size of this study - 7 counties, 78 nursing homes.  I struggle with just trying to improve palliative care in one site!

We discuss with Lieve the results of the study, her take on why they got…