Vitamin E May Slow Functional Decline in Mild Alzheimer's

Megan Brooks

December 31, 2013

For patients with mild to moderate Alzheimer disease (AD), 2000 IU of vitamin E daily slows functional decline and reduces caregiver burden, according to results of a large randomized controlled trial.

"Previous guidelines had recommended vitamin E for those with moderately severe dementia, but hesitation grew based on several unrelated studies," Mary Sano, PhD, director, Alzheimer Disease Research Center, and professor, Department of Psychiatry, Mount Sinai School of Medicine in New York, who worked on the study, told Medscape Medical News.

"Our study indicates that vitamin E could be recommended to improve functional outcomes, such as activities of daily living, for all levels of Alzheimer's disease starting with mild stages and gives good confidence that it is safe," she said.

No benefit was seen in this trial, however, with memantine or the combination of memantine and vitamin E.

The study is published in the January 1, 2014, issue of JAMA.

"Meaningful" Clinical Benefit

The study, conducted at 14 Veterans Affairs medical centers, assessed the effect of vitamin E alone or with memantine on functional decline in 613 patients (97% men) with mild to moderate AD. At baseline, all of them were receiving an acetylcholinesterase inhibitor — most often donepezil (65%) and galantamine (32%).

By random assignment, 152 patients received 2000 IU of α-tocopherol per day, 155 received 20 mg of memantine per day, 154 received the combination of vitamin E and memantine, and 152 received placebo. They were followed for a mean of 2.3 years.

A total of 256 patients (42%) did not complete the trial. The most common reasons were death (128 patients [50%]) and withdrawal of consent (77 patients [30%]). Data from 561 patients were analyzed (140 in the vitamin E group, 142 in the memantine group, 139 in the combination group, and 140 in the placebo group).

Baseline characteristics were similar in the 4 groups. The mean Alzheimer's Disease Cooperative Study/Activities of Daily Living (ADCS-ADL) Inventory score and Mini-Mental State Examination total score at baseline were 56.8 and 21.0, respectively.

During follow-up, patients taking vitamin E alone had significantly slower functional decline than those taking placebo, experiencing 3.15 units less decline on the ADCS-ADL Inventory.

The annual rate of decline in ADLs was reduced by 19% (P = .03) with vitamin E compared with placebo. This treatment effect translates into a "clinically meaningful" delay in progression of functional decline in the vitamin E group of 6.2 months (95% confidence interval [CI], 5.4 - 7.4 months) compared with placebo, the investigators say.

In addition, on the Caregiver Activity Scale, caregiver time increased least in the vitamin E group compared with the other 3 groups. The delay in functional decline coupled with the reduced caregiver burden seen with vitamin E 2000 IU/d could have a "major effect on informal and direct medical care costs," the investigators say.

They note that the magnitude of functional decline in the placebo group (roughly 3 units more on the ADCS-ADL Inventory than in the vitamin E group) "could translate into either the complete loss of being able to dress or bath independently, for example, or losing independence on any 3 different ADLs. Because vitamin E is inexpensive, it is likely these benefits are cost-effective as alpha tocopherol improves functional outcomes and decreases caregiver burden," they write.

Neither memantine nor the combination of vitamin E and memantine showed clinical benefit in the study, the authors report.

"The lack of effectiveness of memantine in the current study is consistent with the negative findings reported in previous studies of AD patients with mild dementia," the investigators say. The findings "reinforce current VA memantine treatment guidelines that restrict the use of memantine to patients with moderately severe AD," they add.

The "Best" in AD Trials

The results for memantine are "not encouraging," Denis A. Evans, MD, Martha Clare Morris, ScD, and Kumar Bharat Rajan, PhD, from Rush University Medical Center in Chicago, Illinois, note in an accompanying editorial.

Memantine is approved by the US Food and Drug Administration for use in moderate to severe AD, they point out, and use in individuals with milder AD "may be widespread despite little evidence suggesting the agent is beneficial at this level of disease severity." This study of memantine in mild to moderate AD "does not provide any new data to support its use" in this group, the editorialists say.

All-cause mortality and safety data from the study showed a difference only in the serious adverse event of "infections or infestations" with greater frequencies in the memantine (31 events in 23 patients) and vitamin E/memantine combination groups (44 events in 31 patients) compared with placebo (13 events in 11 patients). 

Mortality did not increase significantly with vitamin E, a finding that contrasts with a 2005 meta-analysis of vitamin E (Ann Intern Med. 2005;142:37-46), which showed that high-dose vitamin E (400 IU/d or greater) may increase the risk for all-cause mortality, the investigators point out.

In their editorial, Dr. Evans and colleagues say many features of this trial "reflect the best in trials of AD therapy, especially its size, duration, and separation from commercial motivation. However, as with almost all previous AD trials, the therapeutic effect seen was modest and more relevant to AD symptoms and consequences than to reversal of the disease process."

"Considering the difficulties inherent in trying to treat rather than prevent very high-prevalence diseases and the limitations thus far of the therapeutic efforts for people with AD, shifting to more emphasis on prevention seems warranted," they conclude.

The study was supported by the Veterans Affairs Cooperative Studies Program, Office of Research and Development, Clinical Science R&D. Forest Research Institute, a Division of Forest Laboratories, donated the memantine and matching placebo tablets. DSM Nutritional Products donated the DL-α-tocopheryl acetate oil and funding for the purchase of the soybean oil from Arista Industries. A complete list of author disclosures is listed with the original article.

JAMA. 2014;311:29-30, 33-44. Abstract Editorial

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