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Neurology Today:
doi: 10.1097/01.NT.0000444717.40136.88
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Vitamin E has Modest Benefit for Early AD

Fitzgerald, Susan

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ARTICLE IN BRIEF

Investigators reported that patients with mild to moderate Alzheimer's disease who took 2,000 international units of vitamin E daily experienced a slowing of functional decline of about six months over an average of two years compared with patients not taking vitamin E. In addition, their caregivers spent two less hours a day helping them.

Vitamin E may slow functional decline in people with mild to moderate Alzheimer disease (AD), in turn lessening the burden on caregivers.

A study, published in Jan. 1 Journal of the American Medical Association (JAMA), found that patients who took 2,000 international units of vitamin E daily experienced a slowing of functional decline of about six months over an average of two years compared with patients not taking vitamin E. In addition, their caregivers spent two less hours a day helping them.

The study is likely to renew interest in vitamin E for patients with early stages of AD, though the benefits demonstrated in the study were modest. Some clinicians had backed away from recommending vitamin E for AD patients when a 2005 meta-analysis of vitamin E studies in the Annals of Internal Medicine, mostly involving cardiovascular patients, found a link between high-dose vitamin E and increased mortality.

“This study is going to put vitamin E back on the table for discussion,” said Ronald C. Petersen, MD, PhD, director of the Mayo's Alzheimer Disease Research Center, who was not involved in the study. “It does provide some functional improvement, and that's important for patients and also their caregivers.” Still, “is vitamin E a game changer?” Not necessarily, Dr. Petersen told Neurology Today.

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STUDY METHOLOGY

The study of 613 patients was conducted at 14 Veterans Affairs medical centers around the country and was sponsored by the VA Cooperative Studies Program. The participants were randomly assigned to receive one of four daily therapies: 2,000 IU of alpha tocopherol (synthetic vitamin E); 20 mg of the drug memantine; a combination of the two therapies; or a placebo. The study group was 97 percent male and all were also receiving acetylcholinesterase inhibitors. Patients who were taking warfarin were excluded from the study.

The main outcome measure for the study was the Alzheimer's Disease Cooperative Study – Activities of Daily Living (ADCS-ADL) Inventory score — scores range from 0 to 78, with lower scores indicating poorer function. Secondary outcomes included cognitive, neuropsychiatric, functional and caregiver measures. The participants were followed for an average of 2.27 years.

“Participants receiving alpha tocopherol had slower decline than those receiving placebo as measured by the ADCS-ADL,” the researchers concluded. Specifically, their scores on the scale declined on average 3.15 points less than did the average score of patients taking the placebo. “That change translates into a delay in clinical progression of 19 percent per year compared with placebo (approximately 6.2 months over the follow-up period). Caregiver time increased least in the alpha tocopherol group.”

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QUESTIONS ABOUT MEMANTINE'S USEFULNESS

The study found no advantage in taking vitamin E plus memantine, a drug that is approved for use in the US for moderate to severe AD. They were unable to explain why a combination of the two did not lead to better results. The investigators also found that memantine alone conferred no benefit over placebo.

While the group taking vitamin E experienced a slower rate of functional decline, none of the active therapy groups, including those taking vitamin E, differed from the placebo group on measures of cognition that included the Mini-Mental State Examination (MMSE) and the Alzheimer Disease Assessment Scale-Cognitive Subscale (ADAS-cog).

“We would have liked to have seen a change in cognition,” the study's lead author, Maurice W. Dysken, MD, professor of psychiatry at the University of Minnesota, told Neurology Today. “We don't know why we didn't. It's possible that if the magnitude of benefit we saw on the functional level were greater, we might have seen a significant benefit with cognition.”

Dr. Dysken, formerly the director of the Geriatric Research, Education and Clinical Center at the Minneapolis VA Health Care System, said that regardless of the lack of a positive cognitive outcome in the study, the functional benefit should be reason enough for doctors to consider vitamin E therapy for their earlier-stage Alzheimer's patients.

While experts have differing views on the clinical significance of the ADCS-ADL scale, even a modest slowdown in deterioration of function can mean the difference between an Alzheimer patient being able to dress and bathe independently rather than needing the assistance of a caregiver, according to background information in the study.

The “delay in progression with vitamin E is clinically meaningful and is better than nothing,” the study authors wrote.

The study found no increase in serious adverse events in those taking Vitamin E, though there was an increase in a category classified as “infections and infestations” in the group taking memantine and a combination of memantine and vitamin E when compared to placebo.

Research into vitamin's E role in the treatment of Alzheimer disease has been mixed. A 1997 study in the New England Journal of Medicine found that vitamin E was useful for slowing the clinical progression of AD in patients with moderately severe disease, according to the current JAMA study authors. However, a 2005 study, also in the New England Journal of Medicine, found that the vitamin offered no benefit when it came to reducing the rate of conversion from mild cognitive impairment (MCI) to AD.

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CONCERNS ABOUT MORTALITY

Some clinicians became wary of vitamin E when the 2005 meta-analysis, which wasn't specifically about AD, found a link between high doses of vitamin E and an increase in all-cause mortality.

Rachelle S. Doody, MD, PhD, a professor of neurology and director of the Alzheimer's Disease and Memory Center at Baylor College of Medicine, said her center never stopped recommending vitamin E to its patients, however. She and her colleagues undertook a review of their patients and found that vitamin E had no adverse effect on survival in patients followed for up to 15 years. In fact, the study, published in 2009 in the journal, Dementia and Geriatric Cognitive Disorders, found that patients taking vitamin E tended to survive longer.

Dr. Doody said she remains convinced that vitamin E has a place in combination therapy and she typically recommends a dose of 1,000 IUs twice a day.

“I really think it is going to catch on this time,” she said of the latest findings on vitamin E. Dr. Doody said that while some observers lament the lack of home-run therapies for AD, even modest progress in treating the disease needs to be recognized as a good thing for patients and their families.

Walter Kukull, PhD, professor of epidemiology and director of the National Alzheimer's Coordinating Center at the University of Washington, said the new study was “very well done.” But he said he was disappointed to see that the benefit of taking vitamin E appeared to be very modest and limited to functional performance and that cognitive function was not significantly affected.

“I'm not sure what the findings really mean,” Dr. Kukull said. “Maybe it is something, but it does not appear to be a breakthrough that will change things around dramatically.”

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A NEED TO FOCUS ON PREVENTION

An editorial accompanying the JAMA study acknowledged that the new study raised questions that need to be further explored. Why was memantine not shown to be effective? And why did vitamin E show a benefit but not vitamin E plus memantine?

“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,” the editorial by Denis A. Evans MD, of Rush University, and others noted. “The importance of treating patients with AD is clear, but finding the balance between treatment and prevention efforts is challenging for this grim disease affecting millions of people from all developed countries.”

“Considering the difficulties inherent in trying to treat rather than prevent high prevalence diseases and the limitations thus far of the therapeutic efforts for people with AD, shifting to more emphasis on prevention seems warranted,” the editorial concluded.

In the case of vitamin E, however, there is no evidence it can prevent Alzheimer disease.

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LINK UP FOR MORE INFORMATION:

•. Dysken MW, Sano M, Asthana S, et al. Effect of vitamin E and memantine on functional decline in Alzheimer disease: The TEAM-AD VA Cooperative Randomized Trial. JAMA. 2014; 311:(1):33–44.

•. Miller ER III, Pastor-Barriuso R, Dalal D, et al. Meta-analysis: High-dosage vitamin E supplementation may increase all-cause mortality. Ann Intern Med. 2005; 142:(1):37–46.

•. Petersen RC, Thomas RG, Grundman M, et al. for the Alzheimer's Disease Cooperative Study Group. Vitamin E and donepezil for the treatment of mild cognitive impairment. N Engl J Med. 2005; 352:(23):2379–2388.

•. Pavlik VN, Doody RS, Rountree SD, et al. Vitamin E use is associated with improved survival in an Alzheimer's disease cohort. Dement Geriatr Cogn Disord. 2009; 28:(6):536–540.

•. Sano M, Ernesto C, Thomas RG, 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:(17):1216–1222.

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