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Vitamin E may slow functional decline in Alzheimer’s

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Vitamin E: More questions than answers

This study contains both potentially good and bad news for Alzheimer’s disease therapy, Dr. Denis Evans and his coauthors wrote in an accompanying editorial (JAMA 2014;311:29-30).

"For memantine therapy in this context, the trial results are not encouraging," wrote Dr. Evans. "Use in individuals with milder AD may be widespread, despite little evidence suggesting the agent is beneficial at this level of disease severity. This trial ... does not provide any new data to support its use."

For vitamin E, however, the results are more intriguing, especially in light of findings from prior studies.

"A previous trial among individuals with moderate to severe AD found delayed disease progression with 2,000 IU/day of [vitamin E] both alone and in combination with selegiline (N. Engl. J. Med. 1997;336:1216-22). The results of a trial of vitamin E therapy among people with mild cognitive impairment were null, however, as were the results of trials examining the effects of vitamin E on cognitive function among people with normal cognition."

The study begs three questions, Dr. Evans noted. First, is the use of functional ability a more sensitive measure of AD progression than cognition, which showed no improvement?

Second, why did the secondary measures of caregiver time and dependence not confirm the primary finding of a slower functional decline?

Third, how would vitamin E work to delay decline in Alzheimer’s? "Much attention is focused on its antioxidant properties, but this mechanism is not specific for AD," Dr. Evans wrote.

"Although these considerations do not lessen the significance of the difference found between the group randomized to vitamin E and the group randomized to placebo for the primary outcome, this difference would have been more convincing if also supported by parallel improvements in the relevant secondary outcomes and by a vitamin E mechanism of action more specific to AD."

Dr. Evans is the Alla V. and Solomon Jesmer Professor of Medicine at Rush Medical Center, Chicago. He had no commercial financial disclosures. A coauthor, Dr. Martha Clare Morris, reported receiving consultant fees from Nutrispective.


 

High-dose vitamin E significantly slowed functional decline over 2 years in a population of patients with mild-moderate Alzheimer’s disease.

Compared with placebo, 2,000 IU daily of vitamin E reduced progression by 19% per year, Dr. Maurice W. Dysken and his colleagues wrote in the January issue of the Journal of the American Medical Association (JAMA 2014;311:33-44 [doi:10.1001/jama.2013.28283]).

Patients who took vitamin E scored about 3 units higher on a measure of daily function, wrote Dr. Dysken of the Minneapolis Veterans Affairs Health Care System. "A loss of this magnitude could translate into either the complete loss of being able to dress or bathe independently, or losing independence on any three different activities of daily living."

Vitamin E also proved better than memantine at delaying progression, although the difference was not statistically significant. But paradoxically, the combination of vitamin E and memantine was significantly less helpful than either intervention alone.

The 4-year study randomized 613 patients with mild-moderate Alzheimer’s into four treatment groups: placebo, 2,000 IU/day of vitamin E, 20 mg/day memantine, a combination of both, or placebo.

The primary outcome was change on the Alzheimer’s Disease Cooperative Study/Activities of Daily Living Inventory (ADCS-ADL). Secondary endpoints included the Alzheimer’s Disease Assessment Scale-cognitive (ADAS-Cog), the Mini Mental State Examination (MMSE), the Neuropsychiatric Index (NPI), and the Caregiver Activity Survey (CAS), a measure of the time caregivers spend assisting Alzheimer’s patients.

The patients were a mean of 79 years old; 97% were men. About half had at least one apolipoprotein E4 allele. The mean baseline score on the ADCS-ADL was 57 on a scale of 0-78, with lower numbers representing worse function.

The final analysis contained data on 561 patents. The dropout rate was similar between the groups; most of it was from death during the study. Only three withdrew from medication-related adverse events.

The mean follow-up time was just over 2 years. The mean decline on the ADCS-ADL from baseline was 3.15 units less than the decline in the placebo group. "The treatment effect translates into a clinically meaningful delay in progression in the [vitamin E group] of 6.2 months," the investigators wrote. "A delay in progression was sustained throughout most of the trial, with delays at 1, 2, 3, and 4 years of 10.6, 8.7, 9.3, and 1.8 months, respectively."

The placebo group also declined more than both the memantine and combination groups, but those differences were not statistically significant.

However, there was a significant negative treatment interaction between vitamin E and memantine, with patients who took the combination performing worse than patients taking either of the interventions alone.

There were no between-group differences in the rate of cognitive decline or neuropsychiatric symptoms. Patients in the vitamin E group did require about 2 hours less of caregiver time per day, compared with those on memantine, but that difference was not statistically significant, with a confidence interval of 0.63-3.71.

Despite being statistically nonsignificant, the authors said the reduction in caregiver time was clinically meaningful and could have "a major effect on informal and direct medical costs. ... The loss of the ability to perform ADLs is associated not only with increased caregiver burden, but also with nursing home placement," the investigators noted.

Any "infection or infestation" was the only category of adverse events reported significantly more commonly in both the memantine and combination groups. The most common, occurring in at least 5% more of treated than placebo patients, were falls, bleeding, pneumonia, and urinary tract infections.

Annual mortality was similar between the groups: 7% for the vitamin E group, 11% for the memantine group, and 9% for both the combination and placebo groups. This finding is in contrast to a 2005 meta-analysis that found a significant mortality increase associated with vitamin E doses exceeding 400 IU/day (Ann. Intern. Med. 2005;142:37-46).

The meta-analysis included only one Alzheimer’s study, the authors noted. In it, all-cause mortality was lower in the vitamin E groups, compared with the other treatment groups.

The finding of a "rather robust" treatment effect is confusing, given the results of previous studies of vitamin E in Alzheimer’s patients – especially in light of a 2005 trial in patients with mild cognitive impairment, Dr. Richard Caselli, professor of neurology and associate director and clinical core director of the Alzheimer’s Disease Center at the Mayo Clinic in Scottsdale, Ariz., said in an interview.

That trial, part of the Alzheimer’s Disease Cooperative Study, randomized patients to 2,000 IU/day vitamin E, donepezil, or placebo. The overall rate of progression to Alzheimer’s was 16% per year, and there were no differences between either active group and the placebo group.

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