Vitamin E for Alzheimer's Report Cautiously Interpreted

Psychiatric TimesPsychiatric Times Vol 14 No 6
Volume 14
Issue 6

This two-year study of 341 patients is the largest controlled trial conducted in a population with moderately severe Alzheimer's. The primary end points, assessed quarterly, were the onset of severe dementia (clinical dementia rating of 3); death; institutionalization; and loss of ability to perform at least two of three basic daily activities (eating, grooming and toileting).


Functional deterioration associated with Alzheimer's disease was delayed for the first time in a randomized controlled drug trial with use of either vitamin E, selegiline (Eldepryl) or the combination.

Mary Sano, Ph.D., and colleagues of the Alzheimer's Disease Cooperative Study, reported in the April 24 New England Journal of Medicine that patients receiving daily doses of either 2,000 IU alpha-tocopherol, 10 mg of the selective monoamine oxidase inhibitor selegiline or the combination sustained performance of daily living activities without institutionalization for approximately five to seven months longer than those receiving placebo (Sano and others).

This two-year study of 341 patients is the largest controlled trial conducted in a population with moderately severe Alzheimer's. The primary end points, assessed quarterly, were the onset of severe dementia (clinical dementia rating of 3); death; institutionalization; and loss of ability to perform at least two of three basic daily activities (eating, grooming and toileting).

No effect on cognition, a secondary outcome measure, was found in any treatment group. While cognitive measures are typically applied as an index of symptomatic improvement over short intervals, the investigators suggested that these may not serve as well over longer periods to measure deterioration of patients with moderately severe Alzheimer's disease. "Perhaps functional and occupational measures of cognitive capacity are better indicators of disease progression than psychometric measures," they said.

The effects of vitamin E and selegiline on Alzheimer's were investigated in the assumption that oxidative stress and accumulation of free radicals accompany the cholinergic, noradrenergic and dopaminergic neural degeneration in the disease. The antioxidant effect of vitamin E has previously been shown in animal models to reduce cerebral ischemic neuronal damage in hippocampal cells (Hara and colleagues) and enhance neurologic recovery after spinal cord compression (Anderson and cohorts).

In vitro, vitamin E has inhibited lipid peroxidation and reduced cell death associated with the -protein found in the amyloid plaques characteristic of Alzheimer's (Behl and others). The investigators posited that selegiline may also act as an antioxidant that reduces neuronal damage by inhibiting oxidative deamination. They also anticipated that increased levels of brain catecholamines from the monoamine oxidase inhibition of selegiline would prove beneficial in Alzheimer's.

Vitamin E was administered as the racemic mixture dl-alpha-tocopherol 1,000 IU twice daily, and the selegiline as 5 mg twice daily. In addition to the primary outcome measures, changes in cognition were assessed with the cognitive portion of the Alzheimer's Disease Assessment Scale and Mini-Mental State Examination; functional changes with the Blessed Dementia Scale and the Dependence Scale; and behavioral disturbance with the Behavior Rating Scale for Dementia.

Relative to patients receiving placebo, those receiving selegiline experienced an additional 215 days before a primary measure of deterioration occurred; those on vitamin E gained 230 days; and those receiving the combination gained 145 days. The investigators considered several possibilities for the lack of additive effect from the combined treatments. "Perhaps both agents exert their effects through the same mechanism, with either agent producing a maximal benefit," they suggested.

"Alternatively, each agent may work through an independent mechanism, but the disease may have been sufficiently severe that no additive benefit could be observed. Finally, one agent may interfere with the absorption or metabolism of the other, resulting in an effect that is not additive."

An accompanying guest editorial offered a cautious interpretation of this study. Coauthor Paul Leber, M.D., explicitly qualified his comments as those expressed in his private capacity, rather than as director of the Division of Neuropharmacolgic Drug Products, U.S. Food and Drug Administration. The juxtaposition of his critique with an Alzheimer's drug trial in the NEJM is reminiscent, however, of his division's earlier publication there of a critical assessment of a tacrine (Cognex) preliminary trial. While that unprecedented published criticism by the FDA questioned the validity and integrity of the tacrine study, this guest editorial by David Drachman, M.D., University of Massachusetts Medical Center and Leber only poses questions to consider in interpreting the reported benefits of the investigational treatments.

Drachman and Leber concur with the investigators' assumption that effective treatments should delay patients reaching measured end points of deterioration. "For family members and most clinicians," they comment, "a delay of several months in death or institutionalization is more meaningful than a change in the score on a rating scale."

They question, however, whether these end points were appropriate for the study; whether the statistical adjustments were reasonable or obfuscated the extent to which the treatments delayed the end points; and whether the results were internally consistent. Drachman and Leber comment that death does not often occur as a direct consequence of Alzheimer's before other degenerative markers are met; and that institutionalization of the patient can occur as much from diminished tolerance of caregivers or the patient becoming incontinent as from the progression of Alzheimer's.

They observed, as did the investigators, that the significance of treatment efforts emerged only after the score on the Mini-Mental State Examination was included as a covariate in the Cox proportional-hazards model to adjust for baseline differences, ostensibly compensating for any advantages associated with a higher score. "When the statistical significance of a study turns on the choice of the analysis, the interpretation is confounded," Drachman and Leber wrote.

Drachman and Leber question whether the study results were internally consistent when the treatments appeared to delay functional deterioration without affecting scores on the Mini-Mental State Exam or the cognitive portion of the Alzheimer's Disease Assessment Scale. "Perhaps," they suggest, "the treatment effect was only symptomatic, affecting behavior but not the underlying disease process."

Sano and colleagues acknowledge this possibility without discounting its significance. "The outcome of improved function despite the absence of improved cognition raises the possibility that the affect we observed is a nonspecific health benefit to which our primary outcome was sensitive," they said. Whether these treatments affected pathophysiology or were only symptomatic, the investigators concluded, "both selegiline and alpha-tocopherol delayed functional deterioration, particularly as reflected by the need for institutionalization, should be considered for use in patients with moderate dementia."


References1. Anderson DK, Waters TR, Means ED. Pretreatment with alpha tocopherol enhances neurologic recovery after experimental spinal cord compression injury. J Neurotrauma. 1988;5:61-67.
2. Behl C, Davis J, Cole GM, Schubert D. Vitamin E protects nerve cells from amyloid beta protein toxicity. Biochem Biophys Res Comm. 1992;186:944-950.
3. Drachman DA, Leber P. Treatment of Alzheimer's disease--searching for a breakthrough, settling for less. N Engl J Med. 1997;336:1245-1247.
4. FDA Div. of Neuropharmacological Drug Products. Tacrine as a treatment for Alzheimer's disease: editors note. An interim report from the FDA. N Engl J Med. 1991; 324:349-352.
5. Hara H, Kata H, Kogure K. Protective effect of alpha-tocopherol on ischemic neuronal damage in the gerbil hippocampus. Brain Res. 1990;510:335-338.
6. Sano M, Ernesto C, Thomas R, et al. A controlled trial of selegiline, alpha-tocopherol, or both as treatment for Alzheimer's disease. N Engl J Med. 1997;336:1216-1222.

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