Rationale and design of a multicenter study of selegiline and alpha-tocopherol in the treatment of Alzheimer disease using novel clinical outcomes. Alzheimer's Disease Cooperative Study. Vitamin E paradox in Alzheimer's disease: it does not prevent loss of cognition and may even be detrimental.
This report describes the rationale and design of a clinical trial using selegiline (10 mg/day) and alpha-tocopherol (2,000 IU/day) to slow the progression of dementia in Alzheimer disease (AD). This study was developed by the Alzheimer's Disease Cooperative Study (ADCS), a consortium of clinical research centers actively involved in AD research. The major goal of the consortium is to design and conduct clinical investigations leading to the development of treatments for AD. This study uses a randomized double-blind, placebo-controlled, 2 x 2 factorial, parallel group design to test two drugs for the treatment of AD. The primary outcome of the study is the time to reach any one of the following four endpoints: death, institutionalization, loss of two of three basic activities of daily living, and progression of Clinical Dementia Rating (CDR) stage from 2 to 3. Patients with moderately severe disease (CDR = 2) were enrolled and evaluated 10 times over a period of 2 years to determine if these agents reduce the time to reach any endpoint. A database from the Consortium to Establish a Registry for Alzheimer's Disease indicated adequate power analyses to observe a treatment effect on this clinically meaningful outcome measure. Recruitment and baseline characteristics of the population are provided. The rationale for the choice of a factorial design, the use of a novel, clinically meaningful endpoint, and the selection of a cohort of patients with AD of moderate severity are discussed. There is controversy as to whether vitamin E is beneficial in Alzheimer's disease (AD). In this study, we tested if vitamin E prevents oxidative stress and loss of cognition in AD. Fifty-seven AD patients were recruited and divided in two groups: placebo or treated with 800 IU of vitamin E per day for six months. Of these 57 patients, only 33 finished the study. We measured blood oxidized glutathione (GSSG) and used the following cognitive tests: Mini-Mental State Examination, Blessed-Dementia Scale, and Clock Drawing Test. Of those patients treated with vitamin E, we found two groups. In the first group, "respondents" to vitamin E, GSSG levels were lower after the treatment and scores on the cognitive tests were maintained. The second group, "non-respondents", consisted of patients in which vitamin E was not effective in preventing oxidative stress. In these patients, cognition decreased sharply, to levels even lower than those of patients taking placebo. Based on our findings, it appears that vitamin E lowers oxidative stress in some AD patients and maintains cognitive status, however, in those in which vitamin E does not prevent oxidative stress, it is detrimental in terms of cognition. Therefore, supplementation of AD patients with vitamin E cannot be recommended without determination of its antioxidant effect in each patient.
No convincing evidence that vitamin E is of benefit in the treatment of AD or MCI. Future trials assessing vitamin E treatment in AD should not be restricted to alpha-tocopherol.