Why Vitamin E Therapy Fails for Treatment of Alzheimer's Disease

Abstract

ROS damage in the AD brain is widely reported at the levels of nucleic acids [1], protein [2] and lipids [3]. ROS damage is also associated with heart disease, cancer and aging. Consequently, numerous clinical trials of the lipid soluble anti-oxidant, vitamin E, have been conducted for prevention [4] and treatment [5] of age-related morbidity and mortality. The meta-analysis by Miller et al.[5] clearly shows that among 19 clinical trials, only the smaller trials show either an increase or a decrease in all-cause mortality and that the overall effect is near zero. By organizing these studies into a dose-response curve, a significant increase in all-cause mortality was observed for vitamin E doses above 400 IU/day. In an earlier trial of vitamin E treatment for AD at the high dose 2000 IU/day, there was no effect of vitamin E on mini-mental state of moderately severe AD patients, despite delays in nursing home placement [6]. In a trial of MCI patients, Petersen et al. [7] found that even early vitamin E treatment failed to improve cognition. These results prompted Lloret et al. [8] to introduce the novel concept of stratifying AD patients into vitamin E respondents and non-respondents, based on measures of plasma GSSG, the oxidized form of the common antioxidant glutathione (GSH). At the borderline detrimental dose of 800 IU/day [5], about half of the patients failed to respond to vitamin E with lower plasma GSSG; they showed a lower MMSE score after 6 months that suggested a 13% decline in cognitive performance [8]. The other half of the patients for whose GSSG decreased with vitamin E treatment did not significantly change their original MMSE score. Unfortunately, the study was not large enough to detect a decline in MMSE for treatment with placebo. Also provocative from Lloret et al.’s report was a strong negative correlation between GSSG and MMSE, but most of the effect was due to 4 of 19 AD patients with a 5–10% drop in GSSG in response to vitamin E.