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

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 nonrespondents, 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.Given a robust rise in oxidized macromolecules with aging and AD, and the assumption that oxidation is causing symptoms, why is the anti-oxidant vitamin E ineffective?Lloret et al.'s findings indicate that vitamin E does not, in fact, lower plasma oxidative stress for half of the AD patients.To understand this result, we need to consider the broader scope of how anti-oxidants might reduce the load of macromolecular ROS damage.Is it reasonable to expect that a lipid-soluble antioxidant would protect against oxidation of aqueous phase nucleic acids and proteins?The lipophilic vitamin E partitions into membranes, where it is available to receive an unpaired electron ("oxyradical") from an oxidized conjugated lipid.But if the oxidized vitamin E is not removed, it will either accumulate or pass the electron on to another lipid and further damage the membrane.Oxidized vitamin E can be recycled by passing the extra electron to a water soluble electron acceptor such as ascorbate (vitamin C), urea, pyruvate, NADH, cysteine or GSH.As elegantly described by Dean Jones (Emory University), whether an antioxidant is recycled depends on the redox potential in the local Commentary on Lloret et al.J Alzheimer Dis.