Antioxidant Supplements Are Not of Proven Benefit for Alzheimer's Disease
Abstract & Commentary
By Michael Lin, MD, PhD, Associate Professor of Neurology and Neurosciences, Weill Cornell Medical College. Dr. Lin reports no financial relationships relevant to this field of study.
Synopsis: In this well-designed, randomized, placebo-controlled clinical trial of antioxidant supplements for Alzheimer's disease, there was no benefit, and some agents were associated with worse outcome.
Source: Galasko DR, et al, for the Alzheimer's Disease Cooperative Study. Antioxidants for AD: A randomized clinical trial with CSF biomarker measures. Arch Neurol 2012;69:836-841.
Given the few FDA-approved treatments for alzheimer's disease (AD) and their very modest effects, patients frequently take a wide variety of vitamins and supplements, including antioxidants. Unfortunately, although there is extensive preclinical evidence showing benefits of antioxidants in cell and animal models of disease, experience with antioxidants in human AD trials has been mixed. In this vein, a recent trial of antioxidants by the AD Cooperative Study Group (ADCS) showed no clinical benefit. In fact, in the subgroup showing reduced oxidative stress in cerebrospinal fluid (CSF), there was actually a suggestion of more rapid cognitive decline.
The ADCS Antioxidant Biomarker study was a double-blind, randomized, placebo-controlled, multicenter clinical trial conducted at 12 academic medical centers across the United States. Seventy-eight subjects with mild-to-moderate AD (mini-mental state exam [MMSE] score 16-30) were randomized to one of three arms. The first arm tested a combination of vitamin E (800 IU/d), vitamin C (500 mg/d), and alpha-lipoic acid (900 mg/d; E/C/ALA). Vitamin E is a lipid-based antioxidant; vitamin C is a water soluble antioxidant; alpha-lipoic acid is a mitochondrial cofactor, and also induces the nuclear respiratory factor 2 transcription factor, which in turn induces many antioxidant enzymes. Doses were chosen by an expert panel after review of the literature. The second arm tested coenzyme Q10 (CoQ) at a dose of 400 mg three times/day. CoQ is a part of the mitochondrial electron transport chain and helps to protect mitochondria from free radicals generated during oxidative metabolism. The dose chosen is the same as the dose that appeared to have benefit in a Phase 2 trial in Parkinson's disease. The third arm was the placebo arm.
All groups were well matched at baseline (mean MMSE ~23). Study medication was administered for 16 weeks. The primary outcome measures were cognition (assessed by MMSE), function (assessed by the ADCS-ADL scale), and CSF biomarkers of AD pathology (Aβ42, tau, phosphotau) and oxidative damage (F2-isoprostanes). Neither treatment had any effect on CSF biomarkers of AD pathology. The E/C/ALA treatment lowered CSF markers of oxidative damage, suggesting that the treatment penetrated the central nervous system and had the expected antioxidant effect. In contrast, the CoQ treatment had no effect on oxidative markers, suggesting either that the dose was inadequate or that oxidative stress in AD is not mediated by pathways involving CoQ. Neither treatment improved function on the ADCS-ADL scale, and CoQ did not differ from placebo in effect on cognition both placebo and CoQ groups dropped ~1.0 point on MMSE. Of concern, however, the E/C/ALA treatment appeared to exacerbate cognitive decline, with a drop in MMSE of 2.8 points over the trial (P = 0.04), despite decreasing CSF markers of oxidative stress.
These results do not support further investigation into these agents or their use by patients as supplements. Further, they actually suggest discouraging use of the E/C/ALA combination, since cognitive decline was exacerbated, despite documented reduction in oxidative stress. Why this should occur is mysterious, but is at least consistent with recent meta-analyses suggesting that vitamin E in doses > 800 IU/d is associated with excess mortality. More generally, it is difficult to explain the discrepancy between theoretical understanding of the role of oxidative stress in disease pathogenesis and results of human trials. The authors note that oxidative stress is not a single specific process with an obvious single target for intervention, making it challenging to design antioxidant treatments. However, ultimately the results of human trials should guide therapy. Although patients trying multiple supplements often are doing so out of desperation, they should be counseled that no supplement has been shown to have benefit in rigorous trials, and some may actually cause harm.