Eighty-seven subjects were screened at 12 sites, and 78 were randomized to E/C/ALA, CoQ, or placebo, using permuted block randomization (blocks of 3 subjects at each site), generated by the Coordinating Center. The flow of subjects is shown in the , and demographic and clinical data, in . The groups were well matched at baseline.
Flowchart of subject participation in the study. CSF indicates cerebrospinal fluid.
Demographic and Clinical Features of 78 Study Participantsa
The study drugs were well tolerated. There were no significant changes in vital signs or body mass index from baseline to the end of the study in any treatment arm and no group differences in the frequencies of reported adverse events. There were no significant changes in results of a panel of hematological and biochemical blood tests in any of the treatment groups. Three serious adverse events were reported, in different subjects, and were judged to be unrelated to the study drug. One subject was hospitalized briefly after a pacemaker lead fell off. One subject fell and sustained a wrist fracture, which was treated. One subject developed dizziness and headache about 7 days before the week 16 visit. That subject successfully completed the week 16 lumbar puncture but was noted to have drowsiness, worsening mental abilities, and mild left hemiparesis about 5 days later. Brain magnetic resonance imaging revealed a tumor subsequently diagnosed as glioblastoma multiforme. There was no evidence of a tumor on a head computed tomography reviewed when this subject was screened, which was obtained about 18 months before the subject entered the study.
Clinical measures of cognitive abilities (MMSE) and function (ADCS-ADL) did not differ between groups at baseline. The MMSE scores showed a greater decline in the E/C/ALA group relative to placebo. There were no differences between groups in changes in ADCS-ADL total scores, or in scores for subscales of basic or instrumental ADL, although there were trends toward greater decline in the E/C/ALA group.
Cerebrospinal fluid levels of Aβ42, tau, P-tau181, and F2-isoprostanes were measureable in 66 subjects at baseline and week 16 (). Levels of each biomarker did not differ between the 3 groups at baseline. At 16 weeks, mean changes in each of the biomarkers were small. Changes in levels of Aβ42, tau, and P-tau181 did not differ between the 3 groups. Levels of F2-isoprostanes decreased in the E/C/ALA group from baseline but did not change in the CoQ or placebo groups. This was significant before and after adjustment for age and sex and represented a mean decrease of about 19%.
Correlations were examined between clinical scores (MMSE and ADCS-ADL) and CSF biomarker indices (levels of tau, P-tau, Aβ42, and F2-isoprostanes), analyzing baseline and 16-week change data. Significant correlations were found among all subjects for baseline MMSE scores vs ADCS-ADL scores (R = 0.42) and vs CSF total tau level (R = −0.32). No other correlations were significant for baseline or change data, among all subjects or within specific treatment arms.
Basic and observational studies provide strong support for antioxidant treatment in AD. Oxidative stress is a widespread cellular process and lacks a typical treatment target such as a receptor or a single major metabolic pathway. This is a challenge to designing and measuring treatment interventions. Approaches to combat oxidative stress typically involve augmenting antioxidant defenses, eg, with nutritional supplements or vitamins. Key questions include what doses to use, whether defenses are more critical in relation to mitochondrial or cytosolic oxidative stress, and whether a combination of antioxidants is more effective than a single agent at quenching oxidative reactions. A related question, whether a diet high in naturally occurring antioxidants may reduce the risk of developing AD, is difficult to address in an intervention study.
The present study examined the effects of a high dose of CoQ, a naturally occurring antioxidant that may protect mitochondria from reactive oxidative species generated during oxidative metabolism. Oral administration can achieve brain antioxidant effects in animal models.19,31
A phase 2 trial in Parkinson disease suggested that 400 mg of CoQ 3 times/d resulted in slowing of motor progression,32
and a phase 3 trial is currently in progress. A phase 2 trial in amyotrophic lateral sclerosis used a high-dose range of CoQ (1800 and 2700 mg/d) but found no difference in clinical progression over 9 months of treatment compared with placebo.33
Although our study found that CoQ was safe and well tolerated in patients with AD, the absence of a biomarker signal in CSF suggests that CoQ, at the dose tested, does not improve indices of oxidative stress or neurodegeneration. These results do not support further clinical trial development of CoQ in AD. Idebenone, a benzoquinone derivative structurally related to CoQ, has been studied widely in AD and other disorders. A placebo-controlled 12-month clinical trial that assessed 3 different doses of idebenone in mild to moderate AD found no differences between treatment and placebo.34
Doses for the E/C/ALA combination were selected based on expert opinion and clinical trials for other indications. A similar combination of E/C/ALA improved indices of skeletal muscle metabolism in elderly subjects.35
Although prior studies of vitamin E in AD and other neurodegenerative disorders have used high doses, typically 2000 IU/d, we limited vitamin E to 800 mg/d because of a meta-analysis of clinical trials and prevention studies that raised the possibility that more than 800 IU/d of vitamin E may be associated with increased all-cause mortality.36
Increased decline on the MMSE and a trend in this direction on the ADCS-ADL in the E/C/ALA group raises a concern that this combination could adversely affect cognition in AD. The lack of correlation of changes in these measures with changes in CSF biomarkers suggests that the cognitive changes may not be due to worsening of AD-related pathology. Although a mechanism is uncertain, this cognitive finding raises a caution and will need to be carefully monitored if longer-term studies are planned.
The combination of E/C/ALA did not affect CSF biomarkers related to Aβ, tau, or P-tau. The half-life of Aβ42 in CSF is extremely short, measured in hours.37
Tau and P-tau persist for a few weeks in CSF after acute stroke.38
Our clinical trial was therefore long enough to be able to detect a potential anti-AD effect on these bio-markers. Our findings suggest that this antioxidant combination did not influence pathways related to amyloid and tau pathology. However, E/C/ALA did result in a significant decrease in CSF levels of F2-isoprostanes, consistent with antioxidant effects in the brain. These findings are analogous to the transgenic mouse model study cited earlier, in which vitamin E plus vitamin C decreased neuroprostane levels in the brain, without affecting measures of Aβ, plaques, or neuritic changes; in this model, there was improvement of performance on spatial memory testing.11
It is unclear whether the relatively small reduction in CSF F2-isoprostane level seen in this study may lead to clinical benefits in AD. The more rapid MMSE score decline raises a caution and indicates that cognitive performance would need to be assessed if a longer-term clinical trial of this antioxidant combination is considered.