Megan Brooks
March 19, 2012 — The antioxidant combination of vitamin E, vitamin C, and alpha-lipoic acid (ALA) did not alter cerebrospinal fluid (CSF) biomarkers related to amyloid and tau pathology in a 16-week study of patients with mild to moderate Alzheimer's disease (AD).
The antioxidant combination led to a relatively small reduction in CSF F2-isoprostane level, suggesting a decrease in oxidative stress in the brain, but it was also associated with accelerated cognitive decline on the Mini-Mental State Examination (MMSE).
"It is unclear whether the relatively small reduction CSF F2-isoprostane level seen in this study may lead to clinical benefits in AD," the authors say. In addition, 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," they add.
The study also failed to find any beneficial effect of high-dose coenzyme Q (CoQ) on CSF biomarkers. "These results do not support further clinical trial development of CoQ in AD," the authors say.
Douglas R. Galasko, MD, of the University of California, San Diego, and colleaguesreported their findings March 19 in Archives of Neurology.
Data 'Extremely Useful'
In an email to Medscape Medical News, Nikolaos Scarmeas, MD, MSc, associate professor of neurology, Columbia University Medical Center in New York City, who was not involved in the study, said: "It is a negative study but extremely useful in many ways. It is trying to demonstrate whether there are truly the expected antioxidant effects in central nervous system when a series of antioxidant supplements are administered to patients with AD."
"Unfortunately," Dr. Scarmeas noted, "the clinical data seem to move in opposing directions to the biomarker (data): CoQ did not seem to reduce biomarkers of oxidative stress in CSF, while the combination of vitamins C, E, and alphalipoic acid did so, but did not affect AD-related biomarkers and accelerated cognitive decline. But even this is quite informative."
Oxidative damage is associated with aging and is widespread in the brain in AD, Dr. Galasko and colleagues note in their article. Basic and observational studies provide strong support for antioxidant treatment in AD yet randomized controlled trials have yielded mixed results.
The researchers hypothesized that if antioxidant treatment affects key pathogenic mechanisms in AD, this would be reflected in CSF biomarker changes. To investigate, they studied 78 adults with mild to moderate AD from the Alzheimer’s Disease Cooperative Study (ADCS) Antioxidant Biomarker study, a double-blind, randomized multicenter clinical trial.
Study subjects were randomly assigned to 1 of 3 treatments for 16 weeks: 800 IU/d of vitamin E (α-tocopherol) plus 500 mg/d of vitamin C plus 900 mg/d ALA (E/C/ALA); 400 mg of CoQ 3 times a day; or placebo.
All treatments were well tolerated. Clinical measures of cognitive abilities were done using the MMSE and functional assessment using the ADCS Activities of Daily Living (ADCS-ADL) scale.
Although MMSE scores did not differ between groups at baseline, they showed a greater decline in the E/C/ALA group relative to placebo over time. Trends also showed greater decline in ADCS-ADL scores in the E/C/ALA group.
Table. 16-Week Changes in MMSE and ADCS-ADL by Group
| Variable | E/C/ALA | CoQ | Placebo |
| MMSE score, mean | 23.1 | 23.3 | 23.1 |
| MMSE score change | −2.8 | −1.0 | −0.9 |
| ADCS-ADL score, mean | 61.1 | 65.2 | 65.4 |
| ADCS-ADL score change | −4.6 | −2.4 | −2.3 |
ADCS-ADL = Alzheimer’s Disease Cooperative Study – Activities of Daily Living; ALA = alpha-lipoic acid; C = vitamin C; CoQ = coenzyme Q; E = Vitamin E; MMSE = Mini-Mental State Examination
The accelerated decline on the MMSE and a trend in this direction on the ADCS-ADL in the E/C/ALA group hints that this combination could adversely affect cognition in AD, the authors note.
"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 "will need to be carefully monitored if longer-term studies are planned," they write.
Sixty-six patients provided serial CSF specimens adequate for biochemical analyses during the 16-week trial. The combination of E/C/ALA did not affect CSF biomarkers related to beta-amyloid-42 (Aβ42), tau, or P-tau181, suggesting that this antioxidant combination did not influence pathways related to amyloid and tau pathology, the authors say.
However, E/C/ALA did result in a significant (P =.04) decrease in CSF F2-isoprostane levels, consistent with antioxidant effects in the brain. The decrease was 19% on average from baseline to week 16. CSF F2-isoprostane levels were unchanged in the other groups.
They also say the "absence of a biomarker signal" with CoQ suggests that this antioxidant, at the tested dose, does not improve indices of oxidative stress or neurodegeneration.
Commenting on the data, Dr. Scarmeas noted that "cognition is a complex outcome of multiple biological mechanisms, and thus not a direct correlate of a single biomarker (or) pathway. We probably need to simultaneously consider multiple biomarkers (mechanisms) in such studies and always in light of clinical outcomes," he said.
The study was supported by the National Institute on Aging. The authors and Dr. Scarmeas have disclosed no relevant financial relationships.
Arch Neurol. Published online March 19, 2012. Abstract
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