In Alzheimer Disease, Antioxidants Hurt

Antioxidants do not improve AD biomarkers and adversely affect cognition.

Under the hypothesis that oxidative damage leads to Alzheimer disease (AD), some investigators have studied whether antioxidants (e.g., vitamins E and C, α-lipoic acid [ALA], and coenzyme Q [CoQ]) influence amyloid production. Results have generally been positive in animal models, but inconsistent in humans. Now, researchers have examined the effect of these antioxidants on cerebrospinal fluid (CSF) biomarkers and on changes in cognition (on the Mini-Mental State Exam [MMSE]) and function.

The 78 participants had mild-to-moderate AD (mean age, 73; 46% women; mean MMSE score, 23) and were taking memantine, an acetylcholinesterase inhibitor, or both. They were randomized to one of three treatments: a combination of vitamin E (800 IU/day), vitamin C (500 mg/day), and ALA (900 mg/day); CoQ (400 mg/day); or placebo. Four biomarkers (amyloid-β42 [Aβ42], total tau, a phosphorylated tau [P-tau181], and F2-isoprostanes) were assessed in CSF. Fifty-two participants completed the study.

After 16 weeks, there were no between-group differences or changes in Ab42, tau, and p-tau181. F2-isoprostanes decreased by 19% in the combination group. Cognition and function declined in all groups. Combination treatment was associated with significantly greater cognitive decline than placebo (MMSE, €“2.8 vs. €“0.9 points) and showed a trend toward greater functional deterioration.

Comment: Commonly used antioxidants showed no effect on several AD-related biomarkers (except F2-isoprostanes). However, cognitive scores in the combination group deteriorated clinically and statistically after 16 weeks. This finding raises concern that these agents may be detrimental to cognition. The authors do not propose a mechanism, but other researchers have previously hypothesized that antioxidants affect glucose regulation, as demonstrated by the decreased sensitivity of insulin to exercise with administration of antioxidants (JW Psychiatry Jun 8 2009 [Free full-text PNAS article PDF | Medline ® abstract]).The take-home point: Do not take vitamins in the belief that “they couldn’t hurt.”

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