. Antioxidants for Alzheimer Disease: A Randomized Clinical Trial With Cerebrospinal Fluid Biomarker Measures. Arch Neurol. 2012 Mar 19; PubMed.


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  1. These conclusions are based on a four-month treatment, whereas most trials go on for 18 months, and some even for 36 months. Knowing the complexity of AD pathogenesis, would a four-month treatment be considered sufficiently long to test the efficacy of an approach?

    View all comments by Sanjay Pimplikar
  2. I believe that the 19 percent decrease in isoprostane, however small, is very relevant because this is the first time that any antioxidant treatment in AD has been proven to engage its target. However, if oxidative stress is a culprit in AD, then antioxidant treatments, like any other disease-modifying drugs, should be tested at presymptomatic stages of the disease.

    View all comments by Elena Galea
  3. Failure of Antioxidants to Treat Alzheimer's Disease: Toward a Homeostatic View of Chronic Disease
    Failure of antioxidants to improve the course of cognitive decline in Alzheimer's disease (AD) underscores a paradox in oxidative stress: that efforts to increase oxidative defenses are without benefit for chronic conditions (Halliwell, 2012). This unfortunate outcome has been demonstrated in essentially every clinical or epidemiological trial of antioxidant supplements. The question that remains is an obvious one: Why this paradox of no antioxidant benefit, when disease states are so often met with increased oxidative damage and stress response (Nunomura et al., 2006; Moreira et al., 2005)? At the outset, it should be pointed out that efficacy of the antioxidant supplements in altering the oxidative balance was not demonstrated in most studies. Moreover, the absorption and subsequent passage through the blood-brain barrier of many antioxidants are poor. Fortunately, new biomarker studies can determine whether functional incorporation of the antioxidants into biochemical pathways in the brain has occurred. Galasko and colleagues elegantly used these methods to demonstrate that their antioxidant therapy was effective in reducing oxidative damage in the brain, while no clinical benefit was found (Galasko et al., 2012).

    In contrast to antioxidants, studies of nutrient-rich food have shown benefit for AD and other chronic conditions (Solfrizzi et al., 2011), leading many to attempt to purify the “magical” component. None has been found, however, probably because food, by its very nature, is a complex amalgam derived from the spectrum of life processes, which require exquisite balance that may influence bioavailability, the polar opposite of purification. Food intake presents as numerous points in the complex network that defines metabolism and oxidative balance. In contrast, antioxidants add at single and narrowly circumscribed points, possibly misbalancing the oxidant defense system. And while antioxidant combinations working along these same lines may show more promise, it is also important to reconsider the definition of oxidative stress—as simply a breach in antioxidant defenses—as too simplistic for chronic disease.

    Humans live with AD for decades. Prior to AD, oxidative damage is generally demonstrable after age 40, meaning oxidative damage is a chronic condition of the middle-aged and aging brain (Nunomura et al., 2012). Is this imbalance or simply a de novo balance of the chronic condition of aging and disease? The de novo balance concept, which has generally not been considered to date, is supported by the ample antioxidant stress responses induced in AD: stress kinases, antioxidant enzymes, pentose phosphate pathway, and metal regulatory proteins (Castellani et al., 2009). The most interesting are the two latter, as the amyloid-β protein precursor/amyloid-β bind and regulate iron and copper redox activity central to oxidation, as these metals are the primary catalysts of oxidative damage.

    The molecular modifications produced by oxidative stress lead to deleterious consequences with damage to neuronal networks and activation of compensatory mechanisms. Antioxidant therapeutics may reduce oxidative stress in specific molecular pathways, but cannot repair the chronic neuronal network damage or restore to previous levels the function of affected brain systems. Thus, dysfunctional and anatomically remodeled neuronal networks cannot be reverted to normality and their anatomy restored by simply reducing oxidative stress levels.

    Adding single-point antioxidants to the delicate balance of the aging brain and AD has the possibility of disturbing a balance that is likely heterogeneous in terms of oxidative state, since we have found a pleiotropic change in the relationship of oxidative damage to amyloid-β and other features with the transition from normal to mild cognitive impairment (Smith et al., 2010). In an environment with abundant free copper and iron, single-point antioxidants (reductants, in most cases) can actually increase oxidative damage of critical compartments not otherwise discerned by examining biomarkers that address bulk state.

    Finally, oxidative damage and response in AD, and to a lesser extent normal aging, involve alterations in every cellular pathway, so how is it that those of us in middle age and older, ostensibly without AD, function normally with so much going wrong in our cerebral parenchyma? Could it be that oxidative alterations are essential to our function with advanced age, in the so-called age of wisdom? Or alternatively, since oxidative stress marks cell activation at the beginning of life and other critical times in development, is it possible that oxidative stress regulates the aging process and drives it forward, providing for normal function into advanced age? The wonder is not that some become demented with age, but rather that many maintain normal function for 100 years or longer.


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