These two studies cover different aspects of oxidative stress. The Brewer group showed that wild-type mice as well as 3x transgenic mice developed oxidative changes that could be ameliorated with nicotinamide. The Ho group showed calcium-dependent changes in oxidative state in dentate/hippocampal circuits, correlating with reactive oxygen species (ROS) production and treatable with Trolox. Neither group examined human brain tissue.

With a number of cautions (especially in extrapolating from mice to humans), these studies add support to the potential for antioxidant interventions as a preventive strategy for AD, although they do not discount the possibility that antioxidant pathways or damage may be important throughout the course of the disease. There are many other pathways that can be implicated in oxidative mechanisms for AD, as highlighted in a previous Alzforum story (see ARF related news story) and associated comments. Whether to intervene with broad-based, non-specific antioxidants (e.g., vitamin E and vitamin...  Read more

These two studies cover different aspects of oxidative stress. The Brewer group showed that wild-type mice as well as 3x transgenic mice developed oxidative changes that could be ameliorated with nicotinamide. The Ho group showed calcium-dependent changes in oxidative state in dentate/hippocampal circuits, correlating with reactive oxygen species (ROS) production and treatable with Trolox. Neither group examined human brain tissue.

With a number of cautions (especially in extrapolating from mice to humans), these studies add support to the potential for antioxidant interventions as a preventive strategy for AD, although they do not discount the possibility that antioxidant pathways or damage may be important throughout the course of the disease. There are many other pathways that can be implicated in oxidative mechanisms for AD, as highlighted in a previous Alzforum story (see ARF related news story) and associated comments. Whether to intervene with broad-based, non-specific antioxidants (e.g., vitamin E and vitamin C, or Trolox, as used in the Ho study) or try to target specific pathways or cellular compartments is not known. The sobering responses from human clinical trials conducted to date suggest that new antioxidants with clear evidence of brain penetration would help us to further test our ability to intervene to reduce oxidative stress.

It is worth bearing in mind that non-drug interventions, for example, exercise or diet, that are starting to be studied as interventions in AD possibly work, in part, through reducing oxidative stress.

View all comments by Douglas Galasko

Just to be clear, in our paper, we show that nicotinamide acts as a precursor to more NAD(P) and NAD(P)H, not as an antioxidant. More importantly, we begin to advance the concept that redox is not synonymous with reactive oxygen species (ROS). Redox is the relative strength of accepting or donating electrons. ROS are only produced as byproducts of redox reactions. Redox reactions are essential for metabolism. Some ROS are essential for numerous cellular signaling reactions (Finkel, 2003), and most ROS are detoxified by endogenous antioxidants. Hence, ROS levels are the net result of rates of production and detoxification. Our results show that neuron ROS levels did not change with age before six months when others have found cognitive deficits in the mice we studied, while redox agents NADH and glutathione did change at early ages. Therefore, antioxidants do not directly affect the redox reaction; they only consume the byproducts. We show that nicotinamide is most directly a precursor for NAD+ and, hence, NADH and NADPH, not an antioxidant. Given the failure of antioxidant...  Read more

Just to be clear, in our paper, we show that nicotinamide acts as a precursor to more NAD(P) and NAD(P)H, not as an antioxidant. More importantly, we begin to advance the concept that redox is not synonymous with reactive oxygen species (ROS). Redox is the relative strength of accepting or donating electrons. ROS are only produced as byproducts of redox reactions. Redox reactions are essential for metabolism. Some ROS are essential for numerous cellular signaling reactions (Finkel, 2003), and most ROS are detoxified by endogenous antioxidants. Hence, ROS levels are the net result of rates of production and detoxification. Our results show that neuron ROS levels did not change with age before six months when others have found cognitive deficits in the mice we studied, while redox agents NADH and glutathione did change at early ages. Therefore, antioxidants do not directly affect the redox reaction; they only consume the byproducts. We show that nicotinamide is most directly a precursor for NAD+ and, hence, NADH and NADPH, not an antioxidant. Given the failure of antioxidant treatments for AD, cancer, heart disease, and aging, antioxidants that lower ROS may only be targeting a secondary byproduct for which redox state is more proximal to the metabolic deficits of these age-related diseases. Therefore, treating AD with antioxidants may be no better than treating gray hair with hair dye.

View all comments by Gregory J Brewer