Oxidative Stress, Testosterone, and Cognition among Caucasian and Mexican-American Men with and without Alzheimer's Disease

Article type: Research Article

Authors: Cunningham, Rebecca L.^{a; d; e; *} | Singh, Meharvan^{a; d; e} | O'Bryant, Sid E.^{b; d} | Hall, James R.^{c; d} | Barber, Robert C.^{a; d}

Affiliations: [a] Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, Fort Worth, TX, USA | [b] Department of Internal Medicine, University of North Texas Health Science Center, Fort Worth, TX, USA | [c] Department of Psychiatry and Behavioral Health, University of North Texas Health Science Center, Fort Worth, TX, USA | [d] Institute for Aging and Alzheimer's Disease Research, University of North Texas Health Science Center, Fort Worth, TX, USA | [e] Center FOR HER, University of North Texas Health Science Center, Fort Worth, TX, USA

Correspondence: [*] Correspondence to: Rebecca L. Cunningham, Ph.D., Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, 3400 Camp Bowie Boulevard, Fort Worth, TX 76107-2699, USA. Fax: +1 817 735 0408; E-mail: [email protected].

Abstract: Background:The use of testosterone among aging men has been increasing, but results from studies addressing the effectiveness of testosterone replacement therapy have been equivocal. Objective:Given our prior pre-clinical studies that reported a major influence of oxidative stress on testosterone’s neuroprotective effects, we investigated whether the negative effects of testosterone on brain function were predicted by oxidative load. Methods:In order to test our hypothesis, we determined whether circulating total testosterone and luteinizing hormone correlated with cognition in a subset of the Texas Alzheimer’s Research & Care Consortium (TARCC) cohort, consisting of Caucasian (n = 116) and Mexican-American (n = 117) men. We also assessed whether oxidative stress (as indexed by homocysteine levels) modified this relationship between sex hormones and cognition, and whether the levels of two antioxidants, superoxide dismutase-1 and glutathione S-transferase (GST), varied as a function of circulating testosterone. Results:In a low oxidative stress environment, testosterone was positively associated with the level of the antioxidant, GST, while no deleterious effects on cognitive function were noted. In contrast, under conditions of high oxidative stress (homocysteine levels >12 µmol/L), testosterone and luteinizing hormone were associated with cognitive impairment, but only among Caucasians. The ethnic difference was attributed to significantly higher GST levels among Mexican-Americans. Conclusion:While testosterone may be beneficial under conditions of low oxidative stress, testosterone appears to have negative consequences under conditions of elevated oxidative stress, but only in Caucasians. Mexican-Americans, however, were protected from any deleterious effects of testosterone, potentially due to higher levels of endogenous antioxidant defenses such as GST.

Keywords: Androgens, antioxidants, homocysteine, luteinizing hormone, Mexican American

DOI: 10.3233/JAD-131994

Journal: Journal of Alzheimer's Disease, vol. 40, no. 3, pp. 563-573, 2014