A Mitochondrial Biomarker-Based Study of S-Equol in Alzheimer’s Disease Subjects: Results of a Single-Arm, Pilot Trial

Article type: Research Article

Authors: Wilkins, Heather M.^{a; b} | Mahnken, Jonathan D.^{a; c} | Welch, Paul^a | Bothwell, Rebecca^a | Koppel, Scott^d | Jackson, Richard L.^f | Burns, Jeffrey M.^{a; b; d} | Swerdlow, Russell H.^{a; b; d; e; *}

Affiliations: [a] University of Kansas Alzheimer’s Disease Center, Kansas City, KS, USA | [b] Department of Neurology, University of Kansas Medical Center, Kansas City, KS, USA | [c] Department of Biostatistics, University of Kansas Medical Center, Kansas City, KS, USA | [d] Department of Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas City, KS, USA | [e] Department of Biochemistry and Molecular Biology, University of Kansas Medical Center, Kansas City, KS, USA | [f] Ausio Pharmaceuticals LLC, Cincinnati, OH, USA

Correspondence: [*] Correspondence to: Russell H. Swerdlow, Landon Center on Aging, MS 2012, 3901 Rainbow Blvd, Kansas City, KS 66160 USA. Tel.: +1 913 588 0555; Fax: +1 913 588 0681; E-mail: rswerdlow@kumc.edu.

Abstract: Reductions in bioenergetic fluxes, mitochondrial enzyme activities, and mitochondrial number are observed in Alzheimer’s disease (AD). Preclinical work indicates estrogen pathway signaling by either estrogen or selective β estrogen receptor (ERβ) agonists benefits these parameters. To assess whether an ERβ agonist could improve mitochondrial function in actual AD subjects, we administered S-equol (10 mg twice daily) to 15 women with AD and determined the platelet mitochondria cytochrome oxidase (COX) activity before initiating S-equol (lead-in), after two weeks of S-equol (active treatment), and two weeks after stopping S-equol (wash-out). Because the intra-individual variation of this enzyme across samples taken at different times was unknown we used a nonparametric, single-arm, dichotomous endpoint that classified subjects whose active treatment COX activity exceeded the average of their lead-in and wash-out measures as positive responders. Eleven positive responses were observed (p < 0.06). The implications of this finding on our null hypothesis (that S-equol does not influence platelet mitochondria COX activity) are discussed. To our knowledge, this is the first time a direct mitochondrial target engagement biomarker has been utilized in an AD clinical study.

Keywords: Alzheimer’s disease, biomarker, cytochrome oxidase, mitochondria, S-equol

DOI: 10.3233/JAD-170077

Journal: Journal of Alzheimer's Disease, vol. 59, no. 1, pp. 291-300, 2017