P3‐026: Trial of S‐Equol in Alzheimer’s Disease (SEAD)

Mitochondrial dysfunction has been observed in Alzheimer’s disease (AD) patients. Specifically, cytochrome oxidase (COX, a mitochondrial electron transport chain enzyme) activity is reduced in both brain and platelet mitochondria from AD patients. S-equol is an estrogen receptor beta (ER-beta) agonist. ERbeta are localized within mitochondria, and activation stimulates mitochondrial function and mitochondrial biogenesis. Based on these observations we hypothesized S-equol may benefit AD subjects. 15 female AD participants (CDR 0.5 or 1) were enrolled into this 6-week, single-blind trial. The trial was designed to assess the primary outcome of platelet COX activity at baseline, in response to S-equol, and after a washout period. Participants were treated with twice a day placebo for two weeks, followed by 10mg twice a day S-equol for two weeks followed by a 2 week washout period. Phlebotomy, vitals, safety assessments, and a brief cognitive assessment (Montreal Cognitive Assessment exam (MoCA)) were completed at baseline, 2 weeks, 4 weeks, and 6 weeks. 15 participants were enrolled and 14 have completed the study. One subject dropped out prior to initiating the study due to non-study related reasons. In order to be considered a “responder” (i.e. increasing COX activity in response to treatment) the individual change (slope) between visits 2 and 3 had to be greater than the change (slope) between visits 3 and 4. When normalized to citrate synthase (CS) activity and protein concentration, 10 of the participants were considered responders, while 4 were considered non-responders. Of the 4 non-responders, one subject did show an increase in COX activity (normalized to protein and CS), but the visit 3 to 4 slope was greater than the visit 2 to 3 slope. S-equol was well-tolerated by and appeared safe in these AD participants. The study currently plans to enroll at least one additional subject, and upon completion of the study all endpoints will be analyzed. Our data suggest S-equol may increase platelet COX activity, warranting further testing in AD participants.