Development of a selective estrogen β‐receptor phytoestrogen formulation – PhytoSERM – for the reduction of Alzheimer’s risk and relief of menopausal symptoms in women: a phase 2 randomized clinical trial framework

Abstract

AbstractBackgroundThe greatest risk factors for Alzheimer’s disease (AD) are age, APOɛ4 allele and female sex. The estimated lifetime risk for AD is 19.5% for women compared to 10.3% in men. Accumulating evidence points to life‐time estrogen exposure as a protective factor against cognitive decline and AD in women, and to the menopause transition as a trigger for an existing AD predisposition. Estrogen replacement therapy (ERT) is effective for sustaining neurological health, but fear of breast cancer is the principal reason menopausal women reject it. Instead, women utilize over the counter products labeled as natural and considered to be safer. Thus, to attain brain protection and address breast protection we developed a rationally designed combination of select ERβ‐selective phytoestrogens that promote brain health to reduce AD risk without increasing breast cell proliferation.MethodA total of 100 participants, 50 per treatment arm, will be enrolled. Eligible participants are woman, 45‐60 years, peri or post‐menopausal (last menstrual period completed ≥ 60 days and ≤ 4 years), MoCA≥22, and experiencing ≥7 hot flashes per day. Participants will be randomized to 50 mg of PhytoSERM or placebo (orally, once‐per‐day) for a 24‐week period. FDG‐PET scans will be conducted at baseline and 24 weeks. Cognitive measures and clinical ratings will be assessed. Hot flashes will be measured both subjectively with a diary and objectively with a digital wristband measuring electrodermal activity.ResultPrimary endpoint is change from baseline to 24 weeks in regional brain glucose metabolism standardized uptake value ratio (SUVR). Secondary outcome measures include cognitive test battery scores, hot flash score and clinical ratings scores. Exploratory measures will include MRI brain volumes, fractional anisotropy, quantitative anisotropy, functional connectivity, and cerebral blood perfusion.ConclusionHerein we present a phase 2 proof‐of‐concept framework to assess the efficacy of PhytoSERM as a potential non‐pharmacologic therapeutic to improve cognitive health and reduce menopausal symptoms. Results from this study will validate previous findings that indicate that PhytoSERM is a safe alternative to hormone therapy and has the potential to sustain neurological health during the menopausal transition.