Effects of Supplementation With Genistein on the Progression of Cognitive Decline in Patients With Mild Cognitive Impairment Due to Alzheimer Disease: Protocol for a Randomized Controlled Trial

Abstract Background Mild cognitive impairment (MCI) may represent a prodromal stage of Alzheimer disease, but interventions to delay progression remain limited. Genistein is a phytoestrogenic isoflavone with potential effects on several pathways implicated in Alzheimer disease. We previously showed that genistein reverses cognitive decline and lowers brain amyloid β (Aβ) in the Aβ precursor protein/presenilin 1 double transgenic (AβPP/PS1) model of Alzheimer disease. Objective The study aimed to evaluate whether oral genistein supplementation affects cognitive decline in patients with MCI due to Alzheimer disease, compared with a placebo, and to assess its effects on brain amyloid burden and plasma biomarkers. Methods This multicenter, randomized, double-blind, placebo-controlled trial will include adults aged 50 years or older with MCI due to Alzheimer disease. Participants will be randomized 1:1 to genistein (200 mg/day) or a maltodextrin-based placebo for 18 months. The primary outcome is change in the Integrated Alzheimer’s Disease Rating Scale (iADRS) score. Secondary outcomes include other neuropsychological measures, amyloid burden measured by 18 F-flutemetamol positron emission tomography, plasma Alzheimer disease biomarkers, and safety. Outcomes will be assessed at baseline, midstudy, and study completion. Analyses are planned in the intention-to-treat and per-protocol populations using repeated-measures analysis of variance, with time as the within-participant factor, treatment group as the between-participant factor, and study site as a covariate. Results Funding for the study began in January 2024 and was provided by Trugon Investigaciones (AIE) through a grant to the Chair of Geroscience at Universidad Católica de Murcia. Data collection began in July 2026 and is projected to conclude in January 2029, consistent with the estimated 30-month study duration. Enrollment is expected to last approximately 9 months. As of August 5, 2026, a total of 4 participants had been recruited. Data analysis has not begun and will start after the final participant completes follow-up. Results are expected to be published in late 2029. Conclusions This trial will provide evidence on whether genistein supplementation may help slow cognitive decline and reduce amyloid burden in patients with MCI due to Alzheimer disease.