Role of repurposed drugs and herbal medicines to improve cognitive deficit in postmenopausal Alzheimer's disease: a systematic review of preclinical evidence

Abstract

Alzheimer's disease (AD) disproportionately affects postmenopausal women, most likely due to hormonal changes that cause early neuropathological alterations. The ovariectomized/d-galactose (OVX/d-gal) model provides a dependable platform to replicate postmenopausal AD pathophysiology in preclinical studies. Menopause-related estrogen loss is becoming more widely acknowledged as a key window for AD development. Despite the growing interest in potential treatments, it is currently unknown how effective herbal remedies and repurposed medications are in this model. This systematic review assessed preclinical data on cognitive outcomes following the administration of these medications in OVX/d-gal-induced AD. Following the PRISMA guidelines, the research team conducted a systematic search of four databases and extracted the relevant OVX/d-gal AD studies according to specified inclusion and exclusion criteria, assessed the risk of bias using SYRCLE, and rated the certainty of evidence using GRADE. Seventeen pertinent studies were found after searching Web of Science, PubMed, ScienceDirect, and Scopus. Although both herbal extracts and repurposed medications showed encouraging results in enhancing cognitive function, the overall certainty of the evidence was extremely low, mostly because of small trial numbers, unclear risk of bias, and little reporting on the quality of the methods used. The most promising repurposed medications were escitalopram, telmisartan, dimethyl fumarate, and dapagliflozin, and natural compounds such as ginsenoside Rg1 and resveratrol showed persistent effects and solid mechanistic evidence. While preliminary findings are encouraging, methodological heterogeneity and reporting limitations highlight the urgent need for more robust, well-designed preclinical studies before clinical translation can be considered.