Beyond Estrogen: Unraveling the Complexities of Hormonal Signaling Pathways in Alzheimer's Disease and Their Implications for Precision Therapy.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the accumulation of amyloid-beta (Aβ) plaques and neurofibrillary tangles (NFTs), leading to cognitive decline. Women, particularly postmenopausal women, are disproportionately affected by AD, with research indicating that estrogen may play a protective role in cognitive health. Estrogen, primarily 17β-estradiol, has been shown to modulate Aβ metabolism, reduce tau hyperphosphorylation, and enhance synaptic plasticity. These neuroprotective effects are mediated through estrogen receptors, including ERα, ERβ, and GPER, which activate signaling pathways critical for neuronal health. Epidemiological data suggest that hormone replacement therapy (HRT) in postmenopausal women may reduce the risk of AD; however, clinical results remain mixed, with some studies showing limited or even adverse effects. Understanding the complex relationship between estrogen and AD pathogenesis is crucial for advancing therapeutic interventions aimed at mitigating neurodegenerative processes, particularly in women at higher risk for AD. This review aims to synthesize current knowledge on estrogen's impact on AD and highlight potential avenues for future research and therapeutic development. This review explores the intricate relationship between estrogen signaling and AD, emphasizing the hormone's neuroprotective properties and its potential therapeutic applications.