The role of estrogen in Alzheimer's disease pathogenesis and therapeutic potential in women.

ABSTRACT

Estrogens are pivotal regulators of brain function throughout the lifespan, exerting profound effects from early embryonic development to aging. Extensive experimental evidence underscores the multifaceted protective roles of estrogens on neurons and neurotransmitter systems, particularly in the context of Alzheimer's disease (AD) pathogenesis. Studies have consistently revealed a greater risk of AD development in women compared to men, with postmenopausal women exhibiting heightened susceptibility. This connection between sex factors and long-term estrogen deprivation highlights the significance of estrogen signaling in AD progression. Estrogen's influence extends to key processes implicated in AD, including amyloid precursor protein (APP) processing and neuronal health maintenance mediated by brain-derived neurotrophic factor (BDNF). Reduced BDNF expression, often observed in AD, underscores estrogen's role in preserving neuronal integrity. Notably, hormone replacement therapy (HRT) has emerged as a sex-specific and time-dependent strategy for primary cardiovascular disease (CVD) prevention, offering an excellent risk profile against aging-related disorders like AD. Evidence suggests that HRT may mitigate AD onset and progression in postmenopausal women, further emphasizing the importance of estrogen signaling in AD pathophysiology. This review comprehensively examines the physiological and pathological changes associated with estrogen in AD, elucidating the therapeutic potential of estrogen-based interventions such as HRT. By synthesizing current knowledge, it aims to provide insights into the intricate interplay between estrogen signaling and AD pathogenesis, thereby informing future research directions and therapeutic strategies for this debilitating neurodegenerative disorder.