The APOE4-estrogen-microglia axis in perimenopausal cognitive changes: mechanisms and therapeutic implications

Alzheimer's disease (AD) exhibits marked sex differences, with women bearing a disproportionate burden of disease, particularly after midlife. Among the major factors contributing to this vulnerability, the apolipoprotein E ϵ4 allele (APOE4) and the abrupt endocrine transition of perimenopause have emerged as two critical and potentially synergistic drivers of neurodegeneration. Microglia, the resident immune cells of the central nervous system, lie at the center of this interaction because they integrate genetic, hormonal, metabolic, and inflammatory signals that shape amyloid clearance, synaptic remodeling, and neuroimmune homeostasis. Accumulating evidence indicates that APOE4 impairs microglial phagocytosis, disrupts lipid handling and lysosomal function, promotes pro-inflammatory activation, and compromises neurovascular integrity. In parallel, estrogen normally restrains microglial inflammatory signaling and supports phagocytic, metabolic, and reparative functions through estrogen receptor-dependent pathways. During perimenopause, fluctuating estrogen deficiency removes these protective constraints, thereby increasing the susceptibility of microglia to APOE4-driven dysfunction. This review synthesizes current evidence supporting an integrated pathogenic framework centered on the "APOE4-estrogen deficiency-microglia axis." We discuss how this axis promotes chronic neuroinflammation, synaptotoxicity, amyloid and tau pathology, mitochondrial dysfunction, blood-brain barrier disruption, and large-scale network disconnection, ultimately accelerating cognitive decline in women. We also summarize relevant experimental models, including APOE-targeted murine paradigms, ovariectomy and accelerated ovarian failure models, human induced pluripotent stem cell-derived microglia, and emerging single-cell and spatial omics approaches. Finally, we highlight translational opportunities, including precision hormone-based interventions, selective estrogen receptor modulation, TREM2-centered microglial therapies, APOE4-directed molecular and genetic strategies, and biomarker-guided multi-target interventions during the perimenopausal "window of opportunity." By integrating molecular mechanisms with translational perspectives, this review proposes a precision medicine framework for preventing or delaying neurodegenerative progression in high-risk perimenopausal women.