Sex differences and the role of estrogens in the immunological underpinnings of Alzheimer's disease.

UNLABELLED

Alzheimer's disease (AD) affects women more frequently and more severely than men, but the biological mechanisms underlying these sex differences remain poorly understood. This review integrates recent findings from neuroscience, immunology, endocrinology, and genetics to explore how sex steroid hormones, particularly estrogen, shape neuroimmune responses and influence AD risk. We highlight the pivotal roles of microglia and astrocytes, whose inflammatory and neuroprotective actions are modulated by hormonal fluctuations across the female lifespan, including pregnancy, menopause, and menopausal hormone replacement therapy. Key genetic risk factors, such as apolipoprotein E ε4, show sex-specific effects on glial activation, tau pathology, and cognitive decline. Furthermore, life-stage transitions, especially menopause, intersect with changes in brain metabolism, immune signaling, and epigenetic regulation, increasing susceptibility to neurodegeneration in women. We propose a framework for sex-aware, personalized approaches to AD prevention and treatment. By integrating hormone-immune interactions with genetic and glial biology, this review emphasizes the critical need for sex-specific models in AD research.

HIGHLIGHTS

Women develop greater tauopathy, with more cognitive and clinical consequences in Alzheimer's disease (AD).Glial activation is adapted by estrogens to shape vulnerability or resilience to AD.Sex differences in innate and adaptive immunity could contribute to AD progression.Effects of menopausal hormone therapy on immunity in AD remain understudied.Future studies to explore sex differences in immune function during AD are needed.