Journal Article

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

Hohman, Timothy J., Gordon, Marcia N., Sime, Lindsey N., Price, Brittani R., Walker, Keenan A., Eissman, Jaclyn M., Suryadevara, Vidyani

2025

Overview

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. Conceptual framework for sex‐specific Alzheimer's disease (AD) risk. Sex differences in AD vulnerability arise from the intersection of multiple biological systems. Fluctuations in sex hormones across reproductive life stages (e.g., pregnancy, menopause) shape long‐term neuroendocrine tone. These hormonal shifts influence immune modulation, including both peripheral and central immune activity, particularly in glial cells such as microglia and astrocytes. Concurrently, genetic architecture, including sex‐interacting variants such as apolipoprotein E ε4, modifies susceptibility to AD pathology. The dynamic interplay among these systems contributes to a sex‐specific trajectory of AD risk, with distinct implications for disease onset, progression, and therapeutic response in women. (Figure created with BioRender.)

• Publisher: John Wiley and Sons Inc,Wiley
• Subject: adaptive immunity / apolipoprotein E / astrocytes / cognitive decline / estradiol / estrogen / innate immunity / menopause / microglia / neuroinflammation / Review