Testosterone as a mediator of APOE4-linked sex differences in Alzheimer's disease

The pathological mechanisms and clinical manifestations of Alzheimer's disease (AD) exhibit significant gender differences, with a higher proportion of female AD patients. Women carrying the apolipoprotein E4 (APOE4) genotype face a markedly higher risk of developing the disease compared to men. APOE4 plays a crucial role in shaping these gender disparities by influencing the characteristic pathologies of AD. As the primary androgen, testosterone and its metabolites play a vital role in maintaining central nervous system homeostasis by interacting with steroid hormone receptors. Testosterone may mediate these effects through the androgen receptor (AR), participate in immune regulation, influence lipid metabolism, and interfere with the cholinergic system, thereby contributing to gender differences among APOE4 carriers. Key regulatory nodes include IL-17 and TGF-β. Furthermore, we synthesized clinical evidence linking testosterone replacement therapy to cognitive impairment, analyzed current research limitations and gaps in the field, and provided theoretical guidance for developing future targeted interventions and gender-specific therapeutic strategies.