UC San Diego

Alzheimer’s Disease (AD) the most common form of dementia, is a type of tauopathy featured by the deposition of the extracellular plague composed of amyloid beta and the intraneuronal NFTs composed of microtubule-associated protein tau. AD exhibit significant gender differences, with women being more susceptible to developing the disease compared to men. One factor potentially contributing to this increased vulnerability is the hormonal differences between the two sexes, particularly the low testosterone (T) level in women, which has been thought to have neuroprotective effects. However, the role of testosterone in women AD pathogenesis remains poorly understood. In this study, we investigate the effects of androgen supplementation on tau pathology and microgliosis in a female mouse model of tauopathy (P301S). While our work was driven by the hypothesis that testosterone has neuroprotective effect in women through activation of androgen receptor, we found that supplementation with dihydrotestosterone (DHT), a potent and selective metabolite of testosterone, exacerbated tau aggregation and microgliosis in the brains of P301S female mice. These findings suggest that, contrary to previous expectations, supplementing androgen may exacerbate tau pathogenesis and neurodegeneration. Our results highlight the need to reconsider the therapeutic potential of androgens in the treatment of Alzheimer’s disease, particularly in women; and suggest that for transgender individuals assigned female at birth (AFAB) who undergo androgen therapy as part of their transition, it is crucial to consider how long-term DHT therapy may influence neuroinflammation and tau pathogenesis.