Public Health

Abstract

Neurodegenerative disorders such as Alzheimer’s disease and macular degeneration represent major sources of human suffering, yet factors influencing disease severity remain poorly understood. Sex has been implicated as one modifying factor. Here, we show that female sex is a risk factor for worsened outcomes in a model of retinal degeneration and that this susceptibility is caused by the presence of female-specific sex hormones. The adverse effect of female sex hormones was specific to diseased retinal neurons, and depletion of these hormones ameliorated this phenotypic effect, while reintroduction worsened rates of disease in females. Transcriptional analysis of retinas showed significant differences between genes involved in pyroptosis, inflammatory responses, and endoplasmic reticulum stress–induced apoptosis between males and females with retinal degeneration. These findings provide crucial insights into the pathogenesis of neurodegenerative diseases and how sex hormones can affect disease severity. These findings have far-reaching implications for clinical trial design and the use of hormonal therapy in females with certain neurodegenerative disorders.