Alzheimer’s disease (AD) disproportionately impacts women. Almost two-thirds of Americans living with the disease are women. While some reasons for this sex difference have been identified, much remains unknown about how biological sex influences AD risk and how the disease progresses.
Beyond memory loss, AD also disrupts sleep and weight regulation. These functions are controlled by a small but powerful brain region called the hypothalamus. The neurons in this area differ between men and women and respond strongly to sex hormones. Dr. Gate wants to understand how AD impacts neurons and their supporting cells (microglia and astrocytes) in the hypothalamus, and why women experience more severe effects.
The hypothalamus serves as a communication hub between the brain and the body’s hormone (endocrine) system. This relationship is a two-way street: the brain sends signals through the hypothalamus to control hormones that regulate appetite, sleep and wake cycles, and body temperature, while hormones—particularly sex hormones like estrogen and androgen—shape the types and functions of neurons in the hypothalamus. This creates distinct differences between male and female brains.
Despite being well studied in other contexts, the role of the hypothalamus in AD remains poorly understood. Dr. Gate hypothesizes that the disease causes sex-specific changes in hypothalamic cells that help explain why the disease affects men and women differently.
Dr. Gate’s ambitious proposal includes three experimental aims. In the first aim, the Gate lab will examine how Alzheimer’s affects the neurons and glial cells of the hypothalamus. Dr. Gate, a world-leading expert in analyzing gene activity, will identify which of these changes are due to Alzheimer’s, biological sex, or a combination of the two. Across this project, Dr. Gate intends to use tissue from the Seattle Alzheimer’s Disease Brain Cell Atlas (SEA-AD). This resource provides brain tissue samples along with detailed medical histories from donors and sequencing data. The second aim will map exactly where Alzheimer’s damage occurs in the hypothalamus and identify which nearby cells are affected. By doing this, the Gatelab can map the changes observed in the first aim to physical locations relative to pathologies. The final aim will integrate SEA-AD clinical data with the first two aims. This will help generate a comprehensive picture of the relationship between the cell-level changes in the hypothalamus, AD pathologies, and clinically relevant outcome measures.
This study is a foundational step toward a sex-specific therapeutic approach for AD. By identifying which brain processes are vulnerable in the hypothalamus, the Gatelab hopes to eventually develop personalized treatments to resist or prevent AD pathology.
