Midlife Interferon Signaling in the Female Brain: Implications for Neuroimmune Activation in Alzheimer's Disease and Precision Intervention

Abstract

Alzheimer’s disease (AD) is the sixth leading cause of death in the United States and the only disease among the top ten without a reliable treatment or cure. My research investigates sex differences that emerge during midlife aging, focusing on the estrogenic dysregulation of the neuroimmune system in women. This dysregulation may drive immunometabolic risk and late-life AD progression. My work identifies a set of proteins called interferons—pro-inflammatory cytokines that act as master regulators of the immune response—which increase in expression during female midlife aging and may cause sustained neuroinflammation. My studies aim to understand the rise of interferons and their potential as therapeutic targets for AD. The first study examines transcriptomic profiles of the midlife human brain compared to the AD brain, exploring sex differences and potential therapeutic targets. This analysis validates interferons as clinically relevant targets during female midlife aging. Next, using a rodent model with humanized APOE4/4 genotype, I demonstrated that midlife injection of interferon gamma in females induces phenotypes associated with early AD, including neuroimmune activation, increased mean diffusivity in white matter regions, and decreased plasma amyloid 42:40 ratio. This experiment pre-clinically supports interferon gamma as a target for AD risk reduction. Finally, I therapeutically treat an AD-risk model with an FDA-approved anti-inflammatory drug that blocks interferon signaling. This midlife anti-inflammatory intervention demonstrates cognitive resilience, improvement in immunometabolic risk phenotypes, and a reduction in interferon gamma levels in females. Overall, my research highlights interferon gamma as a promising therapeutic target for reducing AD risk in women, contributing to the National Alzheimer’s Project Act’s mission to find a treatment or cure by 2025.