Sex Hormones in the Nucleus Incertus: a Novel Perspective on Sex/gender Differences in Memory and Mood Dysfunction in Alzheimer’s Disease

About 60% of the individuals living with Alzheimer’s disease (AD) in the United States are women. Increasing evidence points to a role for sex hormones, especially estrogen, in making women more vulnerable to AD than men. Several brainstem signaling pathways, as well as multiple neuropeptide modulators and their receptors, are implicated in AD pathology and therapeutic possibilities. However, there is limited research evaluating how the modulatory effects of sex hormones on mood and cognition interact with these brainstem systems. This review seeks to examine possible connections between the nucleus incertus (NI) relaxin-3/relaxin-family peptide receptor 3 (RLN3/RXFP3) system and sex hormone influences in AD to encourage further investigation into how sex hormones may modulate this pathway and contribute to sex differences in disease risk and progression. Understanding how hormone-based interventions, such as hormone replacement therapy (HRT) and hormonal contraceptives (HC), affect NI RLN3/RXFP3 signaling may provide novel insights into how these treatments can slow AD-associated cognitive decline. It is hoped that this data and concept synthesis will drive detailed investigations of these circuits and support the development of sex/gender-informed therapeutic strategies that better reflect the heterogeneity of AD dementia.