Elucidating the Influence of Ovarian Aging and Endocrine Shifts on Spatial Navigation, as an Early Diagnostic Target for Alzheimer's Disease

Project Summary The ability to navigate is a crucial component of daily life, and around the emergence of puberty, men begin to outperform women in navigation tasks that require an accurate “cognitive map,” or an internal representation of an environment. After puberty, there are two critical aspects to ovarian hormones that potentially shape this trajectory: 1) the short-term fluctuations that occur during the menstrual cycle, and 2) the longer-term, sweeping changes in hormones that occur across the menopausal transition. Understanding the role of ovarian hormones on navigation ability is important because the ability to navigate is one of the earliest cognitive abilities to be affected in the development of Alzheimer’s Disease (AD), and women account for 2/3rds of all late-onset cases. The neural circuitry implicated in AD and spatial navigation overlap substantially (e.g., the medial temporal lobe [MTL]), and in animal models and some human studies, estradiol has a positive impact on the ability to navigate. However, little is understood about how sex hormones affect navigation in women, and if aging exacerbates these effects. Even less is known as to how these mechanisms contribute to the disproportionate rate at which women are affected by AD. This proposal will establish the role of ovarian hormones in acquiring spatial knowledge, both at the cycle-phase level and in regards to endocrine aging. In the F99 phase (Aim 1), I will determine associations between ovarian hormones and navigation in young women between the ages of 18-40. First, I will assess the impact of the menstrual cycle on navigation ability and strategy (N=60) in naturally cycling young women across two timepoints–one of low estradiol (the early follicular phase) and one of high estradiol (the ovulatory window/luteal phase). The study will take a within-subjects approach to account for individual variability and isolate effects of estradiol on navigation ability. Next, I will determine the role of ovarian hormone suppression on navigation ability and strategy in young women (Cases) compared to age-matched women, half of which are naturally-cycling and half are on a progestin-only oral contraceptive (Controls, N=40 in each group). Cases will undergo chemically-induced ovarian hormone suppression for 3 months as treatment for endometriosis, and Cases and Controls will be tested on their navigation ability and strategy before and after the time course of Cases’ treatment. In the K00 phase (Aim 2), I will take my skills and insights gained from the F99 phase, including fundamental knowledge of neuroendocrine methods and spatial cognition, and establish the relationship between reproductive aging, brain structure, and biomarkers of AD (via neuroimaging of the MTL and pTau-217). To do this, I will leverage a community cohort (N=180) of midlife women (ages 45-55, stratified into three groups based on menopausal status) to collect hormonal, MRI, and navigation data to build a cohesive understanding of these mechanisms as they pertain to AD risk. Together, this proposal will identify the role of ovarian hormones and endocrine shifts on navigation, as an early diagnostic target for AD and to improve women’s health and outcomes.