American Journal for Young Scientists · ISSN 3068-9015
Perimenopausal Estradiol Loss Links the HPG Axis to Mitochondrial Failure and Amyloid Clearance in Alzheimer’s
Authors: Advithi Motakatla
Published: January 28, 2026
Category: Computational Neuroscience
Abstract
Alzheimer’s disease (AD) disproportionately affects women, with risk accelerating during the perimenopausal transition when estrogen levels decline. We hypothesize that reduced gonadal hormone signaling impairs hippocampal activity and downstream mitochondrial resilience, thereby promoting calcium dysregulation, oxidative stress, and amyloid accumulation. To test this idea, we extend a minimal hypothalamic–pituitary–gonadal (HPG) axis model, formulated as a system of ordinary differential equations, to include a hippocampal signal variable driven by estradiol. The core model describes hypothalamic releasing hormone, pituitary gonadotropins, gonadal hormones, and glandular mass dynamics with nonlinear feedback. The hippocampal extension is represented as a leaky integrator of estrogen, allowing reduced estrogen to diminish hippocampal output. This signal is then coupled to mitochondrial calcium and amyloid dynamics, where it exerts a protective effect by reducing calcium overload and enhancing amyloid clearance. Numerical simulations demonstrate that declining estradiol leads to progressive reductions in hippocampal activity, heightened calcium imbalance, and accelerated amyloid burden. Sensitivity analysis identifies a key parameter controlling the strength of hippocampal mitochondrial coupling and suggest windows in which hormone replacement therapy may mitigate neurodegenerative progression. By linking endocrine decline to hippocampal dysfunction and impaired proteostasis, this model provides a mechanistic framework for understanding female-specific vulnerability in AD and offers a quantitative tool for testing intervention strategies.