Estrogen exposure across the lifetime protects against Alzheimer's disease: Contributions of hormone contraceptives

/ABSTRACT Alzheimer's disease (AD) is the leading cause of dementia, with women twice as likely to develop AD than men. Recent research has highlighted the critical role for gonadal hormones, and specifically lifetime exposure to estradiol, in decreasing risk for AD in women. This sex-specific factor encompasses age of first menstrual period, pregnancies, hormone contraceptive exposure, age of menopause, and hormone therapy, with factors that increase the amount of estrogen exposure decreasing risk for AD. Emerging epidemiological data suggests that hormone contraceptives protect against cognitive decline and dementias even decades after hormone contraceptive use. The main goal of this project is to identify how HC exposure interacts with genetic risk and stress to modify progression of AD-related pathology and behavioral changes. Our overall hypothesis is that HC exposure protects against AD progression via both increased cumulative lifetime estrogen exposure, and via progestin-modulation of stress-related signaling. We will use a mouse model of hormonal contraceptive exposure recently characterized in my laboratory, together with the APP/PS1 mouse model of Alzheimer's disease with behavioral, pharmacological, and molecular tools to address this question. We will focus on both estradiol-mediated protection, and interactions between hormone contraceptives with stress as a modifiable risk factor for Alzheimer's disease. Based on previous findings that hormone contraceptives decrease corticosterone responses to stress, we hypothesize that hormone contraceptives mitigate progression of cognitive impairments and AD-like pathology, including amyloid β accumulation. We further anticipate that hormone contraceptive exposure will decrease stress-induced neuroimmune activation in the hippocampus and prefrontal cortex, thereby protecting against Alzheimer's disease progression. Finally, we hypothesize that whereas ethinyl estradiol exerts protection against ongoing disease progression in part via estrogen receptor β, progestin components of hormonal contraceptives mediate the amelioration of stress-exaggerated disease processes. This project is at the frontier of knowledge on how hormonal contraceptive exposure impacts the brain and exerts long-term protection against Alzheimer's disease. Further, this project will open broad opportunities for future research that extending towards new sex-specific targets for preventive interventions in Alzheimer's disease, related dementias, and age-related cognitive decline. Overall, this project will be an important contribution to understanding sex-specific factors in the development of Alzheimer's disease, and as such, will be an important contribution towards women's health research. Project Number: 1R21AG093754-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Institute on Aging (NIA) | Principal Investigator: Natalie Tronson | Institution: UNIVERSITY OF MICHIGAN AT ANN ARBOR, ANN ARBOR, MI | Award Amount: $424,371 | Activity Code: R21 | Study Section: Special Emphasis Panel[ZRG1 ICN-N (92)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11300303