Alzheimer’s disease (AD) disproportionately impacts women—two-thirds of all cases occur in women. While the reasons aren’t fully understood, recent studies have focused on the endocrine system and its role in regulating hormones in our bodies. Men and women experience very different hormone patterns throughout life, and women also go through menopause, which brings significant hormonal changes when menstrual cycles cease. Yet, while all women experience the menopause transition, not all develop AD. Understanding why menopause affects some women’s AD risk more than others—and what lifestyle factors play a role—is critical for preventing the disease in women.
One key way hormones may influence Alzheimer’s risk is through their role in metabolism—how the body generates and uses energy. When this system isn’t working properly, the body may not get the fuel it needs. Type 2 diabetes is a prime example of disrupted energy regulation. In diabetes, the body struggles to control blood sugar levels and respond to insulin, which affects energy balance, insulin sensitivity, and fat regulation throughout the body.
After menopause, the rates of prediabetes and type 2 diabetes increase considerably. Type 2 diabetes is also a risk factor for AD, and women with type 2 diabetes experience more severe Alzheimer’s symptoms than men. This connection between diabetes and brain health is so strong that some suggest that Alzheimer’s may be a brain-specific form of diabetes. While the effects of menopause and disruptions in metabolism on AD risk have been studied individually, no one has examined their combined effects.
Drs. Sundermann and Banks believe the convergence of diabetes, AD, and menopause is a crucial intersection to study to understand why AD impacts more women than men. They are leveraging data from the Women: Inflammation and Tau Study (WITS)—an ongoing project that explores how biology and lifestyle factors contribute to AD-related brain changes in women—to investigate how hormones influence energy dysregulation and contribute to AD in women. Their preliminary data reveal that postmenopausal women with type 2 diabetes or prediabetes show strong associations between sex hormone levels, AD biomarkers, and cognitive impairment, but women without type 2 diabetes/prediabetes do not. For this proposal, Drs. Banks and Sundermann would like to further expand WITS and the scope of biomarkers, pathologies, and lifestyle factors they are examining.
The project has three primary aims. In the first, Drs. Sundermann and Banks will add 30 new patients to the WITS cohort, all of whom have type 2 diabetes/prediabetes. This will allow them to expand their preliminary studies and compare AD biomarkers and cognitive assessments between postmenopausal women with and without type 2 diabetes/prediabetes, alongside measurements of sex hormones, including testosterone and estrogen. The second aim will expand their study further to include biomarkers of inflammation, vascular dysfunction, and synaptic dysfunction. They believe this expansion will help define the full impact of type 2 diabetes in postmenopausal women on AD. The third aim will incorporate new information they are gathering regarding physical activity and sleep. This will help them account for other lifestyle factors in their analyses and determine whether any can be used to counteract the effects of type 2 diabetes on AD risk.
This project builds the WITS cohort, which serves as a valuable clinical resource and will be impactful beyond the scope of this study. Additionally, this project will help explore the interactions between type 2 diabetes, menopause, and AD in pursuit of a more complete understanding of why women are disproportionately impacted by AD.
