Menopause is a natural part of life for women, marking the end of menstrual cycles and a major shift in hormone levels, especially estrogen. While this transition is universal, it can have wide-ranging effects on a woman’s health. In recent years, researchers have discovered that menopause may play an important role in increasing the risk for Alzheimer’s disease (AD), a condition that disproportionately affects women. During and after menopause, women often experience changes such as increased risk of heart disease, inflammation, and mood disturbances. All of these may contribute to how the brain ages. Yet, we still don’t fully understand how menopause and these midlife health factors affect brain health and memory.
To understand these changes, the Women’s Health Initiative (WHI) was launched in 1991 as a long-term national health study to focus on strategies for preventing heart disease, breast and colorectal cancer, and osteoporosis in postmenopausal women. One part of the original study was a clinical trial to study how oral hormone replacement therapy (HRT) affects health outcomes like dementia. This trial was stopped early due to unfavorable results, but about 1,300 women who took part were between 50 and 55 years old when they started, making them much younger than the average participant age of 65. Thirteen years later, these women participated in a follow-up study from 2008 to 2015, during which they underwent cognitive assessments. This study was called the WHI Memory Study – Young, or WHIMSY. WHIMSY found that women who received HRT at an earlier age showed no significant cognitive decline, whereas their older counterparts in the main trial had an increased risk of decline.
Dr. Buckley wants to re-engage the WHIMSY cohort to gather more information about their ongoing brain health and test for AD biomarkers. This approach saves significant time and money by using participants who have already been tracked for years, rather than starting a new study from scratch. WHIMSY also provides extensive clinical information from various studies, enabling the Buckley lab to consider how other midlife risk factors—such as vascular risks, metabolic syndromes, and inflammatory conditions—affect menopause, HRT, and AD risk. WHIMSY study participants have remained engaged over the years, which provides strong statistical power for these analyses. In addition to data from WHIMSY, Dr. Buckley will also have access to data from the original WHI study with HRT, enabling comparisons between groups to evaluate the impact of age as well.
The project will consist of two primary aims. The first aim will examine how menopause, HRT, and related midlife risk factors—such as cardiovascular risk, metabolic syndromes, and inflammatory conditions—affect AD fluid biomarkers (pTau217, NfL, and GFAP). Part of this aim will also seek to further categorize groups by APOE4 status to examine how it interacts with other risk factors. The second aim will examine the same set of risk factors as the first but will also incorporate cognition changes into the analysis. The Buckley lab has access to cognitive studies spanning decades. With the recent emergence of fluid biomarkers, her lab will be able to perform new analyses of cognitive data to identify links between cognitive trajectories and disease biomarkers.
This project will define the impact of menopause and HRT on AD risk and progression, revealing novel mechanisms that underlie women’s increased vulnerability to AD, and open the door to more personalized and specific therapeutic approaches.
