Two-thirds of all people living with Alzheimer’s disease (AD) are women, and scientists don’t fully understand why. While women living longer and hormonal changes like menopause may contribute, these factors alone don’t fully explain the disparity.
One obvious difference between men and women, and a surprisingly understudied subject, is the presence of two X chromosomes in women versus only one in men. This means that women have two copies of every gene on the X chromosome as opposed to the single copy men have. To avoid a double dose of X-linked genes in females, one of the X chromosomes is silenced early in development. However, some genes escape this silencing, leading to higher expression levels of those genes in women. Dr. Buckley is working to identify which genes escape silencing in AD, and to understand how these genes influence AD risk in women.
Population-level studies have shown that some of the most common X-linked escapees are related to inflammation and immunity, which helps explain why certain autoimmune disorders are more prevalent in women. The growing recognition of the role of inflammation and immunity in AD also suggests that these escapee genes may significantly influence AD development. Dr. Buckley’s preliminary studies have identified several X-linked escapees that interact with amyloid and tau in healthy older adults. She now plans to identify X-linked escapees that contribute to AD vulnerability, both in a sex-specific manner (more in one sex versus the other) and in a sex-agnostic manner (equally in both sexes).
The project has two main experimental goals. First, the Buckley lab will utilize major data repositories such as ROSMAP (Religious Order Study and Memory and Aging Project), ADNI (AD Neuroimaging Initiative), VMAP (Vanderbilt Memory and Aging Project), and A4/LEARN (Anti-Amyloid Treatment in Asymptomatic Alzheimer’s and Longitudinal Evaluation of Amyloid Risk and Neurodegeneration Study) to validate several genes they have already identified. These repositories include extensive gene expression (transcriptomic) data, as well as biomarker and cognitive testing information. This extensive dataset will enable precise analyses to pinpoint the X-linked escapee genes linked to AD risk and its progression. The second goal is to investigate the molecular switches controlling these escapees, as these factors influence gene expression levels. Dr. Buckley’s team will also study the pathways these genes and regulatory elements feed into, and how they interact with amyloid and tau. This will lay the groundwork for future studies of these genes and their functions.
Overall, this project will leverage major data repositories to explore how X-linked gene escapees influence the increased AD risk in women. The findings could facilitate further research and pave the way for personalized therapies based on sex.
