Women have double the lifetime risk of developing Alzheimer’s disease (AD) compared to men, but the reasons for this sex disparity are not well-understood. One factor that may contribute to women’s heightened susceptibility to AD is menopause, which has been identified as a critical inflection point that sharply increases women’s risk AD. Our work and others have shown that earlier age at menopause is especially deleterious for brain health, increasing the risk for cognitive decline, dementia, and AD pathology.
Despite this mounting evidence implicating menopause as a key contributor to AD in women, the mechanisms by which menopause (and its endocrine sequalae) affect late-life brain aging remain unclear. The advent of high-throughput technology now enables the simultaneous characterization of ~5,000 peripherally circulating proteins in the human proteome, and recent large-scale proteomic analyses have uncovered numerous molecular pathways involved in brain aging and neurodegeneration. Many of these biological processes are highly relevant to menopause-related changes and may represent pathways by which menopause and women’s reproductive health history influence AD risk. But no published studies have investigated the proteomic profiles associated with women’s reproductive health history in the brain aging context.
Here, we will leverage UK Biobank’s large scale proteomics data to investigate the plasma proteins associated with female-specific health factors (including menopause history, hormone therapy use, pregnancy history, and other hormonal factors) and will examine how these proteins relate to midlife and late-life cognitive and brain health outcomes. This work will uncover new biological pathways by which menopause and female-specific endocrine factors influence AD risk. Elucidating these sex-specific biological factors is crucial for precision approaches to detect, treat and prevent dementia in both sexes.