Women's obstetric history affects susceptibility to Alzheimer?s disease (AD). The number of pregnancies or the number of children is positively correlated with the neuropathology of AD in several studies, while cumulative estrogen exposure calculated from the number of menstrual cycles is associated with lower AD risk in another study. The discrepancy may be due to differential estrogen levels, durations, and temporal patterns of exposure in each setting. The protective effect of transient low-level estrogen during normal estrous cycles does not necessarily mean that prolonged high-level estrogen exposure during pregnancy is beneficial. Few animal studies have examined the effect of pregnancy-associated high-level estrogen exposure on late-life susceptibility to AD. We intend to address this knowledge gap by determining how multiparity or high-level estrogen exposure during the reproductive age affects late-life AD susceptibility in mice expressing amyloid precursor protein (APP) with AD-causing mutations. We will also determine how multiparity during the reproductive age affects brain gene expression in late-life using single-cell RNA-seq (scRNA-seq). Regarding the role of estrogen in AD risk, most previous studies focused on the immediate effects of low estrogen in the context of estrogen hormone replacement in the postmenopausal stage. In contrast, the enduring effects of high estrogen long after the cessation of the exposure are unclear. Here, we examine the relationship between estrogen and AD from a novel perspective of epigenomic memory, which may provide generalizable insight into how early- or mid-life environmental factors modulate late-life AD risk.
It is unclear how women's pregnancy history affects susceptibility to Alzheimer?s disease (AD). We will use animal models to address this underexplored question regarding the relationship between estrogen and AD. The study may provide novel insight into how early- or mid-life environmental factors modulate late-life AD risk.
