Abstract: The goal of this supplement is to investigate the cellular composition and regulatory mechanisms within the entorhinal cortex (EC) that vary with age and sex, with a focus on their potential implications for differential Alzheimer's disease (AD) etiology. The EC is the gateway between the hippocampus and neocortex, and is therefore a crucial structure for the formation and retrieval of memories. The EC is particularly involved in spatial memory, navigation and the perception of time, and is among the first brain regions affected by Alzheimer’s Disease (AD). This proposal seeks to analyze single nucleus (sn)RNA-seq data from 135 macaque entorhinal cortices, encompassing the natural lifespan of free-living macaques and consisting of 77 females, to identify variations in cellular composition and gene expression associated with age and sex. The research plan for this project uses snRNA-seq data, facilitating the investigation of heterogeneity of cell types and transcriptional states across ages and sexes. The project will generate a comprehensive analysis of which cell types and gene regulatory networks are most strongly impacted by these demographic factors. This information will be leveraged to enhance our understanding of the cellular and molecular etiology of AD, with a particular focus on why females are disproportionately affected. This proposal also focuses on the scientific training and career development of Kelsi Watkins during her graduate studies. Kesi will receive training in computational, statistical, and theoretical analysis of large-scale snRNA-seq data. She will also gain experience and mentorship in public speaking, scientific and professional writing, and project management, with mentorship provided by experts in bioinformatics and statistical approaches to single- cell genomics data analysis, who have successfully trained predoctoral and postdoctoral researchers. This training and development will prepare Kelsi for a successful career as an independent researcher in neurogenomics and the biology of aging. The insights gained from this research have the potential to shed light on the disproportionate impact of AD on females and provide crucial data for addressing the increasing prevalence of the disease in an aging global population. By elucidating the influence of demographic factors on AD etiology and equipping the next generation of researchers with essential skills, this project contributes significantly to addressing the pressing challenges posed by AD in an aging global population.