Sex‐biased hippocampal pathology in the 5XFAD mouse model of Alzheimer's disease: A multi‐omic analysis

Alzheimer's disease is a progressive neurodegenerative disorder and the most common form of dementia. Like many neurological disorders, Alzheimer's disease has a sex‐biased epidemiological profile, affecting approximately twice as many women as men. The cause of this sex difference has yet to be elucidated. To identify molecular correlates of this sex bias, we investigated molecular pathology in females and males using the 5XFamilial Alzheimer's disease mutations (5XFAD) genetic mouse model of Alzheimer's disease. We profiled the transcriptome and proteome of the mouse hippocampus during early stages of disease development (1, 2, and 4 months of age). Our analysis reveals 42 genes that are differentially expressed between disease and wild‐type animals at 2 months of age, prior to observable plaque deposition. In 4‐month‐old animals, we detect 1,316 differentially expressed transcripts between transgenic and control 5XFAD mice, many of which are associated with immune function. Additionally, we find that some of these transcriptional perturbations are correlated with altered protein levels in 4‐month‐old transgenic animals. Importantly, our data indicate that female 5XFAD mouse exhibit more profound pathology than their male counterparts as measured by differences in gene expression. We also find that the 5XFAD transgenes are more highly expressed in female 5XFAD mice than their male counterparts, which could partially account for the sex‐biased molecular pathology observed in this dataset. Shotgun plot showing gene expression differences between 4‐month‐old 5XFAD hippocampus and wild‐type mice. Approximately twice as many differentially expressed transcripts (red points) are up‐regulated (above y = 0) that are down‐regulated (below y = 0) in diseased mice.