GEOapplication/xmlftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE304nnn/GSE304499/primaryOK200TranscriptomicsMus musculusExpression profiling by high throughput sequencinghttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE304499GEOGSEfalseUnique transcriptomic alterations in 5XFAD;PS19 mouse model align with human Alzheimer's diseaseAlzheimer’s disease (AD) is characterized by amyloid-β (Aβ) plaques and tau tangles, yet their combined effects on brain cell types remain poorly understood. To investigate this, we generated a dual-pathology mouse model (5XFAD;PS19) and performed single-nucleus RNA sequencing (snRNA-seq), integrating findings with human AD datasets. We uncovered widespread, synergistic transcriptional disruptions not seen in single-pathology models, including changes in gene co-expression networks and cell type-specific gene expression. Notably, we observed coordinated transcriptomic alterations involving both microglia and oligodendrocytes, particularly in immune-related pathways and suppression of synaptic transmission. The combined model significantly overlapped with human AD transcriptomic profiles at both gene and pathway levels, highlighting its translational relevance. This well-powered, sex-balanced study dissects the synergistic effects of Aβ and tau across multiple brain cell types. Our findings support the importance of modeling combined-pathology to uncover potential pharmacological targets for therapeutic development.2026/08/11GSE304499GSM9151569GSM9151568GSM9151567GSM9151566GSM9151559GSM9151561GSM9151572GSM9151571GSM9151560GSM9151570GSM9151565GSM9151564GSM9151563GSM9151574GSM9151562GSM915157324247304499Mus musculus