Traumatic brain injury (TBI) is a known risk factor for Alzheimer Disease (AD). Both TBI and AD have been found to display similar neurological symptoms and have increasing incidences of disability, morbidity, mortality, and economic burden. Despite these connections, the precise molecular relationship between the two remains relatively underexplored. Single-cell RNA-sequencing (scRNA-seq) has allowed for a progressive understanding of the cellular and genetic landscapes of TBI and AD. This study repurposes single-cell data from the frontal cortex and hippocampus collected at the acute (24-h) and subacute (7-day) phases from mice that underwent fluid percussion injury (FPI) (Arneson et al., 2022). We compared this data to single-cell human data from the parietal cortex of postmortem AD brains (Brase et al., 2021). This includes carriers of pathogenic variants (APP, PSEN1 and PSEN2), also referred to as autosomal dominant AD, and individuals with sporadic AD. We examined the molecular overlap of differentially expressed genes in FPI TBI brains with those differentially expressed in AD brains to identify cell-type-specific biological pathway comparisons across different timescales. Astrocytes and activated microglia, being the most transcriptionally altered cells in the TBI data, were the primary targets of investigation. Statistical analyses revealed substantial molecular resemblance of DEGs co-expressed in both TBI and AD brains in astrocytes, as well as in activated microglia. Our results show specific pathways dysregulated in astrocytic and glial cells in the acute and subacute phases of TBI mouse models that resemble those dysregulated in human postmortem AD brains. By understanding the molecular similarities and differences at single-cell resolution between TBI and AD in a spatiotemporal manner, we aim to uncover specific pathways dysregulated in TBI that contribute to AD etiology.