Integrated single-nucleus transcriptomics reveals stage-dependent neuronal and oligodendroglial remodeling in the Alzheimer's disease prefrontal cortex.

Alzheimer's disease (AD) progression is accompanied by cell-type-specific vulnerability in the human cortex, but how neuronal and glial subtypes are remodeled across pathological stages remains incompletely understood. Here, we integrated five publicly available single-nucleus RNA-seq datasets from the human prefrontal cortex, comprising 945,692 high-quality nuclei, to investigate transcriptional and compositional alterations associated with Braak pathological progression. Seven major cell types were identified across cohorts, including excitatory neurons, inhibitory neurons, astrocytes, oligodendrocytes, oligodendrocyte precursor cells, microglia, and vascular cells. Sample-level pseudobulk differential expression analysis revealed stage-dependent transcriptional remodeling, with prominent alterations in excitatory neurons, oligodendrocytes, and oligodendrocyte precursor cells at advanced pathological stages. Subtype-level compositional analysis further identified selective remodeling of excitatory neuronal and oligodendrocyte subtypes. Exc_0 showed a biphasic pattern across Braak stages, whereas Exc_1 decreased and Exc_4 increased at high pathological burden. In oligodendrocytes, Oligo_1 was enriched at high Braak stages. Functional enrichment analysis linked these key subtypes to synaptic organization, cell junction assembly, cytoplasmic translation, oxidative phosphorylation, and electron transport chain-related processes. These findings suggest that AD pathological progression in the prefrontal cortex involves coordinated neuronal and oligodendroglial remodeling associated with synaptic and metabolic dysfunction.