Glial changes and gene expression in Alzheimer's disease from snRNA-Seq and spatial transcriptomics

Background Alzheimer's disease (AD) is characterized by cortical atrophy, glutamatergic neuron loss, and cognitive decline. However, large-scale quantitative assessments of cellular changes during AD pathology remain scarce. Objective This study aims to integrate single-nuclei sequencing data from the Seattle Alzheimer's Disease Cortical Atlas (SEA-AD) with spatial transcriptomics to quantify cellular changes in the prefrontal cortex and temporal gyrus, regions vulnerable to AD neuropathological changes (ADNC). Methods We mapped differentially expressed genes (DEGs) and analyzed their interactions with pathological factors such as APOE expression and Lewy bodies. Cellular proportions were assessed, focusing on neurons, glial cells, and immune cells. Results RORB-expressing L4-like neurons, though vulnerable to ADNC, exhibited stable cell numbers throughout disease progression. In contrast, astrocytes displayed increased reactivity, with upregulated cytokine signaling and oxidative stress responses, suggesting a role in neuroinflammation. A reduction in synaptic maintenance pathways indicated a decline in astrocytic support functions. Microglia showed heightened immune surveillance and phagocytic activity, indicating their role in maintaining cortical homeostasis. Conclusions The study underscores the critical roles of glial cells, particularly astrocytes and microglia, in AD progression. These findings contribute to a better understanding of cellular dynamics and may inform therapeutic strategies targeting glial cell function in AD.