Shared Transcriptomic Signatures Reveal Synaptic Pruning as a Link Between Alzheimer’s Disease and Epilepsy

The mechanism of epileptogenesis in Alzheimer’s disease (AD) remains poorly understood, though growing evidence indicates shared molecular mechanisms between epilepsy (EP) and AD. This study aims to reveal these overlapping molecular mechanisms by reanalyzing two extensive bulk RNA-seq datasets: one from a pilocarpine-induced temporal lobe epilepsy (TLE) model (n=200) and the other from AD models, specifically rTg4510 (TG) tauopathy and J20 amyloidosis (n=141). We identified 101 differentially expressed genes (DEGs) shared between EP and the tauopathy model, though none were shared between EP and the amyloidosis model. These shared DEGs were significantly enriched in immune-related terms. Weighted gene co-expression network analysis (WGCNA) revealed a highly preserved immune module strongly associated with both EP and tauopathy models, which also significantly overlapped with modules constructed from EP and AD human patient datasets. This module contained 19 shared hub genes enriched in the synapse pruning biological process, with shared regulatory network analysis revealing a pathway where Tyrobp regulates C1q component genes through Trem2. Cell composition deconvolution showed decreased neuronal and increased microglial composition in both EP and tauopathy models, with strong correlations observed between these cellular composition changes and the expression of shared hub genes. Further validation using single-cell/nucleus sequencing data from EP and AD patients confirmed a high microglia-specific expression of key genes, including Tyrobp, Trem2, and C1q components, in both EP and AD patients relative to other hub genes. These findings suggest that immune-related processes, particularly microglial-mediated synaptic pruning, are essential in both disorders and may drive neurodegeneration and epileptogenesis.