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Alzheimer’s disease (AD) and epilepsy (EP) share a complex bidirectional relationship, yet the molecular mechanisms underlying their comorbidity remain insufficiently explored. To identify potential transcriptional programs across animal models and human patients with AD and EP, we conducted a comprehensive genome-wide transcriptomic analysis. Our investigation included mouse models of temporal lobe epilepsy (pilocarpine- and kainic acid-induced; n = 280), AD transgenic models (7 transgenic models expressing human tau or amyloid pathology; n = 257), and performed cross-species validation in human cohorts (EP: n = 182; AD: n = 301). We identified a highly conserved immune-related module across all models and patient cohorts. The hub consensus signatures of this module were centered around a microglial synaptic pruning pathway involving TYROBP , TREM2 , and C1Q complement components. Gene regulatory network analysis identified TYROBP as the key upstream hub signature. These signatures showed consistent up-regulation in both conditions and strong diagnostic potential. Differential expression analyses revealed their predominant expression in specific microglial subpopulations associated with complement-mediated synaptic pruning and immune activation. Neural circuit modeling further demonstrates the asymmetric sensitivity of synaptic pruning to network dynamics. Loss of inhibitory synapses has a disproportionately significant impact on neural network excitation/inhibition balance and synchronization. Our findings support microglial complement-mediated synaptic pruning as a conserved central pathway linking neurodegeneration to epileptogenesis, suggesting a promising therapeutic target for AD and EP comorbidity.

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Highlights

• Genome-wide transcriptomic analysis across epilepsy (EP) and Alzheimer’s disease (AD) models and patients identified a conserved immune module.

• The TYROBP-TREM2-C1Q microglial synaptic pruning pathway was identified as a central consensus signature across model and patient cohorts.

• Consensus signatures possess potential diagnostic utility in AD and EP patients, with predominant expression in specific microglial subpopulations

• Neural circuit modeling demonstrates the asymmetric effects of synaptic pruning, whereby loss of inhibitory synapses disproportionately disrupts the E/I balance, leading to increased network synchronization.