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

Alzheimer’s disease (AD) and epilepsy (EP) exhibit a complex, bidirectional relationship, however, the molecular mechanisms underlying their comorbidity remain poorly understood. To address this gap, we analyzed large-scale transcriptomic datasets from pilocarpine-induced EP mouse models (n = 200), two AD mouse models expressing human tau (rTg4510) or amyloid precursor protein (J20) (n = 141), and transcriptomic profiles from AD and EP patient cohorts. Differential expression and weighted gene co-expression network analyses identified a highly conserved immune-related module enriched in microglia-specific genes, particularlyTyrobp,Trem2, andC1qcomplement component genes (C1qa,C1qb,C1qc) implicated in the synaptic pruning pathway. Gene regulatory network analysis showed thatTyrobpregulates theseC1qcomponents gene throughTrem2. These hub genes were markedly upregulated in both models and human patient datasets, preserved their regulatory relationship across species, and displayed strong diagnostic value. Cell composition deconvolution and single-cell transcriptomics confirmed their high, cell-type-specific expression in microglia from both animal model and human patient datasets. Moreover, computational modeling indicated that excessive synaptic pruning, particularly of inhibitory synapses, alters the excitation/inhibition (E/I) balance toward excitability that increases neural network synchrony. Collectively, our findings reveal how microglial complement-driven synapse elimination may promote both seizure activity and cognitive decline. We suggest that microglia play a central role in the comorbidity of EP and AD, and further exploration of this synaptic pruning pathway in the context of EP may provide promising insights into the treatment of AD and EP comorbidity.