Genome-wide consensus transcriptional signatures identify synaptic pruning linking Alzheimer’s disease and epilepsy

Abstract 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. Graphic abstract 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. Competing Interest Statement The authors have declared no competing interest. Footnotes Updated microglial single-cell subpopulation analysis Polished the structure of the entire manuscript Added supplementary methods file Updated author list Abbreviations - EP - Epilepsy - AD - Alzheimer’s disease - E/I - Excitation/Inhibition - TLE - Temporal lobe epilepsy - Aβ - Amyloid-β - PO - Pilocarpine-induced - KA - Kainic acid-induced - GCNs - Gene co-expression networks - WT - Wild-type - PCA - Principal Component Analysis - BH - Benjamini-Hochberg - GO - Gene Ontology - TOM - Topological overlap matrices - MEs - Module eigengenes - MM - Module membership - GS - Gene-genotype significance - PPI - Protein-protein interaction - FDR - False discovery rate - AUC - Area Under the Receiver Operating Characteristic Curve - ROC - Receiver Operating Characteristic - CBE - Cerebellum - DLPFC - Dorsolateral prefrontal cortex - STG - Superior temporal gyrus - IFG - Inferior frontal gyrus - TCX - Temporal cortex - FP - Frontal pole - SVM - Support vector machine - ES - Event synchrony - BBB - Blood-brain barrier - DAM - Disease-associated microglia - LTP - Long-term potentiation - LTD - Long-term depression - ROSMAP - Rush Memory and Aging Project snRNA-seq Single nucleus RNA-sequencing