Exploratory epilepsy-derived transcriptomic projection reveals region-sensitive molecular remodeling in Alzheimer's disease.

Abstract

Background: Alzheimer's disease (AD) is frequently accompanied by seizures or subclinical epileptiform activity, but the transcriptomic context linking AD-related neurodegeneration with epilepsy-related network dysfunction remains unclear.

Objective: To apply an exploratory epilepsy-derived directional transcriptomic projection framework to examine region-sensitive molecular organization in AD brain tissues.

Methods: A directional reference was generated from GSE268714 by defining seizure onset zone (SOZ)-upregulated and SOZ-downregulated genes from an unpaired exploratory SOZ-versus-non-involved zone (NIZ) contrast, because patient-level identifiers were not recoverable. This reference was projected onto AD cohorts GSE5281, GSE132903, and GSE48350. EpilepsyScore was calculated as ssGSEA_Up minus ssGSEA_Down. In GSE5281, primary inference was restricted to region-stratified analyses.

Results: Region-stratified analyses showed lower EpilepsyScore values across several AD-relevant regions, with the clearest separation in the middle temporal gyrus (MTG). Within MTG, continuous module-level associations with synaptic and glia-associated programs were directionally consistent but not statistically significant. Median-based grouping was used only for exploratory visualization and pathway-level contrast. External cohorts showed directionally concordant but context-dependent support. Matched random-signature benchmarks were not significant, indicating that EpilepsyScore should not be interpreted as an epilepsy-specific molecular signature.

Conclusions: This study provides a hypothesis-generating cross-disease projection framework for exploring region-sensitive transcriptomic organization in AD. Future cell-type, spatial, and mechanistic evaluation is required.