Transcriptomic analyses of human brains with Alzheimer's disease identified dysregulated epilepsy-causing genes.

Background & Objective: Alzheimer's Disease (AD) patients at multiple stages of disease progression have a high prevalence of seizures. However, whether AD and epilepsy share pathophysiological changes remains poorly defined. In this study, we leveraged high-throughput transcriptomic data from sporadic AD cases at different stages of cognitive impairment across multiple independent cohorts and brain regions to examine the role of epilepsy-causing genes. Methods: Epilepsy-causing genes were manually curated, and their expression levels were analyzed across bulk transcriptomic data from three AD cohorts and three brain regions. RNA-seq data from sporadic AD and control cases from the Knight ADRC, MSBB, and ROSMAP cohorts were processed and analyzed under the same analytical pipeline. An integrative clustering approach employing machine learning and multi-omics data was employed to identify molecularly defined profiles with different cognitive scores. Results: We found several epilepsy-associated genes/pathways significantly dysregulated in a group of AD patients with more severe cognitive impairment. We observed 15 genes consistently downregulated across the three cohorts, including sodium and potassium channels, suggesting that these genes play fundamental roles in cognitive function or AD progression. Notably, we found 25 of these genes dysregulated in earlier stages of AD and become worse with AD progression. Conclusion: Our findings showed that epilepsy-causing genes showed changes in the early and late stages of AD progression, suggesting that they might be playing a role in AD progression. We can not establish directionality or cause-effect with our findings. However, changes in the epilepsy-causing genes might underlie the presence of seizures in AD patients, which might be present before or concurrently with the initial stages of AD.