# Unraveling the molecular mechanisms in severe Alzheimer’s disease based on transcriptomic data using next generation knowledge discovery methods

## TL;DR

This study uses brain RNA data to uncover key molecular pathways involved in severe Alzheimer’s disease, focusing on neuroinflammation and energy metabolism.

## Contribution

Novel application of next-generation knowledge discovery methods to identify dysregulated pathways in severe Alzheimer’s disease.

## Key findings

- Dysregulation of energy metabolism and protein synthesis in severe Alzheimer’s disease.
- Enrichment of neuroinflammatory pathways and immune system activation in affected brain regions.
- Downregulation of ribosome biogenesis and oxidative phosphorylation in severe Alzheimer’s disease.

## Abstract

Alzheimer’s disease (AD) is characterized by gradual cognitive decline. Here, we deciphered the molecular mechanisms using transcriptomic data derived from the dorsolateral prefrontal cortex (DLPFC) of patients with severe AD using next-generation knowledge discovery (NGKD) techniques.

RNA sequencing data from the Gene Expression Omnibus (GEO) database (GSE53697) derived from the DLPFC of individuals with severe AD and healthy controls, obtained originally from frozen brain tissues of individuals classified based on the Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) criteria, and differentially expressed genes (DEGs) were identified by GEO2R analysis. The WEB-based GEne SeT AnaLysis Toolkit (WebGestalt) was used for overrepresentation analysis (ORA) using the Kyoto Encyclopedia of Genes and Genomes (KEGG) Pathway Database and Gene Set Enrichment Analysis (GSEA) using the KEGG, Reactome, and Wiki pathway databases. Ingenuity Pathway Analysis (IPA) software was used to decode the key canonical pathways and gene networks implicated in severe AD.

We identified 24,207 DEGs using P ≤0.05, and this list was further filtered with a fold change cut-off ±1.5 to derive 3103 genes. WebGestalt analysis showed that retrograde endocannabinoid signaling, motor proteins, oxidative phosphorylation, and ribosome biogenesis were downregulated, whereas pathways related to immune system activation, such as antigen processing and presentation and cytokine signaling, were enriched in patients with severe AD. IPA analysis showed significant downregulation of ribosomal RNA (rRNA) processing and enrichment of neuroinflammatory signaling pathways. Crucially, dysregulation of energy metabolism, protein synthesis, axonal transport, and immunological responses have been identified in the DLPFC of patients with severe AD.

Using NGKD methods, we identified an array of molecular pathways implicated in neuroinflammation, dysregulation of energy metabolism, and mitochondrial damage in severe AD and their association with disease progression. Our findings add to the existing knowledge on the pathophysiology of severe AD and help in the development of more effective strategies for diagnosis, therapy, and prevention.