Systems Level Analysis of Late Onset Alzheimer’s Disease Across Four Brain Regions

Alzheimer’s Disease (AD) is a neurodegenerative disease that causes loss of memory, among other cognitive functions and is the 6th leading cause of death in the United States. Late Onset Sporadic Alzheimer’s Disease (LOAD) is the most common form of AD and yet still little is known about the disease and there is no cure. The disease is complex, with temporally distinct effects at different stages. Microarray data generated from 885 postmortem patient brain tissue samples (401 control samples, 484 AD samples) was used to study the effects of LOAD on four regions of the brain: the dorsolateral Prefrontal Cortex (PFC), Visual Cortex (VC), Cerebellum (CR) and the Middle Temporal Gyrus (MTG). Various methods were explored and selected to create an analysis pipeline. The use of gene set and transcription factor enrichment enabled functional class sorting that suggested key biological functions affected by AD in each region. Five main endotypes were identified and further analyzed: Cell Cycle (G1-S Phase), Inflammation, Dedifferentiation, Synaptic Signaling and Mitochondrial Metabolism. Custom gene sets were used to create protein-protein interaction networks in order to identify key TF and gene activity within each brain region, revealing that these five endotypes were preferentially enriched in the PFC and VC brain regions