Data-Driven Analysis of Age, Sex, and Tissue Effects on Gene Expression Variability in Alzheimer's Disease

Alzheimer's disease (AD) has been categorized by the Centers for Disease Control and Prevention (CDC) as the 6^th leading cause of death in the United States. AD is a significant health-care burden because of its increased occurrence (specifically in the elderly population), and the lack of effective treatments and preventive methods. With an increase in life expectancy, the CDC expects AD cases to rise to 15 million by 2060. Aging has been previously associated with susceptibility to AD, and there are ongoing efforts to effectively differentiate between normal and AD age-related brain degeneration and memory loss. AD targets neuronal function and can cause neuronal loss due to the buildup of amyloid-beta plaques and intracellular neurofibrillary tangles. Our study aims to identify temporal changes within gene expression profiles of healthy controls and AD subjects. We conducted a meta-analysis using publicly available microarray expression data from AD and healthy cohorts. For our meta-analysis, we selected datasets that reported donor age and gender, and used Affymetrix and Illumina microarray platforms (8 datasets, 2,088 samples). Raw microarray expression data were re-analyzed, and normalized across arrays. We then performed an analysis of variance, using a linear model that incorporated age, tissue type, sex, and disease state as effects, as well as study to account for batch effects, and included binary interactions between factors. Our results identified 3,735 statistically significant (Bonferroni adjusted p < 0.05) gene expression differences between AD and healthy controls, which we filtered for biological effect (10% two-tailed quantiles of mean differences between groups) to obtain 352 genes. Interesting pathways identified as enriched comprised of neurodegenerative diseases pathways (including AD), and also mitochondrial translation and dysfunction, synaptic vesicle cycle and GABAergic synapse, and gene ontology terms enrichment in neuronal system, transmission across chemical synapses and mitochondrial translation. Overall our approach allowed us to effectively combine multiple available microarray datasets and identify gene expression differences between AD and healthy individuals including full age and tissue type considerations. Our findings provide potential gene and pathway associations that can be targeted to improve AD diagnostics and potentially treatment or prevention.