Impaired pathways of detoxification and risk of Alzheimer's disease: Differential gene expression studies via gene set expression analysis.

Background: Alzheimer's disease (AD) is a common dementing disease associated with aging for which no specific etiology has been found. Objective: Quantification and analysis of expression in a curated group of detoxification genes have not previously been reported in AD. Methods: I compare AD and non-AD cohorts in a Gene Expression Omnibus (GEO) datasets study and a tissue RNA sequencing (RNA-seq) study. A list of 203 detoxification "genes of interest" (GOI) was created (see Methods and Supplemental Material). Results: I identify 162 detoxification genes in one or both phases of the study with statistically significant differential detoxification gene expression comparing AD and non-AD samples. In addition, one dataset demonstrates a role of amyloid-β (Aβ) fibrils in regulating detoxification gene expression (phase 1, GSE227221); novel, long non-coding RNA (lncRNA) association with detoxification differential gene expression is also shown with marked upregulation in 6 MT2A groupings in the tissue study (Supplemental Table 22) and downregulation of GSS in GEO analysis (GSE159699 advyoung). Conclusions: This research reports a novel finding of differential expression in multiple detoxification genes in AD compared with non-AD controls, supporting a new hypothesis: detoxification gene expression is related to etiology of AD, as shown by both decreased expression (GSS for example) and increased expression (MT2A for another example) of detoxification genes. Complexity of expression of detoxification genes is suggested by Aβ and lncRNA regulation of detoxification gene expression. Subsequent research to confirm and investigate implications of these findings and how they may relate to the etiology of AD is needed.