Commentary on recent Alzheimer’s trial failures: comparative functional genomic meta-analysis of Alzheimer’s affected and naturally aging brains

• Main Authors: Yi-Shian Peng, 彭奕憲
• Other Authors: Hoong-Chien Lee
• Format: Others
• Language: en_US
• Published: 2019
• Online Access: http://ndltd.ncl.edu.tw/handle/wr6r44

博士 === 國立中央大學 === 系統生物與生物資訊研究所 === 107 === Alzheimer's disease (AD) is a prevalent progressive neurodegenerative human disease. Several initially highly hopeful anti-AD drugs based on the amyloid-β (Aβ) hypothesis of AD have failed recent late-phase tests, and the cause of AD remains unclear. Natural aging (AG) is a high risk factor for AD. Here, five sets of gene expression microarray data from different regions of AD affected brain, and one of AG, were analyzed for identifying putatively disrupted biological pathways or functions and their abnormal molecular contents. Brain-region specificity among AD cases and AG-AD differences in KEGG-termed function disruption were identified. AG was significantly more at risk to cancer than was AD; hippocampus, the region with the strongest AD signatures, showed no risk to cancer. Our results also showed that microbial related KEGG terms were enriched in five AD affected brain regions, especially in E. coli infection Pathway. Oxidative phosphorylation (OXPHOS; Fisher’s exact test p=1.1E-20) and proteasome (p=2.0E-18) were found to be the most putatively disrupted functions and 24 new target genes were identified. Our results highlighted the heterogeneity of AD in the five brain regions, and indicated a possible AG-AD connection. These may be useful in devising strategies for the early detection of AD. Based on our results we comment on a number of recent late-phase failures of anti-AD drug trials.