PT  - JOURNAL ARTICLE
AU  - Guofeng Meng
AU  - Dong Lu
AU  - Feng Yu
AU  - Jijia Sun
AU  - Chong Ding
AU  - Yan Sun
AU  - Xuan Liu
AU  - Jiapei Dai
AU  - Wenfei Jin
AU  - Weidong Zhang
TI  - Accumulated degeneration of transcriptional regulation contributes to disease development and detrimental clinical outcomes of Alzheimer’s disease
AID  - 10.1101/779249
DP  - 2019 Jan 01
TA  - bioRxiv
PG  - 779249
4099  - http://biorxiv.org/content/early/2019/09/28/779249.short
4100  - http://biorxiv.org/content/early/2019/09/28/779249.full
AB  - Alzheimer’s disease (AD) is extremely complex for both causal mechanism and clinical manifestation, requiring efforts to uncover its diversity and the corresponding mechanisms. Here, we applied a modelling analysis to investigate the regulation divergence among a large-scale cohort of AD patients. We found that transcription regulation tended to get degenerated in AD patients, which contributed to disease development and the detrimental clinical outcomes, mainly by disrupting protein degradation, neuroinflammation, mitochondrial and synaptic functions. To measure the accumulated effects, we came up with a new concept, regulation loss burden, which better correlated with AD related clinical manifestations and the ageing process. The epigenetic studies to multiple active regulation marks also supported a tendency of regulation loss in AD patients. Our finding can lead to a unified model as AD causal mechanism, where AD and its diversity are contributed by accumulated degeneration of transcriptional regulation.The significance of this study is that: (1) it is the first system biology investigation to transcription regulation divergence among AD patients; (2) we observed an accumulated degeneration of transcription regulation, which well correlates with detrimental clinical outcomes; (3) transcriptional degeneration also contributes to the ageing process, where its correlation with ages is up to 0.78.