Authors: Rhinn H; Fujita R; Qiang L; Cheng R; Lee JH; Abeliovich A
Abstract: Late-onset Alzheimer's disease (LOAD) risk is strongly influenced by genetic factors such as the presence of the apolipoprotein E epsilon4 allele (referred to here as APOE4), as well as non-genetic determinants including ageing. To pursue mechanisms by which these affect human brain physiology and modify LOAD risk, we initially analysed whole-transcriptome cerebral cortex gene expression data in unaffected APOE4 carriers and LOAD patients. APOE4 carrier status was associated with a consistent transcriptomic shift that broadly resembled the LOAD profile. Differential co-expression correlation network analysis of the APOE4 and LOAD transcriptomic changes identified a set of candidate core regulatory mediators. Several of these--including APBA2, FYN, RNF219 and SV2A--encode known or novel modulators of LOAD associated amyloid beta A4 precursor protein (APP) endocytosis and metabolism. Furthermore, a genetic variant within RNF219 was found to affect amyloid deposition in human brain and LOAD age-of-onset. These data implicate an APOE4 associated molecular pathway that promotes LOAD.
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Journal: Nature Volume: 500 Issue: 7460 Pages: 45-50 Date: July 26, 2013 PMID: 23883936 |
Rhinn H, Fujita R, Qiang L, Cheng R, Lee JH, Abeliovich A (2013) Integrative genomics identifies APOE ε4 effectors in Alzheimer's disease. Nature 500: 45-50.
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