Integrative genomics identifies APOE ε4 effectors in Alzheimer's disease

• Published in: Nature (London) Vol. 500; no. 7460; pp. 45 - 50
• Main Authors: Rhinn, Herve, Fujita, Ryousuke, Qiang, Liang, Cheng, Rong, Lee, Joseph H., Abeliovich, Asa
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.08.2013; Nature Publishing Group
• Subjects: 631/378/1689/1283; Age of Onset; Aged; Alleles; Alzheimer Disease - epidemiology; Alzheimer Disease - genetics; Amyloid beta-Protein Precursor - metabolism; Apolipoprotein E4 - genetics; Biological and medical sciences; Brain - drug effects; Brain - metabolism; Cells, Cultured; Cerebral Cortex - metabolism; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Endocytosis; Epistasis, Genetic; Female; Fibroblasts; Fundamental and applied biological sciences. Psychology; Gene Expression Profiling; Genome, Human - genetics; Genome-Wide Association Study; Genomics; Heterozygote; Humanities and Social Sciences; Humans; Medical sciences; Membrane Glycoproteins - antagonists & inhibitors; Membrane Glycoproteins - genetics; Membrane Glycoproteins - metabolism; multidisciplinary; Nerve Tissue Proteins - antagonists & inhibitors; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Neurology; Neurons - drug effects; Neurons - metabolism; Phenotype; Piracetam - analogs & derivatives; Piracetam - pharmacology; Polymorphism, Genetic - genetics; Proteolysis - drug effects; Science; Transcriptome - genetics; Vertebrates: nervous system and sense organs; Human; Nervous system diseases; Cerebral cortex; Senescence; Alzheimer disease; Genetic variant; Central nervous system; Gene expression; Metabolism; Amyloid precursor protein; Encephalon; Endocytosis; Age of onset; Apolipoprotein E; Degenerative disease; Amyloid
• ISSN: 0028-0836; 1476-4687; 1476-4687
• DOI: 10.1038/nature12415

Late-onset Alzheimer’s disease (LOAD) risk is strongly influenced by genetic factors such as the presence of the apolipoprotein E ε4 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. Whole transcriptome differential gene co-expression correlation analysis of cerebral cortex of APOE ε4 allele carriers and late-onset Alzheimer’s disease patients reveals an APOE ε4 carrier transcription network pattern that resembles that of late-onset Alzheimer’s disease and also identifies new genes of interest for further study. Emergence of late-onset Alzheimer's disease Individuals carrying the apolipoprotein E ε4 ( APOE4 ) allele of the APOE gene can be ten times more likely to develop late-onset Alzheimer's disease than those carrying other variants and may be subject to earlier disease onset. Asa Abeliovich and colleagues analyse whole-transcriptome cerebral cortex gene expression in unaffected APOE ε4 carriers and in patients with late-onset Alzheimer's and find that gene expression patterns in carriers shift with time towards those seen in patients with the disease. They used differential co-expression correlation network analysis to identify candidate 'master regulatory' node genes that mediate the influence of APOE4 on the brain transcriptome. Several of the top 'hits' are previously known or novel regulators of amyloid precursor protein processing and trafficking, including APBA2, FYN, RNF219 and SV2A. Further, common genetic variants of FYN and RNF219 are predictive of the age of disease onset in an APOE4-dependent fashion. Finally, the anti-epileptic SV2A inhibitor levetiracetam was shown to suppress APP processing in cells cultured from APOE4 carriers, an interaction worthy of further study.