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Genetic Evidence Implicates the Immune System and Cholesterol Metabolism in the Aetiology of Alzheimer's Disease

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Lesley Jones, Peter A. Holmans, Marian L. Hamshere, Denise Harold, Valentina Moskvina, Dobril Ivanov, Andrew Pocklington, Richard Abraham, Paul Hollingworth, Rebecca Sims, Amy Gerrish, Jaspreet Singh Pahwa, Nicola Jones, Alexandra Stretton, Angharad R. Morgan, Simon Lovestone, John Powell, Petroula Proitsi, Michelle K. Lupton, Carol Brayne & 62 more David C. Rubinsztein, Michael Gill, Brian Lawlor, Aoibhinn Lynch, Kevin Morgan, Kristelle S. Brown, Peter A. Passmore, David Craig, Bernadette McGuinness, Stephen Todd, Clive Holmes, David Mann, A. David Smith, Seth Love, Patrick G. Kehoe, Simon Mead, Nick Fox, Martin Rossor, John Collinge, Wolfgang Maier, Frank Jessen, Britta Schuermann, Hendrik van den Bussche, Isabella Heuser, Oliver Peters, Johannes Kornhuber, Jens Wiltfang, Martin Dichgans, Lutz Froelich, Harald Hampel, Michael Huell, Dan Rujescu, Alison M. Goate, John S. K. Kauwe, Carlos Cruchaga, Petra Nowotny, John C. Morris, Kevin Mayo, Gill Livingston, Nicholas J. Bass, Hugh Gurling, Andrew McQuillin, Rhian Gwilliam, Panos Deloukas, Ammar Al-Chalabi, Christopher E. Shaw, Andrew B. Singleton, Rita Guerreiro, Thomas W. Muehleisen, Markus M. Noethen, Susanne Moebus, Karl-Heinz Joeckel, Norman Klopp, H. -Erich Wichmann, Eckhard Ruether, Minerva M. Carrasquillo, V. Shane Pankratz, Steven G. Younkin, John Hardy, Michael C. O'Donovan, Michael J. Owen, Julie Williams

Original languageEnglish
Article numbere13950
JournalPL o S One
Volume5
Issue number11
DOIs
Publication statusPublished - 2010

King's Authors

Abstract

Background: Late Onset Alzheimer's disease (LOAD) is the leading cause of dementia. Recent large genome-wide association studies (GWAS) identified the first strongly supported LOAD susceptibility genes since the discovery of the involvement of APOE in the early 1990s. We have now exploited these GWAS datasets to uncover key LOAD pathophysiological processes. Methodology: We applied a recently developed tool for mining GWAS data for biologically meaningful information to a LOAD GWAS dataset. The principal findings were then tested in an independent GWAS dataset. Principal Findings: We found a significant overrepresentation of association signals in pathways related to cholesterol metabolism and the immune response in both of the two largest genome-wide association studies for LOAD. Significance: Processes related to cholesterol metabolism and the innate immune response have previously been implicated by pathological and epidemiological studies of Alzheimer's disease, but it has been unclear whether those findings reflected primary aetiological events or consequences of the disease process. Our independent evidence from two large studies now demonstrates that these processes are aetiologically relevant, and suggests that they may be suitable targets for novel and existing therapeutic approaches.

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