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. 2010 Nov 15;5(11):e13950.
doi: 10.1371/journal.pone.0013950.

Genetic evidence implicates the immune system and cholesterol metabolism in the aetiology of Alzheimer's disease

Lesley Jones  1 , 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, 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 Schürmann, Reinhard Heun, Heike Kölsch, Hendrik van den Bussche, Isabella Heuser, Oliver Peters, Johannes Kornhuber, Jens Wiltfang, Martin Dichgans, Lutz Frölich, Harald Hampel, Michael Hüll, 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 Mühleisen, Markus M Nöthen, Susanne Moebus, Karl-Heinz Jöckel, Norman Klopp, H-Erich Wichmann, Eckhard Rüther, Minerva M Carrasquillo, V Shane Pankratz, Steven G Younkin, John Hardy, Michael C O'Donovan, Michael J Owen, Julie Williams
Affiliations

Genetic evidence implicates the immune system and cholesterol metabolism in the aetiology of Alzheimer's disease

Lesley Jones et al. PLoS One. .

Erratum in

  • PLoS One. 2011;6(2). doi:10.1371/annotation/a0bb886d-d345-4a20-a82e-adce9b047798. Heun, Reinhard [added]; Kölsch, Heike [added]

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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Conflict of interest statement

Competing Interests: Profs Owen, J Williams and Dr Harold have a patent application in respect of genes identified in the GWAS Harold et al. Nature Genetics 2009;41(10):1088–93; this study provided data for this manuscript and was funded by the MRC and the Wellcome Trust. Dr Passmore has consulted for Pfizer and received compensation. Dr Hull has been funded by Wyeth and consulted for Pfizer, Wyeth and Merz; he has a patent pending for AD diagnostic tests. Dr Lynch has received travel expenses from Pfizer and Novartis. Prof Goate's work has been funded by NIH and AHAF. Prof Fox is a board member of the Alzheimer's Research Forum, has consulted for Abbott Laboratories and has received compensation for consulting for GE Healthcare. He has a patent for QA Box that did not arise from this work which contributes funds to his institution. Dr Morris is funded by NIA. Dr Livingston has received compensation from Lundbeck sa. Ms Stretton holds a CASE PhD studentship jointly funded by MRC and GSK. The remaining authors declare no potential conflict of interest. This does not alter the authors' adherence to all the PloS ONE policies on sharing data and materials.

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