The Role of Variation at A beta PP, PSEN1, PSEN2, and MAPT in Late Onset Alzheimer's Disease

Amy Gerrish, Giancarlo Russo, Alexander Richards, Valentina Moskvina, Dobril Ivanov, Denise Harold, Rebecca Sims, Richard Abraham, Paul Hollingworth, Jade Chapman, Marian Hamshere, Jaspreet Singh Pahwa, Kimberley Dowzell, Amy Williams, Nicola Jones, Charlene Thomas, Alexandra Stretton, Angharad R. Morgan, Simon Lovestone, John PowellPetroula 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, Janet A. Johnston, Clive Holmes, David Mann, A. David Smith, Seth Love, Patrick G. Kehoe, John Hardy, Simon Mead, Nick Fox, Martin Rossor, John Collinge, Wolfgang Maier, Frank Jessen, Heike Koelsch, Reinhard Heun, Britta Schuermann, Hendrik van den Bussche, Isabella Heuser, 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, Panagiotis Deloukas, Gail Davies, Sarah E. Harris, John M. Starr, Ian J. Deary, Ammar Al-Chalabi, Christopher E. Shaw, Magda Tsolaki, Andrew B. Singleton, Rita Guerreiro, Thomas W. Muehleisen, Markus M. Noethen, Susanne Moebus, Karl-Heinz Joeckel, Norman Klopp, H-Erich Wichmann, Minerva M. Carrasquillo, V. Shane Pankratz, Steven G. Younkin, Lesley Jones, Peter A. Holmans, Michael C. O'Donovan, Michael J. Owen, Julie Williams*

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)peer-review

56 Citations (Scopus)


Rare mutations in A beta PP, PSEN1, and PSEN2 cause uncommon early onset forms of Alzheimer's disease (AD), and common variants in MAPT are associated with risk of other neurodegenerative disorders. We sought to establish whether common genetic variation in these genes confer risk to the common form of AD which occurs later in life (> 65 years). We therefore tested single-nucleotide polymorphisms at these loci for association with late-onset AD (LOAD) in a large case-control sample consisting of 3,940 cases and 13,373 controls. Single-marker analysis did not identify any variants that reached genome-wide significance, a result which is supported by other recent genome-wide association studies. However, we did observe a significant association at the MAPT locus using a gene-wide approach (p = 0.009). We also observed suggestive association between AD and the marker rs9468, which defines the H1 haplotype, an extended haplotype that spans the MAPT gene and has previously been implicated in other neurodegenerative disorders including Parkinson's disease, progressive supranuclear palsy, and corticobasal degeneration. In summary common variants at A beta PP, PSEN1, and PSEN2 and MAPT are unlikely to make strong contributions to susceptibility for LOAD. However, the gene-wide effect observed at MAPT indicates a possible contribution to disease risk which requires further study.

Translated title of the contributionThe Role of Variation at AβPP, PSEN1, PSEN2, and MAPT in Late Onset Alzheimer's Disease
Original languageEnglish
Pages (from-to)377-387
Number of pages11
JournalJournal of Alzheimer's Disease
Issue number2
Publication statusPublished - Jan 2012

Bibliographical note

Publisher: IOS Press

Structured keywords

  • Dementia Research Group


  • RISK
  • Alzheimer's disease
  • amyloid-beta protein precursor
  • human
  • PSEN1 protein
  • genetics
  • PSEN2 protein
  • MAPT protein


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