Matthew Traylor, Poneh Adib‐Samii, Denise Harold, Martin Dichgans, Julie Williams, Cathryn M. Lewis, Hugh S. Markus, Myriam Fornage, Elizabeth G Holliday, Pankaj Sharma, Joshua C Bis, Bruce M Psaty, Sudha Seshadri, Mike A Nalls, William J Devan, Giorgio Boncoraglio, Rainer Malik, Braxton D Mitchell, Steven J Kittner, M Arfan Ikram, Robert Clarke, Jonathan Rosand, James F Meschia, Cathie Sudlow, Peter M Rothwell, Christopher Levi, Steve Bevan, Laura L Kilarski, Matthew Walters, Vincent Thijs, Agnieszka Slowik, Arne Lindgren, Paul I W de Bakker, Jean‐Charles Lambert, Carla A Ibrahim‐Verbaas, Denise Harold, Adam C Naj, Rebecca Sims, Céline Bellenguez, Gyungah Jun, Anita L DeStefano, Joshua C Bis, Gary W Beecham, Benjamin Grenier‐Boley, Giancarlo Russo, Tricia A Thornton‐Wells, Nicola Jones, Albert V Smith, Vincent Chouraki, Charlene Thomas, M Arfan Ikram, Diana Zelenika, Badri N Vardarajan, Yoichiro Kamatani, Chiao‐Feng Lin, Amy Gerrish, Helena Schmidt, Brian Kunkle, Melanie L Dunstan, Agustin Ruiz, Marie‐Thçrèse Bihoreau, Seung‐Hoan Choi, Christiane Reitz, Florence Pasquier, Paul Hollingworth, Alfredo Ramirez, Olivier Hanon, Annette L Fitzpatrick, Joseph D Buxbaum, Dominique Campion, Paul K Crane, Clinton Baldwin, Tim Becker, Vilmundur Gudnason, Carlos Cruchaga, David Craig, Najaf Amin, Claudine Berr, Oscar L Lopez, Philip L De Jager, Vincent Deramecourt, Janet A Johnston, Denis Evans, Simon Lovestone, Luc Letenneur, Francisco J Morón, David C Rubinsztein, Gudny Eiriksdottir, Kristel Sleegers, Alison M Goate, Nathalie Fiçvet, Matthew J Huentelman, Michael Gill, Kristelle Brown, M Ilyas Kamboh, Lina Keller, Pascale Barberger‐Gateau, Bernadette McGuinness, Eric B Larson, Robert Green, Amanda J Myers, Carole Dufouil, Stephen Todd, David Wallon, Seth Love, Ekaterina Rogaeva, John Gallacher, Peter St George‐Hyslop, Jordi Clarimon, Alberto Lleo, Anthony Bayer, Debby W Tsuang, Lei Yu, Magda Tsolaki, Paola Bossù, Gianfranco Spalletta, Petroula Proitsi, John Collinge, Sandro Sorbi, Florentino Sanchez‐Garcia, Nick C Fox, John Hardy, Maria Candida Deniz Naranjo, Paolo Bosco, Robert Clarke, Carol Brayne, Daniela Galimberti, Michelangelo Mancuso, Fiona Matthews, Susanne Moebus, Patrizia Mecocci, Maria Del Zompo, Wolfgang Maier, Harald Hampel, Alberto Pilotto, Maria Bullido, Francesco Panza, Paolo Caffarra, Benedetta Nacmias, John R Gilbert, Manuel Mayhaus, Lars Lannfelt, Hakon Hakonarson, Sabrina Pichler, Minerva M Carrasquillo, Martin Ingelsson, Duane Beekly, Victoria Alvarez, Fanggeng Zou, Otto Valladares, Steven G Younkin, Eliecer Coto, Kara L Hamilton‐Nelson, Wei Gu, Cristina Razquin, Pau Pastor, Ignacio Mateo, Michael J Owen, Kelley M Faber, Palmi V Jonsson, Onofre Combarros, Michael C O'Donovan, Laura B Cantwell, Hilkka Soininen, Deborah Blacker, Simon Mead, Thomas H Mosley, David A Bennett, Tamara B Harris, Laura Fratiglioni, Clive Holmes, Renee F A G de Bruijn, Peter Passmore, Thomas J Montine, Karolien Bettens, Jerome I Rotter, Alexis Brice, Kevin Morgan, Tatiana M Foroud, Walter A Kukull, Didier Hannequin, John F Powell, Michael A Nalls, Karen Ritchie, Kathryn L Lunetta, John S K Kauwe, Eric Boerwinkle, Matthias Riemenschneider, Mercè Boada, Mikko Hiltunen, Eden R Martin, Reinhold Schmidt, Dan Rujescu, Li‐San Wang, Jean‐François Dartigues, Richard Mayeux, Christophe Tzourio, Albert Hofman, Markus M Nöthen, Caroline Graff, Bruce M Psaty, Lesley Jones, Jonathan L Haines, Peter A Holmans, Mark Lathrop, Margaret A Pericak‐Vance, Lenore J Launer, Lindsay A Farrer, Cornelia M van Duijn, Christine Van Broeckhoven, Valentina Moskvina, Sudha Seshadri, Julie Williams, Gerard D Schellenberg, Philippe Amouyel

Increasing evidence suggests epidemiological and pathological links between Alzheimer's disease (AD) and Ischaemic Stroke (IS). We investigated the evidence that shared genetic factors underpin the two diseases. Using genome wide association study (GWAS) data from METASTROKE+ (15,916 IS cases and 68,826 controls) and IGAP (17,008 AD cases and 37,154 controls), we evaluated known associations with AD and IS. On the subset of data for which we could obtain compatible genotype-level data (4,610 IS cases, 1,281 AD cases and 14,320 controls), we estimated the genome-wide genetic correlation (rG) between AD and IS, and the three subtypes (cardioembolic, small vessel, large vessel), using genome-wide SNP data. We then performed a meta-analysis and pathway analysis in the combined AD and small vessel stroke datasets to identify the SNPs and molecular pathways through which disease risk may be conferred. We found evidence of a shared genetic contribution between AD and small vessel stroke (rG(SE)=0.37(0.17); p=0.011). Conversely, there was no evidence to support shared genetic factors in AD and IS overall, or with the other stroke subtypes. Of the known GWAS associations with IS or AD, none reached significance for association with the other trait (or stroke subtypes). A meta-analysis of AD IGAP and METASTROKE+ small vessel stroke GWAS data highlighted a region (ATP5H/KCTD2/ICT1), associated with both diseases (p=1.8x10(-8) ). A pathway analysis identified four associated pathways, involving cholesterol transport and immune response. Our findings indicate shared genetic susceptibility to AD and small vessel stroke and highlight potential causal pathways and loci. This article is protected by copyright. All rights reserved.