research and perspectives in alzheimer’s disease Fondation Ipsen

Editor Yves Christen, Fondation Ipsen, Paris (France)

Editorial Board Yves Agid, Hôpital Pitié Salpêtrière, Paris (France) Albert Aguayo, McGill University, Montreal (Canada) Brian H. Anderton, Institute of Psychiatry, London (GB) Raymond T. Bartus, Alkermes, Cambridge (USA) Anders Björklund,UniversityofLund(Sweden) Floyd Bloom, Scripps Clinic and Research Foundation, La Jolla (USA) François Boller, Inserm U 324, Paris (France) Carl Cotman, University of California, Irvine (USA) Peter Davies, Albert Einstein College of Medicine, New York (USA) Andre Delacourte, Inserm U 422, Lille (France) Steven Ferris, New York University Medical Center, New York (USA) Jean-François Foncin, Hôpital Pitié Salpêtrière, Paris (France) Françoise Forette, Hôpital Broca, Paris (France) Fred Gage, Salk Institute, La Jolla (USA) Dmitry Goldgaber, State University of New York Stone Brook (USA) John Hardy, National Institute of Health, Bethesda (USA) Jean-Jacques Hauw, Hôpital Pitié Salpêtrière, Paris (France) Claude Kordon, Inserm U 159, Paris (France) Kenneth S. Kosik, Harvard Medical School, Center for Neurological Diseases and Brigham and Women’s Hospital, Boston (USA) Jacques Mallet, Hôpital Pitié Salpêtrière, Paris (France) Colin L. Masters, University of Melbourne, Parkville (Australia) Stanley I. Rapoport, National Institute on Aging, Bethesda (USA) Barry Reisberg, New York University Medical Center, New York (USA) Allen Roses, Duke University Medical Center, Durham (USA) Dennis J. Selkoe, Harvard Medical School, Center of Neurological Diseases and Brigham and Women’s Hospital, Boston (USA) Michael L. Shelanski, Columbia University, New York (USA) Pierre-Marie Sinet, Hôpital Necker, Paris (France) Peter St. George-Hyslop,UniversityofToronto,Toronto(Canada) Robert Terry, University of California, La Jolla (USA) Edouard Zarifian, Centre Hospitalier Universitaire, Caen (France) M. Jucker K. Beyreuther C. Haass R.M. Nitsch Y. Christen (Eds.)

Alzheimer: 100 Years and Beyond

With 143 Figures

123 Mathias Jucker Konrad Beyreuther Department of Cellular Centre for Molecular Biology Hertie Institute for Clinical Research The University of Heidelberg University of Tübingen Neuenheimer Feld 282 72076 Tübingen 6900 Heidelberg Germany e-mail: [email protected] e-mail: [email protected]

Christian Haass Roger M. Nitsch Adolf-Butenandt-Institute Division of Psychiatry Research Department of Biochemistry University of Zurich Laboratory for Alzheimer’s 8008 Zurich and Parkinson’s Disease Research Ludwig-Maximilians-University e-mail: [email protected] 80336 Munich Germany Yves Christen e-mail: [email protected] Foundation IPSEN Pour la Recherche Thérapeutique 24, rue Erlanger 75781 Paris Cedex 16 France e-mail: [email protected]

Cover illustration by Ingram Pinn

ISSN 0945-6066 ISBN-10 3-540-37651-8 Springer Heidelberg New York ISBN-13 978-3-540-37651-4 Springer Berlin Heidelberg New York

This work is subject to copyright. All rights are reserved, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilm or in any other way, and storage in data banks. Duplication of this publication or parts thereof is permitted only under the provisions of the German Copyright Law of September 9, 1965, in its current version, and permissions for use must always be obtained from Springer. Violations are liable for prosecution under the German Copyright Law. Springer is a part of Springer Science+Business Media springer.com © Springer-Verlag Berlin Heidelberg 2006 The use of general descriptive names, registered names, trademarks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. Product liability: The publishers cannot guarantee the accuracy of any information about dosage and appli- cation contained in this book. In every individual case the user must check such information by consulting the relevant literature. Editor: Simon Rallison Desk editor: Anne Claus Cover design: WMX Design, Heidelberg, Germany Typesetting and production: LE-TEX Jelonek, Schmidt & Vöckler GbR, Leipzig, Germany Printed on acid-free paper 27/3100/YL 5 4 3 2 1 0 SPIN 11808305 Acknowledgements

The editors wish to thank Simone Eberle, Astrid de Gerard and the local committee for the organisation of the meeting in Tübingen and Mary–Lynn Gage for the editing of the book One hundred years of Alzheimer research

Few medical or scientific addresses have so unmistakeably made history as the presenta- tion delivered by Alois Alzheimer on November 4, 1906 in Tübingen. The one-hundred year anniversary of that event has been marked on several occasions in 2006, most notably at the very site of the original lecture, namely the Institute of Psychiatry of the University of Tübingen in Germany on November 2–5, 2006. The celebratory event, “Alzheimer 100 Years and Beyond” organized on the initi- ation of the Alzheimer community in Germany and worldwide, in collaboration with the Fondation Ipsen, was the highlight of the Yearof Alzheimer. However, beyond these few months of tributes, the centennial offers a unique opportunity to assess both the progress achieved and the uncertainties remaining. This volume, a collection com- prised mainly of articles by the invited speakers and also of a few other prominent researchers, is meant to be a record of those events. Over the last century of Alzheimer research (1906-2006), remarkable progress has been achieved in many areas: – Progress towards understanding the pathogenesis: In this field progress has been very much dependent on developments in technology and other speciality areas. This was true from the very start: Alois Alzheimer’s research would not have been possible without then-nascent microscopic staining techniques. It has proven true again over the last few decades, with molecular and cellular biology, genetics, and brain imaging all making contributions while benefiting from related fields. For instance, the discovery of the role of apolipoprotein E enabled Alzheimer scientists to apply research findings from the cardiovascular field. On the other hand, research into the pathogenesis of Alzheimer’s disease revealed fundamental findings regarding protein aggregation, or regulated intramembrane proteolysis that has not only been appliedtootherneurodegenerativediseasesbutalsopavedtheroadtounderstanding completely unexpected signalling pathways. – Recognitionofthediseaseandclinicaltreatment. Although no cure has been found for Alzheimer’s disease yet, the outlook is promising. Alzheimer’s disease has ceased to be considered as an inescapable consequence of ageing. – Economic and social considerations. With the aging of our society over the last 100 years, there has been a continuous increase in the number of Alzheimer patients and the burden for individual care-takers, as well as social and medical institutions. Demography has helped to make the public aware and prepared of the social and economic consequences of this devastating form of . Yet, none of the advances made have yet culminated in a fully satisfactory outcome. The pathogenic mechanisms of the disease remain inadequately understood and are at VIII One hundred years of Alzheimer research the centre of serious controversy, such as determining whether the observed lesions in post mortem of patients with Alzheimer’s disease are the cause or a consequence of the disease; in no country have the public authorities provided fully for patients; and treatment options remain largely insufficient, despite hope from various symp- tomatic treatments and ongoing promising clinical studies targeting the pathological mechanisms. Despite these shortcomings, the last one hundred years have been full and active ones. The aim of the meeting held in November 2006 in Tübingen, like that of this volume, is not to lay out the final legacy of a scientific corpus that is, to the contrary, constantly-developing, nor to crown the contributions of a specific researcher, at the expense of his colleagues or competitors. Instead, it is to honor the work accomplished and provide material for the history of science. We asked the invited authors to present their pioneering research explaining the conditions under which they were conducted from their viewpoint, and thus intentionally leaving room for a certain degree of subjectivity. Their testimonials contain unavoidably some contradictions, in particular regarding their part in certain essential discoveries. The editors of this book did not, at any time, wish to take sides in the possible ownership squabbles, but only to provide readers with information from the very individuals who have made Alzheimer research what it is, over the past few decades. The only editing changes related to form alone - no article was changed in substance, none were censured and none were rejected. Some authors invited to present their research at the meeting in Tübingen were unable to hand in their contributions in time, however contributed significantly to the meeting, such as Monique Breteler, Nick Fox, Michael Hutton, Steven Paul, Gerard D. Schellenberg, Sangram S. Sisodia, Bengt Winblad, Bruce Yankner. Lastly, several of the pioneers passed away too early to be able to attend the Tübingen meeting and contribute to this work: George Glenner, Henry Wisniewski, Tsunao Saitoh, Eva Braak, Jean-Louis Signoret, Yvon Lamour, Nelson Butler, Luigi Amaducci, and others. We dedicate this volume to them.

Mathias Jucker Konrad Beyreuther Christian Haass Roger Nitsch Yves Christen Some “players” of the AD story (1987–2006) One hundred years of Alzheimer research XI

01 Paris, 1988, Stanley Rapoport, Charles Epstein 02 Paris, 1988, Carleton Gajduzek, Henry Wisniewski 03 Paris, 1987, Dennis Selkoe 04 Angers, 1987, front row: Annick Pouplard-Bartheleix, Toshiharu Ishii, Mrs Ishii, Taihei Miyakawa – back row: Philippe Brachet, Colin Masters, Konrad Beyreuther, Hugh Fudenberg, Henry Wisniewski, Mrs Glenner, George Glenner, Jacqueline Mervaillie, Mrs Miyakawa, Dennis Selkoe, Jean Emile, Piet Eikelenboom, Jean Lapresle, Yves Christen, André Delacourte 05 Angers, 1987, Toshiharu Ishii, Yves Christen, George Glenner 06 Paris, 1988, Carleton Gajduzek, Yves Christen, Françoise Forette XII One hundred years of Alzheimer research

07 Montpellier, 1988, Allen Roses, Annie Saunders 08 Paris, 1989, Marshal Folstein, Stanley Rapoport 09 Toulouse, 1989, Tsunao Saitoh, Rudolph Tanzi 10 Toulouse, 1989, Jean-Jaques Hauw 11 Paris, 1988 and 2006 (Charles de Gaulle airport), Christine Van Broeckhoven 12 Toulouse, 1989, John Blass, Peter Davies 13 Toulouse, 1989, André Rascol, Jean-Louis Signoret 14 Toulouse, 1989, Rudolph Tanzi, Yves Agid 15 Toulouse, 1989, André Delacourte, Henry Wisniewski, Krystina Wisniewski, Tsunao Saitoh, Ushi Beyreuther, Konrad Beyreuther, Andrew Haynes, John Atack, Jay Pettergrew, François Boller, Jacqueline Mervaillie, Yves Christen, Kenneth Kosik One hundred years of Alzheimer research XIII

16 Marseille, 1992, Luigi Amaducci 17 Strasbourg, 1990, Dan Lindholm, Yoshihiro Arakawa, Robert Terry, William Mobley, Nikolaos Robakis, Kenneth Kosik 18 Paris, 1989, William Klunk 19 Marseille, 1992, Jean-François Foncin, Peter St. George-Hyslop 20 Toulouse, 1989, Henry Wisniewski, Konrad Beyreuther, André Delacourte 21 Strasbourg 1990, Robert Terry, Albert Aguayo 22 La Jolla, 1991, Jean-Pierre Changeux, Robert Katzman, Robert Terry 23 La Jolla, 1991, John Morrison, Francis Crick 24 Dijon, 1993, Steven Younkin, Marie-Christine Chartier-Harlin, Lydia Hendriks, Yves Christen, Jacqueline Mervaillie, Stanley Prusiner XIV One hundred years of Alzheimer research

25 Paris, 1997, John Hardy 26 Paris, 2003, Charles Duyckaerts 27 Paris, 1995, Blass Frangione, Allen Roses, Kazuhiko Ikeda 28 Aix-en-Provence, 1992, first row: André Nieoullon, Zaven Khachaturian, Helen Chui, Yves Christen, Jacqueline Mervaillie – second row: Sam Gandy, Allen Roses, Marcel Mesulam, Victor Bulyzenkov, Richard Mayeux – above: Michel Poncet, Thomas Bird, Henri Dehen, François Boller, François Chain, Bruno Dubois, Peter St. George-Hyslop, John Hardy, Charles Duyckaerts, Dennis Dickson 29 Paris, 1995, Yvon Lamour, Judes Poirier 30 Paris, 1988, Alison Goate 31 Dijon, 1993, David Small, Helen Price, Stanley Prusiner, Donald Price, Rudolph Tanzi One hundred years of Alzheimer research XV

32 Lyon, 1993, Rudolph Tanzi, Ashey Bush, Steven Younkin, Colin Masters 33 Lyon, 1993, Sam Sisodia, Sam Gandy 34 Paris, 1996, Heiko Braak, Zaven Khachaturian 35 Paris, 1997, John Hardy, Michael Wolfe, Christian Haass 36 Paris, 1997, Roger Nitsch, Steven Younkin 37 Paris, 1996, David Felten, Jacqueline Mervaillie, Yves Christen, François Boller, Zaven Khachaturian, Donald Stein, Mark West, Charles Duyckaerts, Eliezer Masliah, Jennifer Altman, Paul Coleman, Dora Games, Bradley Hyman, Gary Van Hoesen, Pierre Tariot 38 Paris, 1997, Karen Duff 39 Paris, 1999, Eckhard Mandelkow, Eva-Maria Mandelkow 40 Paris, 1996, Dora Games, Yves Christen, Eliezer Masliah XVI One hundred years of Alzheimer research

41 Paris, 1999, Peter Lansbury, Virginia Lee, John Trojanowski 42 Paris, 2000, Mathias Jucker, Joachim Herz, Bart de Strooper 43 Paris, 1997, Dennis Selkoe, Christian Haass, Roger Nitsch 44 Paris, 1999, , Luc Buée 45 Paris, 1997, Jean Mariani, Paul Fraser, Christan Haass, Karen Duff, John Hardy, Yves Christen, Steven Younkin, Rudolph Tanzi, Wilma Wasco, Roger Nitsch, Sam Sisodia, Jacqueline Mervaillie, Dennis Selkoe 46 Paris, 1998, Robert Katzman, Richard Mayeux 47 Paris, 2002, Dale Schenk 48 Paris, 1998, Albert Hofman, Jean-François Dartigues One hundred years of Alzheimer research XVII

49 Paris, 2001, Edward Koo 50 Paris, 2001, Alain Israel, Christian Haass, Michael Wolfe 51 Paris, 2001, Peter St. George-Hyslop, Frédéric Checler 52 Markbreit, 2005, Konrad Beyreuther, Jacqueline Mervaillie, Ulrike Maurer, Mathias Jucker, Konrad Maurer 53 Paris, 1999, Gerard Schellenberg, Kirk Wilhelmsen 54 Paris, 2003, Peter St. George-Hyslop, Kenneth Kosik, 55 Paris, 2002, Dale Schenk, David Holtzman 56 Markbreit, 2005, Konrad Beyreuther (A. Alzheimer’s microscope) TableofContents

Alois Alzheimer

Concerning a unique disease of the Alois Alzheimer ...... 3

The history of Alois Alzheimer‘s first case Auguste D. Maurer Konrad ...... 13

Alois Alzheimer and the beginnings of research into Alzheimer’s disease Ralf Dahm ...... 37

Alois Alzheimer and the myth of the pioneer Yves Christen ...... 51

The beginning of modern research

Alzheimer’s Disease at mid-Century (1927–1977) and a little more Robert D. Terry ...... 59

A chapter in the development on Alzheimer’s disease research Zaven S. Khachaturian ...... 63

Anatomy & Neuropsychology

Anatomical changes underlying dementia in Alzheimer’s disease Bradley T. Hyman ...... 89

Staging of cortical neurofibrillary inclusions of the Alzheimer’s type Heiko Braak, Kelly Del Tredici ...... 97

Of stains and brains: a brief account of how microscopic and clinical observations contributed to the understanding of Alzheimer’s disease Charles Duyckaerts, Jean-Jacques Hauw ...... 109

Presenile forms of Alzheimer’s disease in 2006 Michel Poncet, Olivier Felician, Jean-François Pellissier ...... 115 XX Table of Contents

Cholinergic Deficit

The cholinergic deficit in Alzheimer’s disease Peter Davies ...... 123

Acetylcholine in AD: Expectations meet reality John H. Growdon ...... 127

Amyloid and Genetics

The Discovery of β Amyloid Cai’ne W. Wong ...... 135

Pathways to the discovery of the neuronal origin and proteolytic biogenesis of Aβ amyloid of Alzheimer’s disease Colin L Masters, Konrad Beyreuther ...... 143

The Amyloid Hypothesis: history and alternatives John Hardy ...... 151

Segregation of a missense mutation in the amyloid β-protein precursor gene with familial Alzheimer’s disease Alison Goate ...... 157

From the amyloid β protein (A4) to isolation of the first Alzheimer’s disease gene: amyloid β (A4) precursor protein (APP) Rudolph E. Tanzi ...... 163

Commentary on “Correlative memory deficits, Aβ elevation, and in transgenic mice” Karen Hsiao Ashe ...... 171

Vision for the future. Alzheimer’s disease: pathogenesis, models and experimental therapeutics Donald L. Price, Tong Li, Fiona M. Laird, Mohamed Farah, Alena V. Savonenko, Michael Lee, Juan Troncoso, Philip C. Wong ...... 175

PS1, PS2,andAPP mutations that cause Alzheimer’s disease increase Aβ42 Steven G. Younkin ...... 189

Amyloid precursor protein, Alzheimer’s disease, and Down’s syndrome Edward H. Koo ...... 197

Catabolism of amyloid β peptide and pathogenesis of sporadic Alzheimer’s disease: towards understanding the underlying mechanisms Takaomi C. Saido ...... 201 Table of Contents XXI

Synaptic activity, amyloid-β and Alzheimer’s disease John R. Cirrito, David M. Holtzman ...... 209

Molecular pathogenesis of Alzheimer’s disease in human peripheral cells: platelets show it all! Elena Marcello, Barbara Borroni, Fabrizio Gardoni, Alessandro Padovani, Monica Di Luca...... 215

The neuronal origin hypothesis of cerebral amyloid angiopathy Mathias Jucker ...... 221

A neuropathologist and Alzheimer genetics Jean-François Foncin ...... 225

Genetics, molecular biology, and animal modeling of Alzheimer’s disease P.H.StGeorge-Hyslop,P.E.Fraser,D.Westaway,J.McLaurin,E.Rogaeva, G.Schmitt-Ulms,A.Tandon,H.T.JMount,J.Robertson,C.Bergeron...... 231

The genetic Alzheimer- spectrum Christine van Broeckhoven ...... 237

Mutation of the Alzheimer’s disease amyloid gene in hereditary cerebral hemorrhage, Dutch type. The role of amyloid in dementia and stroke Blas Frangione, Jorge Ghiso ...... 243

Physiological generation of Amyloid β-peptide and its Consequences for Alzheimer’s Disease Research Christian Haass ...... 249

Activation of α-secretase as an approach for treatment of Alzheimer’s disease Falk Fahrenholz ...... 255

Challenges to the enigma of γ-secretase and to Alzheimer’s disease Takeshi Iwatsubo ...... 261

Targeting γ-Secretase for Alzheimer’s Disease Michael S. Wolfe ...... 265

The Presenilin/gamma-secretase complex and its potential as a drug target in Alzheimer’s Disease Bart De Strooper ...... 271

Identification of β-secretase Martin Citron ...... 277

ApoE

Apolipoprotein E and Alzheimer’s disease: A brief retrospective Allen D. Roses ...... 283 XXII Table of Contents

Apolipoprotein E4: From synaptic remodeling to genetic risk factor in both familial and sporadic Alzheimer’s disease Judes Poirier ...... 289

Tau

The Alzheimer tangle – 100 years on. Michel Goedert, Maria Grazia Spillantini, Bernardino Ghetti, R. Anthony Crowther, Aaron Klug ...... 297

Immunological demonstration of in neurofibrillary tangles Jean-Pierre Brion ...... 307

Bulk isolation of neurofibrillary tangles and discoveries of tau and its abnormal hyperphosphorylation Khalid Iqbal, Inge Grundke-Iqbal ...... 315

The natural and molecular history of Alzheimer’s disease: Tauispartofthestory André Delacourte ...... 325

Tau focused drug discovery for Alzheimer’s disease and related Neurodegenerative Virginia M.-Y. Lee, John Q. Trojanowski ...... 333

Ubiquitin is a component of paired helical filaments in Alzheimer’s disease Yasuo Ihara ...... 339

Influence of tau on neuronal traffic mechanisms E.-M.Mandelkow,E.Thies,J.Biernat,E.Mandelkow ...... 345

The Search for structure of tau and paired helical filaments E. Mandelkow, M. von Bergen, A. Marx, J. Biernat, E.-M. Mandelkow ...... 355

Oxidative Stress

The Changing landscape of Alzheimer’s disease: From Insoluble to Soluble and from Pathogen to Protector MarkA.Smith,GeorgePerry ...... 367

Molecular and cellular pathways towards and away from Alzheimer’s disease Mark P. Mattson ...... 371

Epidemiology

Paquid: an integrated, multidisciplinary, population-based approach to normal and pathological cerebral aging Jean François Dartigues ...... 379 Table of Contents XXIII

Imaging

Hippocampal imaging in the early diagnosis of AD, 1988 to 2006 Mony J. de Leon ...... 385

Detecting Early-Stage Alzheimer’s Disease in MCI and PreMCI: Thevalueofinformants John C. Morris, Martha Storandt ...... 393

Imaging the pathology of Alzheimer’s disease: Building on a century-Old blueprint William E. Klunk, Chester A. Mathis ...... 399

Therapeutical Perspectives

How do we test drugs? Leon J. Thal ...... 407

Inflammation and the lesions of Alzheimer’s disease Edith G. McGeer, Patrick L. McGeer ...... 413

Aβ immunotherapy prevents and Reverses Alzheimer’s disease neuropathology Dale Schenk, Dora Games, Peter Seubert ...... 419

Immunotherapy of Alzheimer’s disease Roger M. Nitsch, Christoph Hock ...... 425

“Magic” bullets, shotguns or cocktails to treat or prevent Alzheimer’s disease? Todd E. Golde ...... 431

The seventh age of man: Solving senility Dennis J. Selkoe ...... 435

Forum and Network

Fondation Ipsen and Alzheimer’s disease: a 20-year relationship Jacqueline Mervaillie ...... 443

Alzheimer Research Forum: A Knowledge Base and e-Community for AD Research June Kinoshita, Gabrielle Strobel ...... 457

The Potamkin prize for research in Pick’s, Alzheimer’s and related diseases . . . . . 465

References ...... 467

SubjectIndex ...... 539 List of Contributors

Ashe Hsiao Karen Departments of Neurology and , University of Minnesota Medical School, 420 Delaware St., And Geriatric Research, Education and Clinical Center, Minneapolis Veterans Affairs Medical Center, Minneapolis, MN 55417, USA

Bergeron C Departments of Medicine, Medical Biophysics, Laboratory Medicine and Pathobiology, Tanz Neuroscience Bldg, University of Toronto, Toronto, Ontario M5S 3H2, Canada

Beyreuther Konrad Centre for Molecular Biology, The University of Heidelberg, Neuenheimer Feld 282, 6900 Heidelberg, Germany

Biernat J Max-Planck-Unit for Structural Molecular Biology, Notkestrasse 85, 22607 , Germany

Borchelt DR The Johns Hopkins University School of Medicine, Maryland, Baltimore

Borroni Barbara Department of Neurological Sciences, University of Brescia, Piazza Spedali 1, 25125 Brescia,

Braak Heiko Institute for Clinical Neuroanatomy, Theodor Stern Kai 7, 60590 /Main, Ger- many

Brion Jean-Pierre Laboratory of Histology, Neuroanatomy and Neuropathology, Université Libre de Bru- xelles, School of Medicine. 808, Route de Lennik, Bldg C-10, 1070 Brussels, Belgium

Christen Yves Fondation Ipsen 24 Rue Erlanger, 75016 Paris, France XXVI List of Contributors

Cirrito John R Department of Neurology and Psychiatry, The Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO 63110, USA

Citron Martin Amgen M/S 29-2-B, One Amgen Center Drive, Thousand Oaks, CA 91320, USA

Crowther Anthony R MRC Laboratory of Molecular Biology, Hills Road, Cambridge CB2 2QH, UK

Dahm Ralf Medical University of Vienna, Center for Brain Research, Division of Neuronal Cell Biology, Spitalgasse 4, 1090 Vienna, Austria

Dartigues Jean François Inserm unit 593, University of Bordeaux II, 146, Rue Léo Saignat, 33076 Bordeaux cedex, France

Davies Peter Departments of Pathology and Neuroscience, Albert Einstein College of Medicine, 1300 Morris Park Ave, Bronx, New York 10461, USA

De Strooper Bart Center for Human Genetics, V.I.B. 4 and K.U.Leuven, Herestraat 49, 3000 Leuven, Belgium de Leon Mony Center for Brain Health, NYU School of Medicine, 560 First Ave, New York, NY 10016, USA

Delacourte André Unit Inserm 422, 1, Place de Verdun, 59045 Lille Cedex, France

Del Tredici Kelly Institute for Clinical Neuroanatomy, J.W.Goethe University, Theodor Stern Kai 7, 60590 Frankfurt am Main, Germany

Di Luca Monica Department of Pharmacological Sciences, and Center of Excellence on Neurodegener- ative Diseases, University of Milan, Via Balzaretti 9, 20133 Milan, Italy

Duyckaerts Charles Laboratoire de Neuropathologie Raymond Escourolle, InsermU679 et Université Pierre et Marie Curie, 47, Boulevard de l’Hôpital, 75651 Paris Cedex 13, France List of Contributors XXVII

Eisenberg George M Department of Neuroscience, Mayo Clinic College of Medicine, 4500 San Pablo Road, Jacksonville FL 32224, USA

Fahrenholz Falk Johannes Gutenberg-University, Institute of Biochemistry, Becherweg 30, Germany

Farah Mohamed Department of Pathology and Neuroscience, The Johns Hopkins University School of Medicine, 558 Ross Research Building, 720 Rutland Avenue, Maryland 21205-2196, Baltimore, USA

Felician Olivier Department of Neurology and Neuropsychology, Hôpital de la Timone, 27 bd Jean Moulin, 13385 Marseille Cedex 5, France

Foncin Jean-François Laboratoire de Neurohistologie, 47 rue Général Leclerc, 77170 Brie Comte Robert, France

Frangione Blas Departments of Pathology and Psychiatry, New York University School of Medicine, Room TH432, 550 First Avenue, New York, NY 10016, USA

Fraser PE Departments of Medicine, Medical Biophysics, Laboratory Medicine and Pathobiology, Tanz Neuroscience Bldg, University of Toronto, Toronto, Ontario M5S 3H2, Canada

Games Dora Elan Pharmaceuticals, 800 Gateway Blvd., South San Francisco, CA 94080, USA

Gardoni Fabrizio Department of Pharmacological Sciences, and Center of Excellence on Neurodegener- ative Diseases, University of Milan, Via Balzaretti 9, 20133 Milan, Italy

Ghetti Bernardino Department of Pathology and Laboratory Medicine, Indiana University, Indianapolis, USA

Ghiso Jorge Departments of Pathology and Psychiatry, New York University School of Medicine, New York, NY 10016, USA

Goate Alison Depts. of Psychiatry, Neurology & Genetics, Washington University School of Medicine, 660 S. Euclid Ave., St. Louis, MO 63110, USA XXVIII List of Contributors

Goedert Michel MRC Laboratory of Molecular Biology, Hills Road, Cambridge CB2 2QH, UK

Golde Todd E Mayo Clinic College of Medicine, Department of Neuroscience, Mayo Clinic Jack- sonville, 4500 San Pablo Rd., Jacksonville, Florida 32224, USA

Growdon John H Department of Neurology, Harvard Medical School, and Massachusetts General Hos- pital, Boston, MA 02115, USA

Grundke-Iqbal Inge New York State Institute for Basic Research in Developmental Disabilities, Department of Neurochemistry, 1050 Forest Hill Road, Staten Island, New York 10314-6399, USA

Haass Christian Adolf-Butenandt-Institute, Department of Biochemistry, Laboratory for Alzheimer’s and Parkinson’s Disease Research, Ludwig-Maximilians-University, 80336 Munich, Germany

Hardy John Laboratory of Neurogenetics, NIA, Porter Neuroscience Building, NIH Main Campus, Bethesda MD20892, USA

Hauw Jean-Jacques Laboratoire de Neuropathologie Raymond Escourolle, InsermU679 et Université Pierre et Marie Curie, 47, Boulevard de l’Hôpital, 75651 Paris Cedex 13, France

Hock Christoph Division of Psychiatry Research, University of Zurich, Switzerland

Holtzman David M. Department of Neurology, Washington University School of Medicine, 660 S. Euclid, Box 8111, St. Louis MO 63110, USA

Hyman Bradley T Massachusetts General Hospital, Harvard Medical School, Massachusetts General In- stitute for , 114 16th Street, Charlestown, Ma 02129, USA

Ihara Yasuo Department of Neuropathology, Faculty of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan

Iwatsubo Takeshi Department of Neuropathology and Neuroscience, Graduate School of Pharmaceutical Sciences, University of Tokyo, 7-3-1 Hongo Bunkyoku, Tokyo 113-0033, Japan List of Contributors XXIX

Iqbal Khalid New York State Institute for Basic Research in Developmental Disabilities, Department of Neurochemistry, 1050 Forest Hill Road, Staten Island, New York 10314-6399, USA

Jucker Mathias Department of Cellular Neurology, Hertie Institute for Clinical Brain Research, Uni- versity of Tübingen, 72076 Tübingen, Germany

Khachaturian Zaven S Kachaturian, Radebaugh & Associates, Inc., 8912 Copenhaver Drive, Potomac, MD 20584-3009, USA

Klug Aaron MRC Laboratory of Molecular Biology, Hills Road, Cambridge CB2 2QH, UK

Kinoshita June Alzheimer Research Forum, 600 Beaver Street, Waltham, MA 02452, USA

Klunk William E Western Psychiatric Institute & Clinic, Room 1422 TDH, 3811 O’Hara Street, Pittsburgh, PA 15213-2593, USA

Koo Edward H Department of , University of California, San Diego, La Jolla, CA, USA

Laird Fiona M Department of Pathology and Neuroscience, The Johns Hopkins University School of Medicine, 558 Ross Research Building, 720 Rutland Avenue, Maryland 21205-2196, Baltimore, USA

Lee Michael Department of Neurology, The Johns Hopkins University School of Medicine, 558 Ross Research Building, 720 Rutland Avenue, Maryland 21205-2196, Baltimore, USA

Lee Virginia M-Y Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Maloney 3, HUP, 3600 Spruce Street, Philadelphia, PA 19104-4283, USA

Li Tong Department of Pathology and Neuroscience, The Johns Hopkins University School of Medicine, 558 Ross Research Building, 720 Rutland Avenue, Maryland 21205-2196, Baltimore, USA

Mandelkow Eckhard Max-Planck-Unit for Structural Molecular Biology, Notkestrasse 85, 22607 Hamburg, Germany XXX List of Contributors

Mandelkow Eva-Maria Max-Planck-Unit for Structural Molecular Biology, Notkestrasse 85, 22607 Hamburg, Germany

Marcello Elena Department of Pharmacological Sciences, and Center of Excellence on Neurodegener- ative Diseases, University of Milan, Via Balzaretti 9, 20133 Milan, Italy

Marx A Max-Planck-Unit for Structural Molecular Biology, Notkestrasse 85, 22607 Hamburg, Germany

Masters Colin L Department of Pathology, The University of Melbourne, and the Mental Health Re- search Institute of Victoria, Victoria 3010, Australia

Mathis Chester A Western Psychiatric Institute & Clinic, Room 1422 TDH, 3811 O’Hara Street, Pittsburgh, PA 15213-2593, USA

Mattson Mark P Laboratory of Neurosciences, National Institute on Aging Intramural Research Pro- gram, Baltimore, MD, 21224, USA

Maurer Konrad Department of Psychiatry and Psychotherapy 1, Johann Wolfgang Goethe-University, Heinrich Hoffmann Str.10, 60528 Frankfurt, Germany

McGeer Patrick L Kinsmen Laboratory of Neurological Research, University of British Columbia, 2255 Wesbrook Mall, Vancouver, B.C. V6T 1Z3, Canada

McGeer Edith G Kinsmen Laboratory of Neurological Research, University of British Columbia, 2255 Wesbrook Mall, Vancouver, B.C. V6T 1Z3, Canada

McLaurin J Departments of Medicine, Medical Biophysics, Laboratory Medicine and Pathobiology, Tanz Neuroscience Bldg, University of Toronto, Toronto, Ontario M5S 3H2, Canada

Mervaillie Jacqueline Fondation Ipsen, 24 Rue Erlanger, 75016 Paris, France

Morris John C Departments of Neurology, Pathology and Immunology, and the Program on Physical Therapy, Washington University School of Medicine, 4488 Forest Park Avenue, Suite 130, Saint Louis MO 63108, USA List of Contributors XXXI

Mount HTJ Departments of Medicine, Medical Biophysics, Laboratory Medicine and Pathobiology, Tanz Neuroscience Bldg, University of Toronto, Toronto, Ontario M5S 3H2, Canada

Nitsch Roger M Division of Psychiatry Research, University of Zurich, 8008 Zurich, Switzerland

Padovani Alessandro Department of Neurological Sciences, University of Brescia, Piazza Spedali 1, 25125 Brescia, Italy

Pellissier Jean-François Department of Neuropathology, Hôpital de la Timone, 27 bd Jean Moulin, 13385 Mar- seille Cedex 5, France

Perry George Department of Pathology, Case Western Reserve University, 2085 Adelbert Road, Cleve- land, OH 44106, And College of Sciences, University of Texas, San Antonio, Texas, USA

Poirier Judes McGill Centre for Studies in Aging, 6825 LaSalle Blvd., Verdun (Québec) H4H 1R3, Canada

Poncet Michel Department of Neurology and Neuropsychology, Hôpital de la Timone, 27 bd Jean Moulin, 13385 Marseille Cedex 5, France

Price Donald L Departments of Pathology, Neurology and Neuroscience, Division of Neuropathology, The Johns Hopkins University School of Medicine, 558 Ross Research Building, 720 Rutland Avenue, Baltimore, Maryland 21205-2196, Baltimore, USA

Robertson J Departments of Medicine, Medical Biophysics, Laboratory Medicine and Pathobiology, Tanz Neuroscience Bldg, University of Toronto, Toronto, Ontario M5S 3H2, Canada

Rogaeva E Departments of Medicine, Medical Biophysics, Laboratory Medicine and Pathobiology, Tanz Neuroscience Bldg, University of Toronto, Toronto, Ontario M5S 3H2, Canada

Roses Allen D GlaxoSmithKline Research and Development, Five Moore Drive, 5-5616, Research Tri- angle Park, NC 27709, USA

Saido Takaomi C Laboratory for Proteolytic Neuroscience, RIKEN Brain Science Institute, 2-1 Hirosawa, Wako-shi, Saitama 351-0198, Japan XXXII List of Contributors

Savonenko Alena V Department of Pathology, The Johns Hopkins University School of Medicine, 558 Ross Research Building, 720 Rutland Avenue, Maryland 21205-2196, Baltimore, USA

Schenk Dale Elan Pharmaceuticals, 800 Gateway Bld., South San Francisco CA 94080, USA

Schmitt-Ulms G Departments of Medicine, Medical Biophysics, Laboratory Medicine and Pathobiology, Tanz Neuroscience Bldg, University of Toronto, Toronto, Ontario M5S 3H2, Canada

Selkoe Dennis J Center for Neurologic Diseases, Harvard Medical School, and Brigham and Women’s Hospital, Boston, MA 02115, USA

Seubert Peter Elan Pharmaceuticals, 800 Gateway Bld., South San Francisco CA 94080, USA

Smith Mark A Department of Pathology, Case Western Reserve University, Cleveland, Ohio, USA

Spillantini Maria Grazia Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK

St George-Hyslop PH Departments of Medicine, Medical Biophysics, Laboratory Medicine and Pathobiology, Tanz Neuroscience Bldg, University of Toronto, and Division of Neurology and Toronto Western Hospital Research Institute, Toronto Western Hospital, Toronto, Ontario M5S 3H2, Canada

Storandt Martha Departments of Psychology and Neurology, and the Alzheimer’s Disease Research Center, Washington University School of Medicine, St. Louis, Missouri, USA

Strobel Gabrielle Alzheimer Research Forum, 600 Beaver Street, Waltham, MA 02452, USA

Tandon A Departments of Medicine, Medical Biophysics, Laboratory Medicine and Pathobiology, Tanz Neuroscience Bldg, University of Toronto, Toronto, Ontario M5S 3H2, Canada

Tanzi Rudolph E Genetics and Aging Research Unit, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, 114 16th Street, Charlestown, MA 02129, USA List of Contributors XXXIII

Ter ry Robert D Department of Neurosciences, University of California, San Diego School of Medi, Room 350 Medical Teaching Facility, 9500 Gilman Drive, La Jolla, CA 92093-0624, USA

Thal Leon J University of California San Diego, Department of Neurosciences, 9500 Gilman Drive, La Jolla, CA 92093-0624, USA

Thies E Max-Planck-Unit for Structural Molecular Biology, 22607 Hamburg, Germany

Trojanowski John Q Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Maloney 3, HUP, 3600 Spruce Street, USA, Philadelphia, PA 19104-4283

Troncosco Juan Department of Pathology, Neuroscience and Neurology, The Johns Hopkins University School of Medicine, 558 Ross Research Building, 720 Rutland Avenue, Maryland 21205- 2196, Baltimore, USA

Van Broeckhoven Christine VIB8 – Department of Molecular Genetics, University of Antwerp – CDE, Parking P4 – Building V – Room 0.10, Universiteitsplein 1, 2610 Antwerpen, Belgium vonBergenM Max-Planck-Unit for Structural Molecular Biology, Notkestrasse 85, 22607 Hamburg, Germany

Westaway D Departments of Medicine, Medical Biophysics, Laboratory Medicine and Pathobiology, Tanz Neuroscience Bldg, University of Toronto, Toronto, Ontario M5S 3H2, Canada

Wolfe Michael S Center for Neurologic Diseases, Harvard Medical School and Brigham and Women’s Hospital, 77 Avenue Louis Pasteur, H.I.M. 754, Boston, MA 02115, USA

Wong Philip C Department of Pathology, Neuroscience and Neurology, The Johns Hopkins Univer- sity School of Medicine, 558 Ross Research Building, 720 Rutland Avenue, Baltimore, Maryland 21205-2196, USA

Wong Cai’ne W Scarborough, Maine, USA

Younk in Ste ve n G Department of Neuroscience, Mayo Clinic College of Medicine, 4500 San Pablo Road, Jacksonville FL 32224, USA