alzheimers disease

Baki Department of Psychiatry and Fishberg Research Center for Neurobiology, The Mount Sinai School of Medicine, Box 1229, One Gustave Levy Place, New York, NY 10029-6547, USA S.. Hejl M

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Alzheimer’s Disease

ADVANCES IN ETIOLOGY,

PATHOGENESIS AND THERAPEUTICS

Alzheimer’s Disease: Advances in Etiology, Pathogenesis and Therapeutics Edited by Khalid Iqbal, Sangram S Sisodia and Bengt Winblad

Copyright & 2001 John Wiley & Sons Ltd

Print ISBN 0-471-52176-0 Online ISBN 0-470-84645-3

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This publication was supported by an educational grant from

Janssen Pharmaceutica and Janssen Research Foundation

Edited by Khalid Iqbal, Sangram S Sisodia and Bengt Winblad

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Karolinska Institute, Stockholm, Sweden

JOHN WILEY & SONS, LTD

Chichester.New York.Weinheim.Brisbane.Singapore.Toronto

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Copyright & 2001 John Wiley & Sons Ltd.

Baffins Lane, Chichester,

West Sussex PO19 1UD, England

90 Tottenham Court Road, London W1P 9HE, UK, without the permission in writing of the Publisher

Other Wiley Editorial Offices

John Wiley & Sons, Inc., 605 Third Avenue,

New York, NY 10158-0012, USA

WILEY-VCH Verlag GmbH, Pappellallee 3,

D-69469 Weinheim, Germany

John Wiley & Sons Australia Ltd, 33 Park Road, Milton,

Queensland 4064, Australia

John Wiley & Sons (Asia) Pte Ltd, Clementi Loop #02-01,

Jin Xing Distripark, Singapore 129809

John Wiley & Sons (Canada) Ltd, 22 Worcester Road,

Rexdale, Ontario M9W 1L1, Canada

Library of Congress Cataloging-in-Publication Data

Alzheimer’s disease: advances in etiology, pathogenesis and therapeutics / edited by

Khalid Iqbal, Sangram S Sisodia, Bengt Winblad

p ; cm.

Includes bibliographical references and index.

ISBN 0-471-52176-0 (cased : alk paper)

1 Alzheimer’s disease—Congresses I Iqbal, Khalid II Sisodia, Sangram S.

III Winblad, Bengt IV International Conference on Alzheimer’s Diseases and

Related Disorders (7th : 2000 : Washington, D.C.)

[DNLM: 1 Alzheimer Disease—etiology—Congresses 2 Alzheimer Disease— pathology—Congresses 3 Alzheimer Disease—therapy—Congresses WT 155 A4757 2001] RC523 A3753 2001

British Library Cataloguing in Publication Data

A catalogue record for this book is available from the British Library

ISBN 0-471-52176-0

Typeset from authors’ disks in 10 on 12 point Plantin by

Dobbie Typesetting Limited, Tavistock, Devon

Printed and bound in Great Britain by Biddles Ltd, Guildford and King’s Lynn

This book is printed on acid-free paper responsibly manufactured from sustainable forestry,

in which at least two trees are planted for each one used for paper production.

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in the Aging Population

Advances and Challenges

Jonathan L Haines, L Renee Bailey, Janet M Grubber, Dale Hedges,

Jenifer L Hall, Sandra West, Leonard Santoro, Beth Kemmerer,

Anne M Saunders, Allen D Roses, Gary W Small, William K Scott,

Alzheimer’s Disease: Results of the NIMH-AD Genetics InitiativeLars Bertram, Deborah Blacker, Adam S Crystal, Jennifer Jones,

Devon Keeney, Laura A MacKenzie-Ingano, Kristina Mullin, Sanjay Basu,Stephen Yhu, Melvin McInnis, Rodney C P Go, Aleister J Saunders

with a Mutation at Codon 261 of the Presenilin 1 Gene

Martin R Farlow, Jill R Murrell, Frederick W Unverzagt, Michael

between Exon and Intron Splicing Regulatory Sequences

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III DIAGNOSIS AND CLINICAL COURSE 97

10 Preclinical Prediction of AD: Relation Between Neuropsychologicaland Neuroimaging Findings

Marilyn S Albert, Ronald J Killiany, Keith Johnson, Rudolph E Tanzi

11 Neuropsychological Detection of Preclinical Alzheimer’s Disease:Results of a Neuropathological Series of ‘Normal’ Controls

Kathleen A Welsh-Bohmer, Christine Hulette, Donald Schmechel,

12 Potentially Reversible Conditions in Memory Clinic Patients

13 The Alzheimer’s Disease Centers’ Neuropsychological Database

Initiative: A Resource for Alzheimer’s Disease Prevention Trials

Michael Grundman, Hyun T Kim, David Salmon, Martha Storandt,

Glenn Smith, Steven Ferris, Richard Mohs, Jason Brandt, Rachelle

Doody, Kathleen Welsh-Bohmer, Judith Saxton, Kathy Saine,

Frederick Schmitt, Paula Ogrocki, Nancy Johnson, Diane Howieson,

Michelle Papka, Joanne Green, Anthony Gamst, Walter Kukull and

Leon J Thal, for the Alzheimer’s Disease Centers’ Neuropsychological

Agneta Nordberg, Vesna Jelic, Eva Arna´iz, Bengt La˚ngstro¨m and Ove Almkvist 153

16 Amyloid, PHF-tau, Ubiquitin and Synaptic Markers in the

Progression of Alzheimer’s Disease: Immunochemical Analyses

of Frontal Cortex from Prospectively Studied Elderly Humans

D S Wang, E Cochran, D Bennett, E Mufson, C Eckman

17 Imaging the Consequences of Alzheimer’s Disease Pathology

18 Influence of apoE Genotype and PET Brain Imaging on

Preclinical Prediction of Alzheimer’s Disease

Gary W Small, Linda M Ercoli, Daniel H.S Silverman, S.-C Huang,

Susan Y Bookheimer, Helen Lavretsky, Karen Miller, Prabha Siddarth,

John C Mazziotta, Ann M Saunders, Margaret A Pericak-Vance,

19 Overview of Vascular Dementia

20 Clinical and Imaging Characteristics of Vascular Dementia in

a Memory Clinic

21 MRI of Entorhinal Cortex and Hippocampus in Alzheimer’s

Disease, Subcortical Ischemic Vascular Dementia and

Mixed Dementia

N Schuff, A T Du, D Amend, Y Y Hsu, M P Laakso, W Jagust,

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22 Olfactory Function and Event-related Potentials in Alzheimer’s

Disease

23 Phenotypic Differences in Cholinergic Markers within the

Nucleus Basalis in Individuals with Mild Cognitive Impairment

Elliott J Mufson, Michele Gilmor, Shuang Y Ma, Alan I Levey

24 Evaluating CNS Biomarkers for Alzheimer’s Disease

25 CSF Markers for Early Alzheimer’s Disease

26 CSF-Phospho-tau (181P) as a Promising Marker for DiscriminatingAlzheimer’s Disease from Dementia with Lewy Bodies

E Vanmechelen, E Van Kerschaver, K Blennow, P P De Deyn, D Galasko,

L Parnetti, C J M Sindic, H Arai, M Riemenschneider, H Hampel,

27 Increased Levels of a Minor Glycoform of Acetylcholinesterase

in Alzheimer’s Disease Brain and Cerebrospinal Fluid

Javier Sa´ez-Valero, Su San Mok, Lisa Fodero, Alberto Marcos,

Nilufer Ertekin Taner, Neill Graff-Radford, Linda H Younkin,

Christopher Eckman, Jennifer Adamson, Daniel J Schaid, John Blangero,

29 Levels of Total and Deposited Ab are Correlated with Dementia

30 What Should We Tell Patients Attending a Memory Disorders

Clinic About Their Diagnosis?

31 Innate Immunity, Autotoxicity and Degenerative Neurologies

32 Neuroinflammatory Responses in the Alzheimer’s Disease Brain

Promote the Oxidative Post-translational Modification of

Amyloid Deposits

Craig S Atwood, Xudong Huang, Robert D Moir, Mark A Smith,

33 Plasma Antioxidants and Oxidative DNA Damage in Lymphocytesfrom Normal Aged People and Alzheimer’s Disease Patients

Patrizia Mecocci, Maria Cristina Polidori, Tiziana Ingegni, Paola Mattioli,

34 Oxidative Damage and Antioxidant Responses in Alzheimer’s

Disease

George Perry, Akihiko Nunomura, Jesus Avila, Mar Perez,

Catherine A Rottkamp, Craig S Atwood, Xiongwei Zhu, Gjumrakch Aliev,

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35 Cyclooxygenase (COX)-2 and Clinical Progression of Alzheimer’sDisease Dementia: Implications in the Role of Neuronal COX-2

in Cell Cycle

36 Parallels between the Redox Properties and Toxicity of Ab in

Alzheimer’s Disease and Mutant Cu/Zn-SOD in Familial

Amyotrophic Lateral Sclerosis

Cellular Mechanisms

38 Mechanisms of Ab Production and Ab Degradation: Routes to

the Treatment of Alzheimer’s Disease

D J Selkoe, W Xia, W T Kimberly, K Vekrellis, D Walsh,

Accumulation in the CNS of a Transgenic Mouse Model of

Lorenzo M Refolo, Brian Malester, John LaFrancois, Tara Bryant-Thomas,Rong Wang, G Stephen Tint, Kumar Sambamurti, Karen Duff and

40 Electron Microscopy and X-ray Diffraction Studies further Confirm

(Cat’s Claw Derivative) as a

41 Accelerated Ab Generation in a Cell Model of Alzheimer’s

Disease-related Endosomal–Lysosomal System Upregulation

Paul M Mathews, Carolyn B Guerra, Ying Jiang, Benjamin H Kao,

42 The Amyloid Precursor Protein V717I Mutation Increases

Susceptibility to Cell Death in a Cholesterol-dependent Manner

Luigi Puglielli, Laura A MacKenzie Ingano, Rudolph E Tanzi and

Influenced by APP Mutations

Heike S Grimm, Stefan F Lichtenthaler, Konrad Beyreuther

44 Familial British Dementia

Jorge Ghiso, Tamas Re´ve´sz, Agueda Rostagno, Ruben Vidal,

45 Cellular Metabolism of Familial British Dementia-associated

BRI-L

Amyloid Peptide that Causes Dementia in a Danish Kindred

Ruben G Vidal, Tamas Re´ve´sz, Agueda Rostagno, Toke Bek,

47 Familial Alzheimer’s Disease-linked Mutant

Presenilins Attenuate Capacitative Calcium Entry

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48 Presenilin-1 Is a Regulatory Component of the Cadherin Cell AdhesionComplex: Implications for Alzheimer’s Disease

Anastasio Georgakopoulos, Philippe Marambaud, Nikolaos K Robakis

49 Presenilins and Notch Signaling Pathway

Salvador Soriano, David E Kang, Nathalie Chevallier, Hui Zheng

51 A Novel Protease Active Site Motif Conserved in Presenilins

and Polytopic Bacterial Aspartyl Proteases?

52 The Unfolded Protein Response-mediated Upregulation of BiP

and CHOP Is not Affected by Presenilin Expression

Makoto Hashimoto, Edward Rockenstein, Takato Takenouchi,

54 Neurofibrillary Degeneration: Patterns of Tau Isoform Expression

55 Phosphorylation, Microtubule Binding and Aggregation of Tau

Protein in Alzheimer’s Disease

Jesu´s A´vila, Jose´ J Lucas, Filip Lim, Mar Pe´rez, Fe´lix Herna´ndez,

Montserrat Arrasate, Rosario Armas Portela, Elsa Champion, George Perry,

56 Phosphorylation of Protein Tau and Rescue of Protein

Tau-induced Axonopathy by GSK-3b in GSK-3b6htau40

Double Transgenic Mice

Kurt Spittaels, Chris Van den Haute, Jo Van Dorpe, Hugo Geerts

57 Pathogenic Implication of Altered Tau Properties Caused by

FTDP-17 Mutations

P Nacharaju, S Yen, M DeTure, C Easson, M Hutton

the Aggregation of Tau Protein to Paired Helical Filaments

59 Formation of Neurofibrillary Tangles in Mouse Brain

60 Inducible Transgenic Expression of Wild-type tau in H4

Neuroglioma Cells

61 Lewy-like Pathology in Mice Transgenic for Mutant (A53T)

Bernd Sommer, Samuel Barbieri, Katja Hofele, Karl-Heinz Wiederhold,

Alphonse Probst, Claudia Mistl, Simone Danner, Sabine Kauffmann,

Willibrordus Spooren, Markus Tolnay, Graeme Bilbe and

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62 Somal and Neuritic Accumulation of the Parkinson’s

Disease-associated Mutant [A30P]a-Synuclein in Transgenic MicePhillipp J Kahle, Manuela Neumann, Laurence Ozmen,

and GT1-7 Cell Lines

Sylvain Lehmann, Hubert Laude, David A Harris, Richard I Carp,

of Alzheimer’s Disease Pathology

Ralph A Nixon, Paul M Mathews, Anne M Cataldo, Panaiyur S Mohan,Stephen D Schmidt, Karen Duff, Martin Berg, Neville Marks,

65 Changes in Cognitive Characteristics of Tg(APP)CRND8 Mice

at Early Stages of Immunization with Beta-Amyloid Peptide

Christopher Janus, Jacqueline Pearson, Patrick Horne, Richard Renlund,

Karen Parisien, Azhar Chishti, Donna Heslin, Catherine Bergeron, Paul Fraser,

66 Galantamine, a Novel Treatment for Alzheimer’s Disease:

A Review of Long-term Benefits to Patients and Caregivers

67 Benefits of Donepezil on Cognition, Function and

Neuropsychiatric Symptoms in Patients with Mild and ModerateAlzheimer’s Disease over One Year

Gunhild Waldemar, Bengt Winblad, Knut Engedal, Hilkke Soininen,

Frans Verhey, Anders Wimo, Anne-Lena Wetterholm, Richard Zhang,

Processing and Other Post-translational Modifications

Mitsuru Haniu, Brian D Bennett, Paul Denis, Yunjen Young,

Elizabeth A Mendiaz, Janis Fuller, John O Hui, Steven Kahn,

Safura Babu-Khan, Sandra Ross, Teresa Burgess, Viswanatham Katta,

Margery Nicolson, Jonathan Lull, Shue-Yuan Wang, Gary Rogers,

69 Androgen Treatment Reduces Cognitive Deficits in Female

apoE4 Transgenic Mice

Jacob Raber, Anthony LeFevour and Lennart Mucke

70 Studies with the Memory-enhancing Drug AIT-082 in PC12 Cells

71 Generation of Auto-antibodies toward Alzheimer’s Disease

Vaccination

Analog Inhibitors

William P Esler, W Taylor Kimberly, Beth L Ostaszewski,

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73 Photoactivated, Active-site-directedg-Secretase Inhibitors

Covalently Label Presenilin 1

Stephen J Gardell, Yue-Ming Li, Min Xu, Ming-Tain Lai, Qian Huang,

Jose L Castro, Jillian DiMuzio-Mower, Timothy Harrison, Colin Lellis,

Alan Nadin, Joseph G Neduvelil, R Bruce Register, Mohinder K Sardana,Mark S Shearman, Xiao-Ping Shi, Adrian L Smith, Kuo-Chang Yin

Structural Homology Modeling

Gwen Tatsuno, John Anderson, Jin Hong, David A Agard,

with Tetracycline Compounds

Tazeen Awan, Gianluigi Forloni, Enzio Ragg, Selina Iussich,

Giacomina Rossi, Laura Colombo, Laura Girola, Tania Massignan,

76 Influence of a Memory Training Program on Attention and

Memory Performance of Patients with Dementia

77 Prediction of Use of Emergency Community Services by

Cognitively Impaired Seniors who Live Alone: Preliminary

Findings of a Prospective Study

Mary C Tierney, Jocelyn Charles, W Gary Snow, John P Szalai,

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J Adamson Mayo Clinic Jacksonville, 4500 San Pablo Road, Jacksonville, FL 32224, USA

D A Agard The Howard Hughes Medical Institute and the Department of Biochemistry and Biophysics, University of California, San Francisco, CA 94143, USA

M S Albert Harvard Medical School, Massachusetts General Hospital, MGH East 149 9124, Charlestown, MA 02129, USA

G Aliev Department of Anatomy, Case Western Reserve University, 2085 Adelbert Road, Cleveland,

OH 44106-2622, USA

O Almkvist Karolinska Institute, NEUROTEC, Huddinge University Hospital B84, S 141 86 Huddinge, Sweden

D Amend DVA Medical Center, 4150 Clement Street 114M, San Francisco, CA 94121, USA

A Anderson Institute for Brain Aging and Dementia, University of California at Irvine, 1113 Gillespie, Irvine, CA 92697-4540, USA

J Anderson Elan Pharmaceuticals, 800 Gateway Blvd, South San Francisco, CA 94080, USA

H Arai Tohoku University, Department of Geriatric Medicine, Sendai, Miyagi, Japan

E Arna ´ iz Karolinska Institute, NEUROTEC, Huddinge University Hospital B84, S 141 86 Huddinge, Sweden

M Arrasate Centro de Biologia Molecular ‘Severo Ochoa’, Room 403, Universidad Autonomia de Madrid, Cantoblanco, 28049 Madrid, Spain

C S Atwood Institute of Pathology, Case Western Reserve University, 2085 Adelbert Road, Cleveland, OH 44106-2622, USA

J Avila Centro de Biologia Molecular ‘Severo Ochoa’, Facultad De Ciencias, Universidad Autonomia de Madrid, Cantoblanco, 28049 Madrid, Spain

T Awan Istituto Nazionale Neurologico Carlo Besta, via Celoria 11, 20133 Milan, Italy

S Babu-Khan Amgen Inc., One Amgen Center Dr, Thousand Oaks, CA 91320-1799, USA

L Ba ¨ ckman NEUROTEC, Karolinska Institute, Huddinge University Hospital B84, S 141 86 Huddinge, Sweden

L R Bailey Program in Human Genetics, 519 Light Hall, Vanderbilt Medical Center, Nashville,

TN 37323, USA

M Baker Mayo Clinic Jacksonville, 4500 San Pablo Road, Jacksonville, FL 32224, USA

L Baki Department of Psychiatry and Fishberg Research Center for Neurobiology, The Mount Sinai School of Medicine, Box 1229, One Gustave Levy Place, New York, NY 10029-6547, USA

S Barbieri Nervous System Research, Novartis Pharma AG, WSJ-386.709, CH-4002 Basel, Switzerland

M.-S Barquero Department of Neurology, Hospital Clinico San Carlos, Madrid, Spain

J R Barrio Department of Molecular and Medical Pharmacology, University of California at Los Angeles, 10833 Le Conte Avenue, Los Angeles, CA 90095-6948, USA

G Basi Elan Pharmaceuticals, 800 Gateway Blvd, South San Francisco, CA 94080, USA

S Basu Genetics and Aging Unit, Department of Neurology, MGH-East, 149 13th Street, Charlestown, MA 02129, USA

T Bek Department of Ophthalmology, Aarhus Hospital, Aarhus, Denmark

B D Bennett Amgen Inc., One Amgen Center Dr, Thousand Oaks, CA 91320-1799, USA

D Bennett Department of Neurological Sciences, Rush Presbyterian Medical Center, 2242 West Harrison Street, Chicago, IL 60612, USA

M Berg Center for Dementia Research, Nathan Kline Institute, 140 Old Orangeburg Road, Orangeburg, New York 10962, USA

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C Bergeron Centre for Research in Neurodegenerative Diseases, 6 Queen’s Park Cr W., Toronto, Ontario, Canada M5S 3H2

T Bernhardt Johann Wolfgang Goethe-University, Department of Psychiatry, Str 10, D-60528 Frankfurt, Germany

Heinrich-Hoffmann-L Bertram Genetics and Aging Unit, Department of Neurology, MGH-East, 149 13th Street, Charlestown, MA 02129, USA

K Beyreuther Center for Molecular Biology, University of Heidelberg, INF 282, D-69120 Heidelberg, Germany

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

G Bilbe Nervous System Research, Novartis Pharma AG, WSJ-386.709, CH-4002 Basel, Switzerland

D Blacker Gerontology Research Unit, Department of Psychiatry, MGH-East, 149 13th Street, Charlestown, MA 02129, USA

J Blangero Southwest Foundation for Biomedical Research, San Antonio, Texas, USA

K Blennow Department of Clinical Neuroscience, Neurochemistry Unit, Sahlgrens University Hospital, University of Go¨teborg, SE 43180 Mo ¨ lndal, Sweden

S Y Bookheimer University of California at Los Angeles, Brain Mapping Center, 660 Charles Young Drive South, Room 205, Los Angeles, CA 90095, USA

G L Boulianne Department of Molecular and Medical Genetics, University of Toronto, Toronto, Ontario, Canada

H Braendgaard Department of Neurology, Odense University Hospital, Odense, Denmark

J Brandt Department of Psychiatry and Behavioral Sciences, The Johns Hopkins University School

of Medicine, 600 North Wolf Street, Meyer 218, Baltimore, MD 21287-7218, USA

R Bruce Register Department of Biological Chemistry, Merck Research Laboratories, West Point,

PA 19486, USA

T Bryant-Thomas University of South Alabama Medical School, Mobile, AL, USA

O Bugiani Istituto Nazionale Neurologico Carlo Besta, via Celoria 11, 20133 Milan, Italy

T Burgess Amgen Inc., One Amgen Center Dr, Thousand Oaks, CA 91320-1799, USA

J Burke Box 2900, Duke University Medical Center, Durham, NC 27710, USA

A I Bush Laboratory for Oxidation Biology, Genetics and Aging Unit, Massachusetts General Hospital East, Building 149, 13th Street, Charlestown, MA 02129, USA

J D Buxbaum Department of Psychiatry, The Mount Sinai School of Medicine, One Gustave Levy Place, Box 1230, New York, NY 10029, USA

R I Carp Institute for Basic Research, Staten Island, New York, USA

A D Cash Institute of Pathology, Case Western Reserve University, 2085 Adelbert Road, Cleveland,

OH 44106-2622, USA

G M Castillo ProteoTech Inc., 12026 115th Avenue NE, Kirkland, WA 98034, USA

J L Castro Neuroscience Research Centre, Merck, Sharp and Dohme Research Laboratories, Terlings Park, Harlow, Essex CM20 2QR, UK

A M Cataldo Center for Dementia Research, Nathan Kline Institute, 140 Old Orangeburg Road, Orangeburg, New York 10962, USA

M Catani Institute of Gerontology and Genetics, University of Perugia, via Eugubina 42, 06122 Perugia, Italy

R Cecchetti Institute of Gerontology and Genetics, University of Perugia, via Eugubina 42, 06122 Perugia, Italy

E Champion Centro de Biologia Molecular ‘Severo Ochoa’, Facultad De Ciencias, Room 403, Universidad Autonomia de Madrid, Cantoblanco, 28049 Madrid, Spain

J Charles Department of Family and Community Medicine, University of Toronto, Toronto, Ontario, Canada

I Cheng Genetics and Aging Unit, Massachusetts General Hospital, Harvard Medical School, 149 13th Street, Charlestown, MA 02129-2000, USA

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A Cherubini Institute of Gerontology and Genetics, University of Perugia, via Eugubina 42, 06122 Perugia, Italy

N Chevallier Department of Neurosciences, University of California at San Diego, La Jolla, CA

M Citron Amgen Inc., One Amgen Center Dr, Thousand Oaks, CA 91320-1799, USA

E Cochran Department of Neurological Sciences, Rush Presbyterian Medical Center, 2242 West Harrison Street, Chicago, IL 60612, USA

L Colombo Istituto di Richerche Farmacologiche Mario Negri, via Eritrea 62, 20157 Milan, Italy

P M Conneally Indiana University Medical Center, 425 University Blvd, Indianapolis, IN

A Delacourte INSERM U422, 1 Place de Verdun, 59045 Lille cedex, France

C Delmaire Department of Neuroradiology, University Hospital, Hospital Roger Salengro, 59037 Lille, France

P Denis Amgen Inc., One Amgen Center Dr, Thousand Oaks, CA 91320-1799, USA

M DeTure Mayo Clinic Jacksonville, 4500 San Pablo Road, Jacksonville, FL 32224, USA

D W Dickson Department of Pathology, Neuropathology Laboratory, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA

J DiMuzio-Mower Department of Biological Chemistry, Merck Research Laboratories, West Point,

A T Du DVA Medical Center, 4150 Clement Street 114M, San Francisco, CA 94121, USA

K Duff Center for Dementia Research, Nathan Kline Institute, 140 Old Orangeburg Road, Orangeburg, New York 10962, USA

C Easson Mayo Clinic Jacksonville, 4500 San Pablo Road, Jacksonville, FL 32224, USA

C Eckman Mayo Clinic Jacksonville, 4500 San Pablo Road, Jacksonville, FL 32224, USA

K Engedal Department of Geriatric Medicine, Ullevaal University Hospital, Oslo, Norway

L M Ercoli Department of Psychiatry and Behavioral Sciences, University of California at Los Angeles, Neuropsychiatric Institute, 760 Westwood Plaza, Los Angeles, CA 90024, USA

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W P Esler Brigham and Women’s Hospital and Harvard Medical School, Center for Neurologic Diseases, 77 Avenue Louis Pasteur, HIM 632, Boston, MA 02115, USA

M R Farlow Department of Neurology, Indiana University School of Medicine, 541 Clinical Drive, Suite 520, Indianapolis, IN 46217, USA

S Ferris Department of Psychiatry, New York University School of Medicine, 550 First Avenue, Room 312B, New York, NY 10016, USA

R H Fisher Division of Geriatric Medicine, Sunnybrook & Women’s College Health Sciences Centre, A439, 2075 Bayview Avenue, Toronto, Ontario, Canada M4N 3M5

L Fodero Department of Pathology, University of Melbourne, Victoria 3010, Australia

G Forloni Istituto di Richerche Farmacologiche Mario Negri, via Eritrea 62, 20157 Milan, Italy

B Frangione Department of Pathology and Laboratory Medicine, MS A133, Indiana University School of Medicine, 635 Barnhill Drive, Indianapolis, IN 46202, USA

P Fraser Center for Research in Neurodegenerative Diseases, 6 Queen’s Park Cr W., Toronto, Ontario, Canada M5S 3HZ

L Fratiglioni Division of Geriatric Medicine, NEUROTEC, Karolinska Institute, The sholmen Project, A¨ldrecentrum Box 6401, S 113 82 Stockholm, Sweden

Kung-D Frenkel Department of Molecular Microbiology, Faculty of Life Sciences, Tel-Aviv University, Ramat-Aviv, Tel-Aviv 69978, Israel

L Fro ¨ lich Johann Wolfgang Goethe-University, Department of Psychiatry, Heinrich-Hoffmann-Str.

10, D-60528 Frankfurt, Germany

J Fuller Amgen Inc., One Amgen Center Dr, Thousand Oaks, CA 91320-1799, USA

D Galasko Department of Neuroscience, University of California at San Diego, 9500 Gilman Drive,

B Ghetti Department of Neurology, Indiana University School of Medicine, 541 Clinical Drive, Suite 520, Indianapolis, IN 46217, USA

J Ghiso Department of Pathology, New York University School of Medicine, 550 First Avenue,

TH-432, New York, NY 10016, USA

L Girola Istituto di Richerche Farmacologiche Mario Negri, via Eritrea 62, 20157 Milan, Italy

R C P Go Department of Epidemiology, School of Public Health, University of Alabama, Birmingham, AL, USA

N Graff-Radford Mayo Clinic Jacksonville, 4500 San Pablo Road, Jacksonville, FL 32224, USA

J Green Department of Neurology, Emory University School of Medicine, 1841 Clifton Road NE, Atlanta, GA 30329, USA

H S Grimm AG Beyreuther Center for Molecular Biology, University of Heidelberg, Im Neuenheimer Feld 282, D-69120 Heidelberg, Germany

J H Growdon Massachusetts General Hospital, WACC 330, Boston, MA 02114, USA

J M Grubber Duke University Medical Center, Durham, NC 27710, USA

M Grundman Department of Neurosciences, University of California at San Diego, 8950 Villa La Jolla Drive, Suite 2200, San Diego, CA 92037, USA

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C B Guerra Alfred I DuPont Hospital for Sick Children, Wilmington, DE 19899, USA

C Haass Department of Biochemistry, Adolf Butenandt Institute, Ludwig Maximilians University, Schillerstrasse 44, D-80336 Munich, Germany

A Haglund Pfizer AB, Taby, Sweden

J L Haines Program in Human Genetics, 519 Light Hall, Vanderbilt Medical Center, Nashville,

TN 37323, USA

J L Hall Program in Human Genetics, 519 Light Hall, Vanderbilt Medical Center, Nashville, TN

37323, USA

H Hampel Ludwig-Maximilian University, Department of Psychiatry, Munich, Germany

M Haniu Amgen Inc., One Amgen Center Dr, Thousand Oaks, CA 91320-1799, USA

V Haroutunian Department of Psychiatry, Mount Sinai School of Medicine, One Gustave L Levy Place, Box 1230, New York, NY 10029, USA

D A Harris Department of Cell Biology and Physiology, Washington University School of Medicine,

St Louis, Missouri, USA

T Harrison Neuroscience Research Centre, Merck, Sharp and Dohme Research Laboratories, Terlings Park, Harlow, Essex CM20 2QR, UK

T Hartmann Center for Molecular Biology, University of Heidelberg, INF 282, D-69120 Heidelberg, Germany

M Hashimoto Department of Neurosciences, University of California at San Diego, La Jolla, CA 92093-0624, USA

D Hedges Duke University Medical Center, Durham, North Carolina, USA

A.-M Hejl Memory Disorders Research Unit, Department of Neurology, The Neuroscience Center, Copenhagen University Hospital, Rigshospitalet, Denmark

F Herna ´ ndez Centro de Biologia Molecular ‘Severo Ochoa’, Universidad Autonomia de Madrid, Cantoblanco, 28049 Madrid, Spain

D Heslin Centre for Research in Neurodegenerative Diseases, 6 Queen’s Park Cr W., Toronto, Ontario, Canada M5S 3H2

K Hofele Nervous System Research, Novartis Pharma AG, WSJ-386.709, CH-4002 Basel, Switzerland

P Høgh Memory Disorders Research Unit, Department of Neurology, The Neuroscience Center, Copenhagen University Hospital, Rigshospitalet, Denmark

J Hong Elan Pharmaceuticals, 800 Gateway Blvd, South San Francisco, CA 94080, USA

P Horne Centre for Research in Neurodegenerative Diseases, 6 Queen’s Park Cr W., Toronto, Ontario, Canada M5S 3H2

D Howieson Department of Neurology, Oregon Health Sciences University, 3181 SW Sam Jackson Park Road, Portland, OR 97201, USA

Y Y Hsu DVA Medical Center, 4150 Clement Street 114M, San Francisco, CA 94121, USA

Q Huang Department of Biological Chemistry, Merck Research Laboratories, West Point, PA

J O Hui Amgen Inc., One Amgen Center Dr, Thousand Oaks, CA 91320-1799, USA

C Hulette Duke University Medical Center, Durham, North Carolina, USA

F Hulstaert Innogenetics NV, Industripark Zwijnaarde 7, Box 4, B-9052 Ghent, Belgium

M Hutton Mayo Clinic Jacksonville, 4500 San Pablo Road, Jacksonville, FL 32224, USA

T Ingegni Institute of Gerontology and Genetics, University of Perugia, via Eugubina 42, 06122 Perugia, Italy

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

S Iussich Istituto Nazionale Neurologico Carlo Besta, via Celoria 11, 20133 Milan, Italy

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S Jaglal Graduate Department of Rehabilitation Sciences, University of Toronto, Toronto, Ontario, Canada

W Jagust Department of Neurology, University of California at Davis, One Shields Avenue, Davis,

K Jones Heller Graduate School, Brandeis University, MS 035, Waltham, MA 02454-9110, USA

P J Kahle Department of Biochemistry, Adolf Butenandt Institute, Ludwig Maximilians University, Schillerstrasse 44, D-80336 Munich, Germany

S Kahn Amgen Inc., One Amgen Center Dr, Thousand Oaks, CA 91320-1799, USA

D E Kang Department of Neurosciences, University of California at San Diego, La Jolla, CA

92093, USA

B H Kao 20/F, 10 Pottinger Street Central, Hong Kong

S Katamine Department of Molecular Microbiology and Immunology, Nagasaki University Graduate School of Medical Science, Nagasaki, Japan

V Katta Amgen Inc., One Amgen Center Dr, Thousand Oaks, CA 91320-1799, USA

R Katzman University of California San Diego, 9500 Gilman Drive, San Diego, CA 92093-0949, USA

S Kauffmann Nervous System Research, Novartis Pharma AG, WSJ-386.709, CH-4002 Basel, Switzerland

D Keeney Genetics and Aging Unit, Department of Neurology, MGH-East, 149 13th Street, Charlestown, MA 02129, USA

B Kemmerer Program in Human Genetics, 519 Light Hall, Vanderbilt Medical Center, Nashville,

D M Kovacs Genetics and Aging Unit, Massachusetts General Hospital, Harvard Medical School,

149 13th Street, Charlestown, MA 02129-2000, USA

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H A Kretzschmar Department of Biochemistry, Adolf Butenandt Institute, Ludwig Maximilians University, Schillerstrasse 44, D-80336 Munich, Germany

W Kukull Department of Epidemiology, University of Washington, National Alzheimer’s Coordinating Center, 4225 Roosevelt Way NE, Suite 301, Seattle, WA 98105-6099, USA

J LaFrancois Rockefeller University, New York, USA

M P Laakso Department of Neurology, University of Kuopio, PO Box 1627, FIN-70211 Kuopio, Finland

D K Lahiri Institute of Psychiatric Research, Indiana University School of Medicine, 791 Union Drive, Indianapolis, IN 46202-4887, USA

M.-T Lai Department of Biological Chemistry, Merck Research Laboratories, West Point, PA

19486, USA

B La ˚ ngstro¨m Uppsala University, Box 256, 751 05 Uppsala, Sweden

H Laude INRA Unite´ de Virologie Immunologie Mole´culaires, 78352 Jouy-en-Josas Cedex, France

H Lavretsky University of California at Los Angeles, 760 Westwood Plaza, #37-384 NPI, Los Angeles, CA 90024-1759, USA

F Lebert Department of Neurology, Memory Clinic, University Hospital, Hospital Roger Salengro,

S F Lichtenhaler Massachusetts General Hospital, Department of Molecular Biology, Wellman Building, 9th Floor, 50 Blossom Street, Boston, MA 02114, USA

F Lim Centro de Biologia Molecular ‘Severo Ochoa’, Universidad Autonomia de Madrid, Cantoblanco, 28049 Madrid, Spain

I Livne-Bar Program in Developmental Biology, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario, Canada M5G 1X8

J J Lucas Centro de Biologia Molecular ‘Severo Ochoa’, Universidad Autonomia de Madrid, Cantoblanco, 28049 Madrid, Spain

J Lull Amgen Inc., One Amgen Center Dr, Thousand Oaks, CA 91320-1799, USA

S Y Ma Department of Neurological Sciences, Rush Presbyterian–St Luke’s Medical Center, Chicago, IL 60612, USA

L A MacKenzie-Ingano Genetics and Aging Unit, Department of Neurology, MGH-East, 149 13th Street, Charlestown, MA 02129, USA

J.-Y Madec Unite Virologie ATNC, AFSSA, Lyon, France

C P Maguire Department of Care of the Elderly, Royal Victoria Hospital, Craigleith Road, Edinburgh EH4 2DN, UK

B Malester Nathan S Kline Institute for Dementia Research, 140 Old Orangeburg Road, Orangeburg, NY 10962, USA

M Mallory Department of Pathology, University of California at San Diego, La Jolla, CA

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P Marambaud Department of Psychiatry and Fishberg Research Center for Neurobiology, The Mount Sinai School of Medicine, Box 1229, One Gustave Levy Place, New York, NY 10029-6547, USA

A Marcos Department of Neurology, Hospital Clinico San Carlos, Madrid, Spain

W R Markesbery University of Kentucky Medical Center, 800 Rose Street, Lexington, KY 40536, USA

N Marks Center for Dementia Research, Nathan Kline Institute, 140 Old Orangeburg Road, Orangeburg, New York 10962, USA

E Masliah Department of Neurosciences, University of California at San Diego, La Jolla, CA 92093-0624, USA

T Massignan Istituto di Richerche Farmacologiche Mario Negri, via Eritrea 62, 20157 Milan, Italy

P M Mathews New York University School of Medicine, Nathan Kline Institute Center for Dementia Research, 140 Old Orangeburg Road, Orangeburg, New York 10962, USA

P Mattioli Institute of Gerontology and Genetics, University of Perugia, via Eugubina 42, 06122 Perugia, Italy

K Maurer Johann Wolfgang Goethe-University, Department of Psychiatry, Strasse 10, D-60528 Frankfurt, Germany

Heinrich-Hoffmann-J C Mazziotta University of California at Los Angeles, Brain Mapping Center, 660 Charles Young Drive South, Room 247, Los Angeles, CA 90095, USA

C McLean Department of Pathology, University of Melbourne, Victoria 3010, Australia

L C McConlogue Elan Pharmaceuticals, 800 Gateway Blvd, South San Francisco, CA

E A Mendiaz Amgen Inc., One Amgen Center Dr, Thousand Oaks, CA 91320-1799, USA

K Miller University of California at Los Angeles, 760 Westwood Plaza, #88-201 NPI, Los Angeles,

CA 90024-1759, USA

C Mistl Institute for Pathology, Scho¨nbeinstrasse 40, CH 4003 Basel, Switzerland

P S Mohan Center for Dementia Research, Nathan Kline Institute, 140 Old Orangeburg Road, Orangeburg, New York 10962, USA

R Mohs Department of Psychiatry, Mount Sinai School of Medicine, VA Medical Center, 130 West Kingsbridge Road, Bronx, NY 10468, USA

R D Moir Genetics and Aging Unit, Department of Psychiatry, Harvard Medical School, Boston,

MA 02129, USA

S S Mok Department of Pathology, University of Melbourne, Victoria 3010, Australia

C D Morgan San Diego State University, 6363 Alvarado Ct., Suite 101, San Diego, CA

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C Murphy San Diego State University, 6363 Alvarado Court, Suite 101, San Diego, CA

92120-4913, USA

J R Murrell Department of Neurology, Indiana University School of Medicine, 541 Clinical Drive, Suite 520, Indianapolis, IN 46217, USA

P Nacharaju Mayo Clinic Jacksonville, 4500 San Pablo Road, Jacksonville, FL 32224, USA

A Nadin Neuroscience Research Centre, Merck, Sharp and Dohme Research Laboratories, Terlings Park, Harlow, Essex CM20 2QR, UK

J Naslund Karolinska Institute, NEUROTEC, KFC Novum Plan 4, 14186 Huddinge, Sweden

J G Neduvelil Neuroscience Research Centre, Merck, Sharp and Dohme Research Laboratories, Terlings Park, Harlow, Essex CM20 2QR, UK

M Neumann Department of Biochemistry, Adolf Butenandt Institute, Ludwig Maximilians University, Schillerstrasse 44, D-80336 Munich, Germany

M Nicholson Amgen Inc., One Amgen Center Dr, Thousand Oaks, CA 91320-1799, USA

J D Nido Centro de Biologia Molecular ‘Severo Ochoa’, Universidad Autonomia de Madrid, Cantoblanco, 28049 Madrid, Spain

N Nishida Institut de Ge´ne´tique Humanine, CNRS UPR 1142, 141, rue de la Cardonille, 34396 Montpellier Cedex 5, France

R A Nixon Center for Dementia Research, Nathan Kline Institute, 140 Old Orangeburg Road, Orangeburg, New York 10962, USA

A Nordberg Karolinska Institute, NEUROTEC, MNP, Huddinge University Hospital, B84,

M A Pappolla University of South Alabama Medical School, Mobile, AL, USA

K Parisien Division of Comparative Medicine, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada M5S 1A8

L Parnetti Department of Neuroscience, University of Perugia, Piazza Universita` n.1, 06100 Perugia, Italy

S Parvathy Department of Psychiatry, Mount Sinai School of Medicine, One Gustave L Levy Place, Box 1230, New York, NY 10029, USA

G M Pasinetti Neuroinflammation Research Center, Department of Psychiatry, Mount Sinai School of Medicine, One Gustave L Levy Place, New York, NY 10029, USA

F Pasquier Clinique Neurologique, Centre Hospitalier et Universitaire, 59037 Lille, France

J Pearson Centre for Research in Neurodegenerative Diseases, 6 Queen’s Park Cr W., Toronto, Ontario, Canada M5S 3H2

M Perez Centro de Biologia Molecular, Universidad Autonomia de Madrid, Madrid, Spain

M A Pericak-Vance Duke University Medical Center, Durham, North Carolina, USA

G Perry Institute of Pathology, Case Western Reserve University, 2085 Adelbert Road, Cleveland,

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M E Phelps University of California at Los Angeles, Department of Pharmacology, 650 Charles Young Drive South, 23-132 CHS, Los Angeles, CA 90095-1735, USA

M Phillips Department of Neurology, Indiana University School of Medicine, 541 Clinical Drive, Suite 520, Indianapolis, IN 46217, USA

G Plant National Hospital for Neurology and Neurosurgery, London, UK

M C Polidori Institute of Gerontology and Genetics, University of Perugia, via Eugubina 42,

06122 Perugia, Italy

R A Portela Centro de Biologia Molecular ‘Severo Ochoa’, Universidad Autonomia de Madrid, Cantoblanco, 28049 Madrid, Spain

H Pottel Innogenetics NV, Industripark Zwijnaarde 7, Box 4, B-9052 Ghent, Belgium

A Probst Institute for Pathology, Scho¨nbeinstrasse 40, CH 4003 Basel, Switzerland

J.-P Pruvo Department of Neuroradiology, University Hospital, Hospital Roger Salengro, 59037 Lille, France

L Puglielli Genetics and Aging Unit, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Building 149, 13th Street, Charlestown, MA 02129-2000, USA

J Raber Gladstone Institute of Neurological Disease and Department of Neurology, University of California, San Francisco, CA 94141-9100, USA

E Ragg Dipartimento di Scienze Molecolari Agroalimentari, Facolta` di Agraria, Universita` di Milan, via Celoria 2, 20133, Milan, Italy

R Redlund Division of Comparative Medicine, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada M5S 1A8

L M Refolo Nathan S Kline Institute, Dementia Research Group, 140 Old Orangeburg Road, Orangeburg, NY 10963, USA

T Re´ve´sz Department of Neuropathology, Institute of Neurology, University College London, London, UK

M Riemenschneider Department of Psychiatry, Technische Universita¨t Munchen, Munich, Germany

N K Robakis Department of Psychiatry and Fishberg Research Center for Neurobiology, Mount Sinai School of Medicine, Box 1229, One Gustave Levy Place, New York, NY 10029-6547, USA

E Rockenstein Department of Neurosciences, University of California at San Diego, La Jolla, CA 92093-0624, USA

G Rogers Amgen Inc., One Amgen Center Dr, Thousand Oaks, CA 91320-1799, USA

A E Roher Haldeman Laboratory for Alzheimer Disease Research, Sun Health Research Institute, Sun City, AZ 85351, USA

A D Roses Glaxo Wellcome, Inc., Research Triangle Park, North Carolina, USA

S Ross Amgen Inc., One Amgen Center Dr, Thousand Oaks, CA 91320-1799, USA

G Rossi Istituto Nazionale Neurologico Carlo Besta, via Celoria 11, 20133 Milan, Italy

A Rostagno Department of Pathology and Laboratory Medicine, MS A133, Indiana University School of Medicine, 635 Barnhill Drive, Indianapolis, IN 46202, USA

C A Rottkamp Institute of Pathology, Case Western Reserve University, 2085 Adelbert Road, Cleveland, OH 44106-2622, USA

J Sa ´ ez-Valero Instituto de Neurociencias, Universidad Miguel Herna`ndez, 03550 San Juan de Alicante, Spain

K Saine Department of Psychiatry, University of Texas, Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-8898, USA

D Salmon Department of Neurosciences, University of California at San Diego, 8950 Villa La Jolla Drive, Suite 2200, San Diego, CA 92037, USA

M Salmona Istituto di Richerche Farmacologiche Mario Negri, via Eritrea 62, 20157 Milan, Italy

K Sambamurti Mayo Clinic Jacksonville, 4500 San Pablo Road, Jacksonville, FL 32224, USA

L Santoro Duke University Medical Center, Durham, North Carolina, USA

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M K Sardana Department of Biological Chemistry, Merck Research Laboratories, West Point, PA

A Saunders Duke University Medical Center, Durham, North Carolina, USA

J Saxton Department of Psychiatry, University of Pittsburgh, Room E-1098, WPIC, 3811 O’Hara Street, Pittsburg, PA 15213, USA

D J Schaid Mayo Clinic Jacksonville, 4500 San Pablo Road, Jacksonville, FL 32224, USA

G D Schellenberg Divisions of Gerontology and Geriatric Medicine, Department of Medicine, University of Washington, Seattle, WA 98195, USA

D Schmechel Bryan ADRC, 220 West Main Street, Suite A230, Durham, NC 27705, USA

S D Schmidt Center for Dementia Research, Nathan Kline Institute, 140 Old Orangeburg Road, Orangeburg, New York 10962, USA

F Schmitt Department of Neurology, University of Kentucky, 312 Sanders-Brown Center on Aging, Lexington, KY 40536-0230, USA

N Schuff Department of Radiology, Veterans Affairs Medical Center, 4150 Clement St, 114M, San Francisco, CA 94121, USA

N Schupf New York State Institute for Basic Research, 1050 Forest Hill Road, Staten Island, NY

10314, USA

W K Scott Duke University Medical Center, Durham, North Carolina, USA

D J Selkoe Brigham and Women’s Hospital and Harvard Medical School, Center for Neurologic Diseases, 77 Avenue Louis Pasteur, HIM 632, Boston, MA 02115, USA

U Senin Institute of Gerontology and Genetics, University of Perugia, via Eugubina 42, 06122 Perugia, Italy

H Sershen Center for Dementia Research, Nathan Kline Institute, 140 Old Orangeburg Road, Orangeburg, New York 10962, USA

J A Shafer Department of Biological Chemistry, Merck Research Laboratories, West Point, PA

D H S Silverman Department of Molecular and Medical Pharmacology, University of California

at Los Angeles, Brain Mapping Center, 660 Charles Young Drive South, Los Angeles, CA 90095, USA

C J M Sindic Cliniques Universitaires Saint-Luc, Department of Neurochemistry, Brussels, Belgium

S Sinha Elan Pharmaceuticals, 800 Gateway Blvd, South San Francisco, CA 94080, USA

S S Sisodia Department of Neurobiology, Pharmacology and Physiology, University of Chicago, Abbott 316, 947 East 58th Street, Chicago, IL 60637, USA

R M Slinn Department of Old Age Psychiatry, The BRACE Centre, Blackberry Hill Hospital, Manor Road, Fishponds, Bristol, UK

B Small Division of Geriatric Medicine, NEUROTEC, Karolinska Institute, Stockholm, Sweden

D H Small Laboratory of Molecular Neurobiology, Department of Pathology, University of Melbourne, Victoria 3010, Australia

G W Small Neuropsychiatric Institute, Memory and Aging Research Center, University of California at Los Angeles, 760 Westwood Plaza, Los Angeles, CA 90095-1361, USA

S Small Sergievsky Center, 630 West 168th Street, NY 10032, USA

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A L Smith Neuroscience Research Centre, Merck, Sharp and Dohme Research Laboratories, Terlings Park, Harlow, Essex CM20 2QR, UK

G Smith Department of Psychology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA

M A Smith Institute of Pathology, Case Western Reserve University, 2085 Adelbert Road, Cleveland, OH 44106-2622, USA

A D Snow ProteoTech Inc., 12026 115th Avenue NE, Kirkland, WA 98034, USA

W G Snow Geriatric Research and Psychology, Sunnybrook & Women’s College Health Sciences Centre, A439, 2075 Bayview Avenue, Toronto, Ontario, Canada M4N 3M5

H Soininen Department of Neurology, University and University Hospital of Kuopio, Finland

B Solomon Department of Molecular Microbiology, Faculty of Life Sciences, Tel-Aviv University, Ramat-Aviv, Tel-Aviv 69978, Israel

B Sommer Nervous System Research, Novartis Pharma AG, WSJ-386.709, CH-4002 Basel, Switzerland

W Song Department of Neurology, The Children’s Hospital, Harvard Medical School, Enders 260,

300 Longwood Avenue, Boston, MA 02115, USA

S Soriano Department of Neurosciences, University of California at San Diego, La Jolla, CA

92093, USA

K F F Spittaels Experimental Genetics Group (EGG), Flemish Institute for Biotechnology (VIB), Centre for Human Genetics, Katholik Universitaet Leuven, Campus Gasthuisberg O&N 06, B-3000 Leuven, Belgium

F Spizzirri Geriatric Research and Psychology, Sunnybrook & Women’s College Health Sciences Centre, A439, 2075 Bayview Avenue, Toronto, Ontario, Canada M4N 3M5

W Spooren Nervous System Research, Novartis Pharma AG, WSJ-386.709, CH-4002 Basel, Switzerland

H Steiner Adolf-Butenande-Institute, Ludwig-Maximilians-University Munich, Department of Biochemistry, Schillerstrasse 44, 80336 Munich, Germany

Y Stern Columbia University, College of Physicians and Surgeons, 630 West 168th Street, New York, NY 10032, USA

P St George-Hyslop Centre for Research in Neurodegenerative Diseases, 6 Queen’s Park Cr W., Toronto, Ontario, Canada M5S 3H2

M Storandt Department of Psychology, Washington University, Campus Box 1125, One Brookings Drive, St Louis, MO 63130, USA

J Su Institute for Brain Aging and Dementia, University of California at Irvine, 1113 Gillespie, Irvine, CA 92697-4540, USA

P Subbiah Pfizer Pharmaceuticals Group, Pfizer Inc., New York, USA

J P Szalai Clinical Epidemiology and Health Services, Sunnybrook & Women’s College Health Sciences Centre, A439, 2075 Bayview Avenue, Toronto, Ontario, Canada M4N 3M5

F Tagliavini Istituto Nazionale Neurologico Carlo Besta, via Celoria 11, 20133 Milan, Italy

M Takao Department of Neurology, Indiana University School of Medicine, 541 Clinical Drive, Suite 520, Indianapolis, IN 46217, USA

A Takashima Laboratory for Alzheimer’s Disease, Brain Science Institute, RIKEN, 2-1 Hirosawa, Wako-shi, Saitama 351-0198, Japan

T Takenouchi Department of Neurosciences, University of California at San Diego, La Jolla, CA 92093-0624, USA

K Tanemura Laboratory for Alzheimer’s Disease, Brain Science Institute, RIKEN, 2-1 Hirosawa, Wako-shi, Saitama 351-0198, Japan

N E Taner Mayo Clinic Jacksonville, 4500 San Pablo Road, Jacksonville, FL 32224, USA

R E Tanzi Genetics and Aging Unit, Department of Neurology, MGH-East, 149 13th Street, Charlestown, MA 02129, USA

P Tariot Department of Psychiatry, Medicine and Neurology, University of Rochester Medical Center, New York, New York, USA

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G Tatsuno Elan Pharmaceuticals, 800 Gateway Blvd, South San Francisco, CA 94080, USA

L J Thal Department of Neurosciences, University of California at San Diego, 8950 Villa La Jolla Drive, Suite 2200, San Diego, CA 92037, USA

G Thinakaran Department of Neurobiology, Pharmacology and Physiology, Center for Neurobiology, University of Chicago, Knapp R212, 924 East 57th Street, Chicago, IL 60637, USA

M C Tierney Geriatric Research and Psychology, Sunnybrook & Women’s College Health Sciences Centre, A439, 2075 Bayview Avenue, Toronto, Ontario, Canada M4N 3M5

G Stephen Tint Department of Veterans Affairs, East Orange, NJ, USA

M Tolnay Institute for Pathology, Scho¨nbeinstrasse 40, CH 4003 Basel, Switzerland

L Tong Institute for Brain Aging and Dementia, University of California at Irvine, 1113 Gillespie, Irvine, CA 92697-4540, USA

F W Unverzagt Department of Neurology, Indiana University School of Medicine, 541 Clinical Drive, Suite 520, Indianapolis, IN 46217, USA

A Valgaeren Innogenetics NV, Industripark Zwijnaarde 7, Box 4, B-9052 Ghent, Belgium

H van der Putten Nervous System Research, Novartis Pharma AG, WSJ-386.709, CH-4002 Basel, Switzerland

J M Vance Duke University Medical Center, Durham, North Carolina, USA

C Van den Haute Experimental Genetics Group (EGG), Flemish Institute for Biotechnology (VIB), Centre for Human Genetics, Katholik Universitaet Leuven, Campus Gasthuisberg O&N 06, B-3000 Leuven, Belgium

H Vanderstichele Innogenetics NV, Industripark Zwijnaarde 7, Box 4, B-9052 Ghent, Belgium

E Van Kerschaver Innogenetics NV, Industripark Zwijnaarde 7, Box 4, B-9052 Ghent, Belgium

J Van Dorpe Experimental Genetics Group (EGG), Flemish Institute for Biotechnology (VIB), Centre for Human Genetics, Katholik Universitaet Leuven, Campus Gasthuisberg O&N 06, B-3000 Leuven, Belgium

F Van Leuven Experimental Genetics Group (EGG), Centre for Human Genetics, Katholik Universita¨t Leuven, Campus Gasthuisberg O&N 06, B-3000 Leuven, Belgium

E Vanmechelen Innogenetics NV, Industsriepark Zwijnaarde 7, Box 4, B-9052 Ghent, Belgium

M Van Slegtenhorst Mayo Clinic Jacksonville, 4500 San Pablo Road, Jacksonville, FL 32224, USA

R Vassar Amgen Inc., One Amgen Center Dr, Thousand Oaks, CA 91320-1799, USA

K Vekrellis Center for Neurologic Diseases, Brigham and Women’s Hospital, 77 Avenue Louis Pasteur, HIM 730, Boston, MA 02115, USA

F Verhey Department of Psychiatry, University Hospital of Maastricht, Institute of Brain and Behavior, Maastricht, The Netherlands

R G Vidal Department of Pathology and Laboratory Medicine, MS A133, Indiana University School of Medicine, 635 Barnhill Drive, Indianapolis, IN 46202, USA

D Vilette INRA Unite´ de Virologie Immunologie Mole´culaires, 78352 Jouy-en-Josas Cedex, France

M von Bergen Max-Planck-Unit for Structural Molecular Biology, Notkestrasse 85, 22607 Hamberg, Germany

G Waldemar The Neuroscience Center, Copenhagen University Hospital, Rigshospitalet, Copenhagen DK-2100, Denmark

D Walsh Center for Neurologic Diseases, Brigham and Women’s Hospital, 77 Avenue Louis Pasteur, HIM 730, Boston, MA 02115, USA

D S Wang Mayo Clinic Jacksonville, 4500 San Pablo Road, Jacksonville, FL 32224, USA

R Wang Rockefeller University, New York, NY, USA

S.-Y Wang Amgen Inc., One Amgen Center Dr, Thousand Oaks, CA 91320-1799, USA

M W Weiner DVA Medical Center, 4150 Clement Street, 114M, San Francisco, CA 94121, USA

K A Welsh-Bohmer Department of Psychiatry, Duke–Bryan Alzheimer’s Disease Research Center/Division of Neurology, 2200 W Main Street, Suite A-230, Durham, NC 27705, USA

S West Duke University Medical Center, Durham, North Carolina, USA

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D Westaway Centre for Research in Neurodegenerative Diseases, 6 Queen’s Park Cr W., Toronto, Ontario, Canada M5S 3H2

A L Wetterholm Pfizer AB, Taby, Sweden

K.-H Wiederhold Nervous System Research, Novartis Pharma AG, WSJ-386.709, CH-4002 Basel, Switzerland

A Wimo Department of Family Medicine, Umea˚ University, Sweden

B Winblad Karolinska Institute, NEUROTEC, Huddinge University Hospital, B 84, S-141 86 Huddinge, Sweden

M S Wolfe Brigham and Women’s Hospital and Harvard Medical School, Center for Neurologic Diseases, 77 Avenue Louis Pasteur, HIM 632, Boston, MA 02115, USA

W Xia Brigham and Women’s Hospital and Harvard Medical School, Center for Neurologic Diseases, 77 Avenue Louis Pasteur, HIM 632, Boston, MA 02115, USA

M Xu Department of Biological Chemistry, Merck Research Laboratories, West Point, PA 19486, USA

B A Yankner Department of Neurology, The Children’s Hospital, Harvard Medical School, Enders

260, 300 Longwood Avenue, Boston, MA 02115, USA

K Yasojima Kinsmen Laboratory of Neurological Research, University of British Columbia, 2255 Westbrook Mall, Vancouver, BC V6T 1Z3, Canada

A G Yee Department of Biology, Boston College, Chestnut Hill, MA 02467, USA

S.-H Yen Mayo Clinic Jacksonville, 4500 San Pablo Road, Jacksonville, FL 32224, USA

S Yhu Genetics and Aging Unit, Department of Neurology, MGH-East, 149 13th Street, Charlestown, MA 02129, USA

K.-C Yin Department of Biological Chemistry, Merck Research Laboratories, West Point, PA

19486, USA

A S Yoo Genetics and Aging Unit, Massachusetts General Hospital, Harvard Medical School, 149 13th Street, Charlestown, MA 02129, USA

Y Young Amgen Inc., One Amgen Center Dr, Thousand Oaks, CA 91320-1799, USA

L H Younkin Mayo Clinic Jacksonville, 4500 San Pablo Road, Jacksonville, FL 32224, USA

S G Younkin Mayo Clinic Jacksonville, 4500 San Pablo Road, Jacksonville, FL 32224, USA

R Zhang Pfizer Pharmaceuticals Group, Pfizer Inc., New York, New York, USA

H Zheng Huffington Center on Aging and Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA

X Zhu Institute of Pathology, Case Western Reserve University, 2085 Adelbert Road, Cleveland, OH 44106-2622, USA

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This book is dedicated to Drs Eva Braak and Henry M Wisniewski, twodistinguished Alzheimer’s disease researchers who have died since thepublication of our previous book on Alzheimer’s disease, two years ago

EVA BRAAK, ‘OUTSTANDING BUT UNASSUMING’

Eva Braak, after several years of bold fight, died of ovarian cancer on 25August, 2000 in Frankfurt, Germany

Eva was one of the most outstanding but unassuming neuroanatomists andneurobiologists of her generation, who made major research contributions toAlzheimer’s disease and related disorders In the 1970s, Eva and her husband,Heiko Braak, developed the special histological techniques to study wholehuman brain 100mm sections, and implemented their use for immunocy-tochemistry and advanced silver impregnation methods to study thehistopathology of Alzheimer’s disease and related disorders They successfullyemployed these techniques, not only to correlate distinctive pigmentationpatterns of several types of nerve cells with the features of these cells in Golgiand immunostained sections but also, in 1989, to identify a new, notinfrequently occurring tauopathy, argyrophilic grain disease or ‘Braak’sdisease’, which is often marked by cognitive impairment In 1991, theydeveloped a now widely used staging system for the evolution of Alzheimer’sdisease histopathology called the Braak Staging System For these path-breaking research achievements, Eva was honored at the Sixth InternationalConference on Alzheimer’s Disease and Related Disorders, held inAmsterdam, The Netherlands, in July 1998 Eva was the first female scientist

to receive the award

Eva obtained her PhD in Biology from the Georg August University,Go¨ttingen, Germany, in 1967, and her postdoctoral training at the VogtInstitute for Brain Research, University of Du¨sseldorf, Germany, in 1967–

1971 In 1971, she moved to the Christian Albrecht University of Kiel,Germany, where she and Heiko started their pioneering studies on thecytoarchitecture of the human brain In 1979, Eva followed Heiko to the J.W

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Goethe University of Frankfurt, to work in the Department of ClinicalNeuroanatomy, where she was appointed to the rank of Associate Professor.Eva was born on 26 November, 1939 in Scho¨nwald, Germany She issurvived by her husband, Heiko, whom she married in 1973 and who is theChairman of the Department of Clinical Neuroanatomy at the J.W GoetheUniversity They had no children.

We had the privilege of both carrying out collaborative studies with Eva andhaving her serve on the Scientific Program Committee of the SixthInternational Conference on Alzheimer’s Disease and Related Disorders.Eva was one of the most meticulous and outstanding scientists, but at thesame time a reserved and quiet person Her death is a truly great loss to theAlzheimer’s disease field and we miss her

HENRY M WISNIEWSKI, ‘PIONEER AND VISIBLE’

Henry M Wisniewski, a pioneer and one of the most visible Alzheimer’sdisease researchers, died of chronic kidney disease on 5 September, 1999 athis home on Staten Island, New York He was born in Luszkowko, Poland,

on 27 February, 1931 He received both his medical (MD in 1955) andresearch degrees (PhD in 1960, and Docent in 1965) from the GdanskMedical School in Poland

In 1961, Henry left Poland for postdoctoral training in Canada and theUSA He spent 1 year in the laboratory of Jerzy Olszewski at the Department

of Anatomy and Pathology of the Burke Research Institute, University ofToronto During 1962–1963 he worked as a research fellow in the laboratory

of Igor Klatzo at the NIH, NINCDS, Bethesda, where he made the seminaldiscovery of the induction of neurofibrillary changes by injection of aluminuminto rabbit brain

In 1966, Henry returned to the USA to join as a Research Associate, theresearch group of Robert D Terry at the Albert Einstein College of Medicine,Bronx, New York He rose at the Einstein College of Medicine from ResearchAssociate to the positions of Assistant, Associate and then, in 1974, to fullProfessor During his stay at Einstein he made several major researchcontributions in the fields of demyelinating diseases and brain aging anddementia His major contributions in the neurobiology of aging and dementiaincluded the structural characterization of plaque pathogenesis, ultrastructure

of Alzheimer’s disease paired helical filaments and the documentation of theneuropathological changes in experimentally induced conditions and in agedanimals He documented the similarities and differences between the changes

in animals and those occurring in the brains of normal aged persons andpatients with Alzheimer’s disease

In 1974, Henry left Einstein to take over the position of Director, MRCDemyelinating Diseases Unit, in Newcastle upon Tyne, UK In collaboration

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with Harish Narang at the MRC Unit Henry confirmed the ultrastructure ofpaired helical filaments by tilt stage microcopy of these filaments inAlzheimer’s disease brain and X-ray images of the models of PHF madefrom wires After 2 years he returned to the USA as Director of the New YorkState Institute for Basic Research in Developmental Disabilities, in StatenIsland, New York He held this position from 1976 until his death in 1999.During his 23 years’ reign, 1976–1999 the Institute expanded several-fold interms of scientific staff and became world renowned for research inAlzheimer’s disease At the Institute, along with Jerzy Wegiel, he carriedout pioneering studies on the role of microglia in senile plaque formation inAlzheimer’s disease; and with Eirene Popovitch, Andrzej Vorbrodt andRichard Carp, he demonstrated the occurrence of Alzheimer’s-type plaquesand tangles in conditions with developmental disabilities, and the distribution

of plaques in prion disease and the animal analog, scrapie in mice

In 1988, Henry joined us as a Founder Convener of the InternationalConferences on Alzheimer’s Disease and Related Disorders Although he hadstrong views of his own on the pathobiology of Alzheimer’s disease and relatedconditions, he recognized and accepted the importance of the presentation ofviews counter to his own at the conferences

Henry was most known for being full of ideas and one who loved discussingand even debating science at public forums He was a very warm, friendly,hospitable and optimistic person He fought and worked hard andcollaborated with a large number of scientists He published over 700scientific papers and review articles and edited or co-edited several books onAlzheimer’s disease and related disorders

With Henry’s death, neuroscience, especially the Alzheimer’s diseaseresearch community, has lost a pioneer and a provocative discussant ofAlzheimer’s disease research He is survived by his wife, Krystyna Wisniewski,and his son, Thomas Wisniewski

Khalid IqbalBengt Winblad

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Scientists Honored for

Pioneering Research

LIFETIME ACHIEVEMENT AWARDS IN

ALZHEIMER’S DISEASE RESEARCH

LEONARD BERG MD

Leonard Berg is Professor Emeritus of Neurology at Washington UniversitySchool of Medicine, St Louis, Missouri, USA, where he founded anddirected the Alzheimer’s Disease Research Center (ADRC) from 1985 to1997

A St Louis native, he completed both BA (1945) and MD (1949) degrees

at Washington University He completed his neurology residency at theNeurological Institute of New York and then held a research appointment atthe National Institutes of Health In 1955 he returned to St Louis, joined thefaculty at the Washington University School of Medicine, and began privatepractice Dr Berg was promoted to Clinical Professor in the Department ofNeurology in 1972; that same year he initiated the School’s Dementia StudyGroup He started the University’s multidisciplinary Memory and AgingProject with a grant from the National Institute of Mental Health in 1979 In

1984 he was awarded a National Institute on Aging Program Project Grant,

‘Healthy Aging and Senile

Dementia’, and in 1985 was

awarded the Alzheimer’s Disease

Research Center grant, also from

the National Institute on Aging

Dr Berg became a full Professor

in the Department of Neurology in

1989, leaving private practice to

focus full-time on dementia

research until he retired in 1998

He and his colleagues developed

the Clinical Dementia Rating

(CDR) which is now used

world-wide to stage Alzheimer’s disease

and distinguish between mild

Alzheimer’s disease and

non-demented aging

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Dr Berg has published extensively and given lectures throughout thecountry and abroad He served on the Board of Directors of the NationalAlzheimer’s Association for 10 years, chairing its Medical and ScientificAdvisory Board during 1991–1995 In 1985 he served as President of theAmerican Board of Psychiatry and Neurology and served on its Board ofDirectors for 8 years He was Chairman of the Missouri State Advisory Board

on Alzheimer’s Disease and Related Disorders during 1988–1995 He hadbeen on the Advisory Panel on Alzheimer’s disease for the Department ofHealth and Human Services since 1993

Washington University presented Dr Berg with a Distinguished AlumnusAward in 1983, an Alumni/Faculty Award from the Medical AlumniAssociation in 1989, and the Second Century Award for his long-termcommitment and dedication to the medical school in 1999 A DistinguishedAlumni Scholarship was established in his honor in 1995 The St LouisChapter of the Alzheimer’s Association honored him with their 1989 PublicService Award In 1998, the St Louis Academy of Science honored Dr Bergwith the Peter H Raven Lifetime Award

INGE GRUNDKE-IQBAL PHD

Inge Grundke-Iqbal is Head of the Neuroimmunology Laboratory, New YorkState Institute for Basic Research in Developmental Disabilities, StatenIsland, New York, USA She received her PhD in Biology and Biochemistryfrom Georg August University, Go¨ttingen, Germany, in 1967 and heldpostdoctoral fellowships at the Max-Planck Institute for Immunobiology,Freiburg, Germany, the University of Michigan, Ann Arbor, New YorkUniversity, and Albert Einstein College of Medicine, New York DrGrundke-Iqbal was Assistant Professor of Pathology (Neuropathology) in1974–1977 at Albert Einstein College of Medicine and then in 1977 she took

up her present position (equivalent to the rank of full professor) at theInstitute for Basic Research

in Staten Island

In 1979, Dr

Grundke-Iqbal raised the first

anti-body to Alzheimer’s disease

paired helical filaments and

discovered the

cross-reac-tivity of these aberrant

filaments with brain

micro-tubules Recognizing the

importance of this

cross-reactivity, Dr

Grundke-Iqbal pursued a systematic

analysis of the microtubule

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proteins and in 1986 she identified the microtubule-associated protein tau asthe major protein subunit of Alzheimer’s paired helical filaments During thesame year, she discovered that tau in paired helical filaments and also in braincytosol from Alzheimer’s disease was abnormally hyperphosphorylated Theabnormal hyperphosphorylation of tau is not only one of the most importantfindings made in the Alzheimer’s disease field but also opened a major newarea of research Subsequent studies by Dr Grundke-Iqbal and her colleaguesdemonstrated that the levels of tau in abnormally hyperphosphorylated formare increased several-fold in Alzheimer’s disease, and that the mechanism ofthe neurofibrillary degeneration, a key lesion in Alzheimer’s disease, involvesthe sequestration of normal microtubule-associated proteins and disassembly

of microtubules by the abnormally hyperphosphorylated tau

She and her colleagues also discovered: (1) that the abnormal lation of tau precedes its polymerization into paired helical filaments andincorporation of ubiquitin; (2) that the levels of conjugated ubiquitin areelevated in both the brains and cerebrospinal fluids of patients withAlzheimer’s disease; (3) that there is a significant pool of soluble abnormallyphosphorylated tau in Alzheimer’s disease brain; (4) that the abnormallyphosphorylated tau is three- to four-fold more phosphorylated than thenormal brain tau; and (5) that by dephosphorylation in vitro, paired helicalfilaments dissociate, the tau released has normal microtubule assembly-promoting activity, and protein phosphatase-2A is a major regulator of thephosphorylation of tau

phosphory-Dr Grundke-Iqbal has been a member of the International ScientificAdvisory Committee of the International Conferences on Alzheimer’s Diseaseand Related Disorders since their inception In 1994 she received the NewYork State Governor’s Award

ROBERT KATZMAN

Robert Katzman, a native of Denver, Colorado, a graduate of the University

of Chicago and Harvard Medical School, trained in Neurology at theNeurological Institute, Columbia Presbyterian Medical School After joiningthe faculty of the Einstein College of Medicine, he served as Professor andChair of Neurology there from 1964 to 1984, then as Chair of Neurosciencesand founding director of the Alzheimer Research Center at the University ofCalifornia at San Diego from 1984 to 1990 He continues to work as ResearchProfessor of Neurosciences at the University of California at San Diego.Although Dr Katzman’s initial entry into Alzheimer’s disease (AD) workwas a neurochemical analysis of the ganglioside loss in the AD brain, carriedout with Dr Kinuko Suzuki in 1965, and a recent finding with the late DrSaitoh was that of an LRP polymorphism that modifies the risk of AD, hismajor interests have been in the clinical, epidemiological and public healthaspects of AD His experience in the early 1970s as a clinician working with

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older individuals with dementia,

confirmed in his mind the

frequency of AD in the elderly

In 1976 he marshaled evidence

that AD was the fourth most

common cause of death in the

USA His editorial on this topic

led to the first NIH-sponsored

symposium on AD in 1977,

chaired by Drs Katzman, Terry

and Bick In 1979, as an

investi-gator and as a family member, he

helped found the Alzheimer

Disease and Related Disorders

Association (now the Alzheimer’s

Association), co-chaired its first

Scientific Advisory Board and

Dr Katzman is a member of the Institute of Medicine and he was a recipient of the Potamkin Prize for Alzheimer’s Disease Research in 1992 Arecent contribution, together with Dr Karen Bick, is the oral history,Alzheimer Disease: The Changing View, a book describing the events between

co-1960 and 1980 that led to recognition of the public health importance of AD

GEORGE M MARTIN

George M Martin is Professor of Pathology, Adjunct Professor of Geneticsand Associate Director of the Alzheimer’s Disease Research Center,University of Washington He received his MD from the University ofWashington and has been a member of its faculty since 1957 As theFounding Director of the University of Washington Alzheimer DiseaseResearch Center, he assembled a team of investigators to carry out a linkageanalysis of familial Alzheimer’s disease, an effort that led to the assignment ofthe commonest form to chromosome 14 and to the mapping and positionalcloning of a related locus on chromosome 1 His laboratory then developedthe first presenilin 1 ‘knockin’ mutation in a mouse model and, together with

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the Mattson laboratory,

eluci-dated an unusual sensitivity of

neuronal cells from such animals

to excitotoxic and beta amyloid

(Ab)-induced injury His group

described a strong interaction

between the Ab precursor protein

and a human adaptor protein,

known as FE65 This was

followed by the discovery of a

polymorphic form of FE65 that

is associated with increased

susceptibility to late onset Alzheimer’s disease (LOAD) He has publishedevidence that two isoforms of FE65 are upregulated in relatively unaffectedregions of the brain of patients with LOAD, and has emphasized theimportance of such investigations as a means of detecting the earliest events inpathogenesis

Most of his other lines of research have also used genetics to further ourunderstanding of the pathobiology of human aging Examples include theelucidation of the dominant nature of replicatively senescent cells, thebiochemical genetic basis of the Werner syndrome, the first determinations ofthe rates of accumulation of somatic mutations in aging human epithelialcells, and the first estimates of the number of human genes involved in specificaspects of the senescent phenotype, including adult-onset dementias

Dr Martin is a Senior Member of the Institute of Medicine of the NationalAcademy of Sciences He has served on the National Advisory Council andthe Board of Scientific Counselors of the National Institute on Aging, andcurrently serves on the Scientific Advisory Boards of the Ellison MedicalFoundation and the Buck Center He is President-elect of the AmericanFederation for Aging Research

HENRY M WISNIEWSKI AWARD FOR

LIFETIME ACHIEVEMENT IN ALZHEIMER’S

DISEASE RESEARCH

BLAS FRANGIONE MD, PHD

Dr Frangione has contributed to our present-day knowledge of cerebralamyloid and its role in Alzheimer’s disease (AD) and aging Early in 1980, hedeveloped a method for extracting cerebral amyloid from leptomeninges, and

he deserves credit for the initial discovery of the role of mutated genes ininherited neurodegenerative disorders associated with cerebrovascularfibrillogenesis

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Working with a vascular variant offamilial AD (FAD)-like syndrome inDutch patients, he showed that theDutch amyloid was similar to betaamyloid (Ab) extracted from ADpatients He also showed that thesame protein was deposited inasymptomatic elderly people DrFrangione then postulated that: (1)

in FAD genetic mutations areresponsible for different phenotypicexpressions; and that (2) theprecursor of amyloid (as in differenttypes of systemic and localizedamyloidosis) is present in the circula-tion Dr Frangione demonstrated in

1990 that in Dutch patients, the genecoding for the amyloid precursorprotein (APP) contained a pointmutation This work provided anenormous stimulus to look for mutations in other amyloidosis and established

a rationale for examination of mutations of the APP gene in pedigrees ofFAD

Dr Frangione proposed that a conformation change occurs in sA due topoint mutations and/or a post-translational modification leading to aggrega-tion and fibrillation This conformational/aggregational transformation couldalso result from changes in pH, local concentration, lack of clearance andinteraction with other molecules, which he terms ‘pathological chaperones’,and he identified apolipoprotein E (apoE) as one of these long before linkageanalysis demonstrated an association between apoE and late onset FAD andsporadic AD

Dr Frangione began his research career as a physician in Buenos Aires Heworked at New York University Medical Center before going to Cambridge,

UK, where he received his PhD He also worked at Oxford University and atthe Imperial Cancer Research Fund in London before returning to New YorkUniversity

He has been recognized by the National Institutes of Health with a 1989MERIT Award for his studies of systemic amyloidosis, and a 1992 LEADAward for his work on AD In 1993, he received the Potamkin Prize forAlzheimer’s Disease Research In 1994, he was awarded the MetropolitanLife Award for Medical Research and, in 1997, the National Institutes ofAging recognized his work with a second MERIT Award In 1999 he wasawarded the Doctor of Science, Honoris Causa, from the University ofBuenos Aires in recognition of his contribution to science

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Alzheimer’s disease has no geographical, racial or economic boundaries It isthe major cause of dementia in middle- to old-age individuals throughout theworld With the increase in human life span, the prevalence of this age-associated disease continues to grow The importance and the scientificchallenge of this disease have been well recognized by the neuroscienceresearch community New important research findings have been made onthe biology, diagnosis and treatment of the disease since the publication of ourprevious book on Alzheimer’s disease, 2 years ago In the present book thescientists studying the disease have described the advances made by them andothers in epidemiology and genetic risk factors, disease mechanisms, earlydiagnosis and in therapeutic opportunities and new therapeutic drugs Thearticles in this book were selected from over 1300 papers presented on thelatest findings in the field at the 7th International Conference on Alzheimer’sDisease and Related Disorders, held as the major component of the WorldAlzheimer’s Congress 2000 in Washington, DC, in July 2000 We believe thisvolume will be useful, both to basic scientists and to clinicians interested inAlzheimer’s disease and related disorders

Khalid IqbalSangram S SisodiaBengt Winblad

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We are most grateful to the chapter contributors for prompt submission oftheir articles and to the following members of the Scientific ProgramCommittee for helping us select the contributors from over 1300 paperspresented at the 7th International Conference on Alzheimer’s Disease andRelated Disorders held as a major component of the World AlzheimerCongress 2000, Washington, DC: Professors Marilyn S Albert, David R.Borchelt, Steven T DeKosky, Rachelle Doody, Laura Fratiglioni, BernardinoGhetti, Charlie Glabe, Claudia Kawas, Edward Koo, Eliezer Masliah,Richard Mayeux, Marsel Mesulam, John C Morris, Ronald C Petersen,Donald Price, Gerald Schellenberg, Rudolph Tanzi, Leon Thal, John Q.Trojanowski, and Bruce Yankner

Our special thanks to Janet Biegelson at the New York State Institute forBasic Research, Staten Island, New York, for her secretarial assistance incorresponding with all the authors and in all stages of the work involved withthe production of the book in the Senior Editor’s office

Financial support for the book was generously provided by JanssenPharmaceutica and Research Foundation

Khalid IqbalSangram S SisodiaBengt Winblad

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acetylcholinesterase, minor glycoform

of, in AD brain and CSF 293–9

age-related cognitive decline 143

age-specific dementia, prevalence 11, 12

aging, cognitive functioning and 3

AIT-082, effect on PC12 cells 759–66

Alpha Span Test 102

a1-antitrypsin Portland (a1-PDX) 499

Alzheimer Disease International 13

Alzheimer’s Disease Centers

Neuropsychological Database Initiative

as marker of progression 165microglial activation of post-transla-tional modification 349–50microglial activation promotion345–7

oxidative post-translational tions of 347–9

modifica-production, mechanisms of 421–9soluble and deposited, in AD 311–16synthesis promotion by energy andoxidative stresses 342–5toxicity 407–17

animal models 413–14apoptosis and 412initiation phase, CREB transcrip-tional control and 408–10propagation phase 410–13

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furin-dependence for propeptideprocessing 744

as glycosylated integral membraneprotein 740–42

intramolecular disulfide bonds 742–3N-terminal processing in Golgiapparatus 743

propeptide cleavage 743–4benign senescent forgetfulness 143biological correlates 267, 268, 271biomarkers, CNS 265–71

Boston Naming Test 102bovine spongiform encephalopathy(BSE) 679, 809

Braak staging of neurofibrillary changes

in AD 113brain biometals 396–8BRI 495, 496–7Danish variant, proteolytic proces-sing 501–2

effects of protein convertases onprocessing 499–500furin-mediated endoproteolyticprocessing 497–8

BRI-L, familial British associated 495–503

dementia-furin enhanced processing 498–9Brief Cognitive Rating Scale (BCRS)827–8

Buschke–Fuld test 199Buschke Selective Reminding Test(SRT) 112

butyrylcholinesterase 708butyrylcholinesterase gene (BCHE) 46genotyping 47, 48

K variant gene 35bystander lysis 332

E-cadherin 522, 524, 526, 527–8cadherin cell adhesion complexregulation by presenilin (PS1) 521–8N-cadherin 524, 526, 528

Caenorhabditis elegans presenilin gene62

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capacitative calcium entry, AD-linked

mutant presenilins and 515–18

Caregiver Time Questionnaire 717–18

carers, attitudes, disclosure of diagnosis

cerebral autosomal dominant

arterio-pathy with subcortical infarcts and

APP processing and 442

plasma and CNS cholesterol levels

8q13 39

9 389p22 3910q22 3811q25 39

12 35, 4512p11 3819q13 34, 38clathrin 65Clinical Dementia Rating (CDR) Scale

100, 148co-enzyme Q10 367cognitive functioningaging and 3changes in initial phases of dementia4

characterization and evolution ofdefects 4–7

2–4 years before diagnosis 5–6, 55þ years before diagnosis 6–7, 6course of impairment 7

identification of subjects with clinical and 7–8, 8

pre-complementC1q 333, 336–7C3d 332C4d 332C5b-9 332C9 333, 336–7complement receptor CD11b 333, 337conditional linkage analysis 39Congo red 810

congophilic amyloid angiopathy (CAA)487

Controlled Word Association Test 102,114

copper 396–8SOD neurotoxicity and 399–400coronary stenosis as risk factor 18corticobasal degeneration (CBD) 87phosphorylated tau in 285, 290tau and 71, 74–5, 83

Cox proportional hazards models 135C-reactive protein 333, 335, 342Creutzfeldt–Jakob disease (CJD) 582,

679, 809, 816b-amyloid in 277CSF-tau in 276phosphorylated tau in 289CrmA 412

crystallized intelligence 3

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in discriminating between AD and

dementia with Lewy bodies

285–90

CT 124

Cued Reaction Time 102

Cued Selective Reminding Test 102

Delayed Word Recall Test 102

dementia associated with stroke 205

Dementia Rating Scale 220

dementia with Lewy Bodies

Digit Span Backward 102

Digit Span Forward 102

disclosure of diagnosis, ethics of 321–7

fears 323–4

discriminant analysis 104, 156

dithiothreitol 559dityrosine 346donepezil 130, 160, 707, 708, 725–35,759

efficacy 729–31safety 732Down’s syndrome 342, 490age at onset of menopause 26, 27b-amyloid deposition 373

apolipoprotein E in 25, 26apoptotic mechanisms 414atypical karyotypes 24–5epidemiology in 23–8estrogen deficiency in 26, 28Drosophila presenilin gene (Dps) 61–8genetic modifiers 64–5

interaction with endocytosismachinery 65–6DSIV 124

DSM-IV 206, 219, 225, 226dynamin 65

early onset AD, genes involved in 33–4education as a protective factor 15–17emergency community services, needfor 833–40

prediction of use of 838–8reasons for use 837role of social resources 837–8entorhinal cortex 106–7MRI and 229–344-epichlorotetracycline 812, 813epidemiology 11–18

in Down’s syndrome 23–8episodic memory 3, 4deficits, 5þ years before diagnosis 6estrogen deficiency

in Down’s syndrome 26estrogen replacement therapy (ERT)26

estrogens as protective factor 17ethics of disclosure of diagnosis 321–7Eurodem analysis 11

event-related potentials in AD 242–7Fairhill Guidelines on Ethics of the Care

of People with AD 324familial Alzheimer’s disease (FAD)mutant presenilins attenuating Caentry 515–18

familial amyotrophic lateral sclerosis(FALS) 393–401

Tiêu đề	Alzheimer’s Disease: Advances in Etiology, Pathogenesis and Therapeutics
Tác giả	Khalid Iqbal, Sangram S. Sisodia, Bengt Winblad
Trường học	New York State Institute for Basic Research, New York
Chuyên ngành	Medical Sciences
Thể loại	book
Năm xuất bản	2001
Thành phố	New York

Định dạng
Số trang	846
Dung lượng	9,42 MB