Alzheimer's Disease: Advances in Etiology, Pathogenesis and Therapeutics

List of Contributors xii

Dedications xxvi

Scientists Honored for Pioneering Research xxix

Preface xxxv

Acknowledgments xxxvi

I. EPIDEMIOLOGY AND RISK FACTORS 1

1. The Transition from Normal Functioning to Dementia in the Aging Population 3
Laura Fratiglioni, Brent Small, Bengt Winblad and Lars Bäckman

2. Epidemiology of Alzheimer’s Disease and Dementia: Advances and Challenges 11
Robert Katzman

3. Epidemiology of Dementia in Down’s Syndrome 23
Nicole Schupf

II. GENETICS 31

4. A Genomic Search for Alzheimer’s Disease Genes 33
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, P. Michael Conneally, Jeffery M. Vance and Margaret A. Pericak-Vance

5. Candidate Genes Showing No Evidence of Association with Alzheimer’s Disease: Results of the NIMH-AD Genetics Initiative 45
Lars 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 and Rudolph E. Tanzi

6. Familial Alzheimer’s Disease with Spastic Paraparesis Associated with a Mutation at Codon 261 of the Presenilin 1 Gene 53
Martin R. Farlow, Jill R. Murrell, Frederick W. Unverzagt, Michael Phillips, Masaki Takao, Christine Hulette and Bernardino Ghetti

7. Genetic Analysis of the Presenilin Pathway in Drosophila 61
Izhar Livne-Bar and Gabrielle L. Boulianne

8. Molecular Genetics and Transgenic Modeling of the Tauopathies 71
Jada Lewis, Matt Baker, Marjon Van Slegtenhorst and Mike Hutton

9. Regulation of Four-repeat tau Expression: Interactions between Exon and Intron Splicing Regulatory Sequences 87
Ian D’Souza and Gerard D. Schellenberg

III. DIAGNOSIS AND CLINICAL COURSE 97

10. Preclinical Prediction of AD: Relation Between Neuropsychological and Neuroimaging Findings 99
Marilyn S. Albert, Ronald J. Killiany, Keith Johnson, Rudolph E. Tanzi and Kenneth Jones

11. Neuropsychological Detection of Preclinical Alzheimer’s Disease: Results of a Neuropathological Series of ‘Normal’ Controls 111
Kathleen A. Welsh-Bohmer, Christine Hulette, Donald Schmechel, James Burke and Ann Saunders

12. Potentially Reversible Conditions in Memory Clinic Patients 123
Anne-Mette Hejl, Peter Høgh and Gunhild Waldemar

13. The Alzheimer’s Disease Centers’ Neuropsychological Database Initiative: A Resource for Alzheimer’s Disease Prevention Trials 129
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 Database Initiative

14. Mild Cognitive Impairment: Transition from Aging to Alzheimer’s Disease 141
Ronald C. Petersen

15. Brain Functional Imaging in Early and Preclinical Alzheimer’s Disease 153
Agneta Nordberg, Vesna Jelic, Eva Arnáiz, Bengt Långström and Ove Almkvist

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 165
D. S. Wang, E. Cochran, D. Bennett, E. Mufson, C. Eckman and D. W. Dickson

17. Imaging the Consequences of Alzheimer’s Disease Pathology 181
Yaakov Stern and Scott Small

18. Influence of apoE Genotype and PET Brain Imaging on Preclinical Prediction of Alzheimer’s Disease 193
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, Allen D. Roses, Jorge R. Barrio and Michael E. Phelps

19. Overview of Vascular Dementia 205
William R. Markesbery

20. Clinical and Imaging Characteristics of Vascular Dementia in a Memory Clinic 219
F. Pasquier, X. Douay, C. Delmaire, F. Lebert and J. P. Pruvo

21. MRI of Entorhinal Cortex and Hippocampus in Alzheimer’s Disease, Subcortical Ischemic Vascular Dementia and Mixed Dementia 229
N. Schuff, A. T. Du, D. Amend, Y. Y. Hsu, M. P. Laakso, W. Jagust, H. C. Chui and M. W. Weiner

22. Olfactory Function and Event-related Potentials in Alzheimer’s Disease 237
Claire Murphy and Charlie D. Morgan

23. Phenotypic Differences in Cholinergic Markers within the Nucleus Basalis in Individuals with Mild Cognitive Impairment 253
Elliott J. Mufson, Michele Gilmor, Shuang Y. Ma, Alan I. Levey and Jeffrey H. Kordower

24. Evaluating CNS Biomarkers for Alzheimer’s Disease 265
John H. Growdon

25. CSF Markers for Early Alzheimer’s Disease 275
Kaj Blennow, Pia Davidsson and Eugeen Vanmechelen

26. CSF-Phospho-tau (181P) as a Promising Marker for Discriminating Alzheimer’s Disease from Dementia with Lewy Bodies 285
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, H. Pottel, A. Valgaeren, F. Hulstaert and H. Vanderstichele

27. Increased Levels of a Minor Glycoform of Acetylcholinesterase in Alzheimer’s Disease Brain and Cerebrospinal Fluid 293
Javier Sáez-Valero, Su San Mok, Lisa Fodero, Alberto Marcos, Maria-Sagrario Barquero, Catriona McLean and David H. Small

28. Plasma b-Amyloid as a Surrogate Genetic Marker in Late-onset Alzheimer’s Disease 303
Nilufer Ertekin Taner, Neill Graff-Radford, Linda H. Younkin, Christopher Eckman, Jennifer Adamson, Daniel J. Schaid, John Blangero, Michael Hutton and Steven G. Younkin

29. Levels of Total and Deposited Ab are Correlated with Dementia 311
S. Parvathy, J. Naslund, V. Haroutunian and J. D. Buxbaum

30. What Should We Tell Patients Attending a Memory Disorders Clinic About Their Diagnosis? 319
Conor P. Maguire and Rebecca M. Slinn

IV. MECHANISMS OF NEURODEGENERATION 329

31. Innate Immunity, Autotoxicity and Degenerative Neurologies 331
Patrick L. McGeer, Koju Yasojima and Edith G. McGeer

32. Neuroinflammatory Responses in the Alzheimer’s Disease Brain Promote the Oxidative Post-translational Modification of Amyloid Deposits 341
Craig S. Atwood, Xudong Huang, Robert D. Moir, Mark A. Smith, Rudolph E. Tanzi, Alex E. Roher, Ashley I. Bush and George Perry

33. Plasma Antioxidants and Oxidative DNA Damage in Lymphocytes from Normal Aged People and Alzheimer’s Disease Patients 363
Patrizia Mecocci, Maria Cristina Polidori, Tiziana Ingegni, Paola Mattioli, Antonio Cherubini, Marco Catani, Roberta Cecchetti and Umberto Senin

34. Oxidative Damage and Antioxidant Responses in Alzheimer’s Disease 371
George Perry, Akihiko Nunomura, Jesus Avila, Mar Perez, Catherine A. Rottkamp, Craig S. Atwood, Xiongwei Zhu, Gjumrakch Aliev, Adam D. Cash and Mark A. Smith

35. Cyclooxygenase (COX)-2 and Clinical Progression of Alzheimer’s Disease Dementia: Implications in the Role of Neuronal COX-2 in Cell Cycle 379
Giulio Maria Pasinetti

36. Parallels between the Redox Properties and Toxicity of Ab in Alzheimer’s Disease and Mutant Cu/Zn-SOD in Familial Amyotrophic Lateral Sclerosis 393
Ashley I. Bush

37. b-Amyloid Toxicity: Diverse Biological Activities Drive Multiple Cellular Mechanisms 407
C. W. Cotman, L. Tong, A. Anderson, D. Cribbs and J. Su

38. Mechanisms of Ab Production and Ab Degradation: Routes to the Treatment of Alzheimer’s Disease 421
D. J. Selkoe, W. Xia, W. T. Kimberly, K. Vekrellis, D. Walsh, W. P. Esler and M. S. Wolfe

39. A High Fat, High Cholesterol Diet Accelerates b-Amyloid Accumulation in the CNS of a Transgenic Mouse Model of Alzheimer’s Disease 433
Lorenzo M. Refolo, Brian Malester, John LaFrancois, Tara Bryant-Thomas, Rong Wang, G. Stephen Tint, Kumar Sambamurti, Karen Duff and Miguel A. Pappolla

40. Electron Microscopy and X-ray Diffraction Studies further Confirm the Efficacy of PTI-00703TM1 (Cat’s Claw Derivative) as a Potential Inhibitor of Alzheimer’s b-Amyloid Protein Fibrillogenesis 449
Gerardo M. Castillo, Daniel A. Kirschner, Ann G. Yee and Alan D. Snow

41. Accelerated Ab Generation in a Cell Model of Alzheimer’s Disease-related Endosomal–Lysosomal System Upregulation 461
Paul M. Mathews, Carolyn B. Guerra, Ying Jiang, Benjamin H. Kao, Ravi Dinakar, Pankaj Mehta, Anne M. Cataldo and Ralph A. Nixon

42. The Amyloid Precursor Protein V717I Mutation Increases Susceptibility to Cell Death in a Cholesterol-dependent Manner 469
Luigi Puglielli, Laura A. MacKenzie Ingano, Rudolph E. Tanzi and Dora M. Kovacs

43. Intracellular and Secreted Ab42/40 Ratios Are Differently Influenced by APP Mutations 479
Heike S. Grimm, Stefan F. Lichtenthaler, Konrad Beyreuther and Tobias Hartmann

44. Familial British Dementia 487
Jorge Ghiso, Tamas Révész, Agueda Rostagno, Ruben Vidal, Gordon Plant and Blas Frangione

45. Cellular Metabolism of Familial British Dementia-associated BRI-L 495
Seong-Hun Kim and Sangram S. Sisodia

46. A Decamer Duplication in the BRI Gene Originates a de novo Amyloid Peptide that Causes Dementia in a Danish Kindred 507
Ruben G. Vidal, Tamas Révész, Agueda Rostagno, Toke Bek, Hans Braendgaard, Gordon Plant, Jorge Ghiso and Blas Frangione

47. Familial Alzheimer’s Disease-linked Mutant Presenilins Attenuate Capacitative Calcium Entry 515
Isaac Cheng, Andrew S. Yoo, Rudolph E. Tanzi and Tae-Wan Kim

48. Presenilin-1 Is a Regulatory Component of the Cadherin Cell Adhesion Complex: Implications for Alzheimer’s Disease 521
Anastasio Georgakopoulos, Philippe Marambaud, Nikolaos K. Robakis and Lia Baki

49. Presenilins and Notch Signaling Pathway 531
Weihong Song and Bruce A. Yankner

50. Functional Consequences of the Association of PS1 with b-Catenin 541
Salvador Soriano, David E. Kang, Nathalie Chevallier, Hui Zheng and Edward H. Koo

51. A Novel Protease Active Site Motif Conserved in Presenilins and Polytopic Bacterial Aspartyl Proteases? 549
Harald Steiner and Christian Haass

52. The Unfolded Protein Response-mediated Upregulation of BiP and CHOP Is not Affected by Presenilin Expression 559
Naoyuki Sato and Gopal Thinakaran

53. Mechanisms of a-Synuclein and NAC Fibrillogenesis 569
Makoto Hashimoto, Edward Rockenstein, Takato Takenouchi, Margaret Mallory and Eliezer Masliah

54. Neurofibrillary Degeneration: Patterns of Tau Isoform Expression 587
André Delacourte

55. Phosphorylation, Microtubule Binding and Aggregation of Tau Protein in Alzheimer’s Disease 601
Jesús Ávila, José J. Lucas, Filip Lim, Mar Pérez, Félix Hernández, Montserrat Arrasate, Rosario Armas Portela, Elsa Champion, George Perry, Mark A. Smith and Javier Díaz Nido

56. Phosphorylation of Protein Tau and Rescue of Protein Tau-induced Axonopathy by GSK-3b in GSK-3b6htau40 Double Transgenic Mice 609
Kurt Spittaels, Chris Van den Haute, Jo Van Dorpe, Hugo Geerts and Fred Van Leuven

57. Pathogenic Implication of Altered Tau Properties Caused by FTDP-17 Mutations 621
P. Nacharaju, S. Yen, M. DeTure, C. Easson, M. Hutton and S.-H. Yen

58. A Hexapeptide Motif (306VQIVYK311)-forming b Structure Induces the Aggregation of Tau Protein to Paired Helical Filaments 631
M. von Bergen, J. Biernat, E.-M. Mandelkow and Eckhard Mandelkow

V. ANIMAL AND CELLULAR MODELS 641

59. Formation of Neurofibrillary Tangles in Mouse Brain 643
Akihiko Takashima and Kentaro Tanemura

60. Inducible Transgenic Expression of Wild-type tau in H4 Neuroglioma Cells 651
Michael DeTure, Li-Wen Ko, Colin Easson, Mike Hutton and Shu-Hui Yen

61. Lewy-like Pathology in Mice Transgenic for Mutant (A53T) and Wild-type Human a-Synuclein 661
Bernd Sommer, Samuel Barbieri, Katja Hofele, Karl-Heinz Wiederhold, Alphonse Probst, Claudia Mistl, Simone Danner, Sabine Kauffmann, Willibrordus Spooren, Markus Tolnay, Graeme Bilbe and Herman van der Putten

62. Somal and Neuritic Accumulation of the Parkinson’s Disease-associated Mutant [A30P]a-Synuclein in Transgenic Mice 671
Phillipp J. Kahle, Manuela Neumann, Laurence Ozmen, Hans A. Kretzschmar and Christian Haass

63. Ex vivo Transmission of Mouse-adapted Prion Strains to N2a and GT1-7 Cell Lines 679
Sylvain Lehmann, Hubert Laude, David A. Harris, Richard I. Carp, Didier Vilette, Shigeru Katamine, Jean-Yves Madec and Noriyuki Nishida

64. In Vivo Perturbation of Lysosomal Function Promotes Neurodegeneration in the PS1M146V/APPK670N,M671L Mouse Model of Alzheimer’s Disease Pathology 687
Ralph A. Nixon, Paul M. Mathews, Anne M. Cataldo, Panaiyur S. Mohan, Stephen D. Schmidt, Karen Duff, Martin Berg, Neville Marks, Corinne Peterhoff and Henry Sershen

65. Changes in Cognitive Characteristics of Tg(APP)CRND8 Mice at Early Stages of Immunization with Beta-Amyloid Peptide 697
Christopher Janus, Jacqueline Pearson, Patrick Horne, Richard Renlund, Karen Parisien, Azhar Chishti, Donna Heslin, Catherine Bergeron, Paul Fraser, Peter St George-Hyslop and David Westaway

VI. THERAPEUTICS AND THERAPEUTIC STRATEGIES 705

66. Galantamine, a Novel Treatment for Alzheimer’s Disease: A Review of Long-term Benefits to Patients and Caregivers 707
Pierre Tariot and Bengt Winblad

67. Benefits of Donepezil on Cognition, Function and Neuropsychiatric Symptoms in Patients with Mild and Moderate Alzheimer’s Disease over One Year 725
Gunhild Waldemar, Bengt Winblad, Knut Engedal, Hilkke Soininen, Frans Verhey, Anders Wimo, Anne-Lena Wetterholm, Richard Zhang, Anders Haglund, Ponni Subbiah and the Donepezil Nordic Study Group

68. Characterization of Alzheimer’s b-Secretase Protein BACE: Processing and Other Post-translational Modifications 739
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, Robert Vassar and Martin Citron

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 747
Debomoy K. Lahiri, Yuan-Wen Ge and Martin R. Farlow

71. Generation of Auto-antibodies toward Alzheimer’s Disease Vaccination 759
Beka Solomon and Dan Frenkel

72. Toward the Identification of c-Secretase: Using Transition State Analog Inhibitors 777
William P. Esler, W. Taylor Kimberly, Beth L. Ostaszewski, Weiming Xia, Dennis J. Selkoe and Michael S. Wolfe

73. Photoactivated, Active-site-directed g-Secretase Inhibitors Covalently Label Presenilin 1 789
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 and Jules A. Shafer

74. Functional Analysis of b-Secretase Using Mutagenesis and Structural Homology Modeling 799
Gwen Tatsuno, John Anderson, Jin Hong, David A. Agard, Nobuyuki Ota, Sukanto Sinha, Guriqbal Basi and Lisa McConlogue

75. Therapeutic Approaches to Prion Diseases: In Vitro Studies with Tetracycline Compounds 809
Tazeen Awan, Gianluigi Forloni, Enzio Ragg, Selina Iussich, Giacomina Rossi, Laura Colombo, Laura Girola, Tania Massignan, Orso Bugiani, Mario Salmona and Fabrizio Tagliavini

VII. PSYCHOSOCIAL CARE 821

76. Influence of a Memory Training Program on Attention and Memory Performance of Patients with Dementia 823
Tanja Bernhardt, Konrad Maurer and Lutz Frölich

77. Prediction of Use of Emergency Community Services by Cognitively Impaired Seniors who Live Alone: Preliminary Findings of a Prospective Study 833
Mary C. Tierney, Jocelyn Charles, W. Gary Snow, John P. Szalai, Susan Jaglal, Franca Spizzirri and Rory H. Fisher

Index 835