Alzheimer’sDisease:AdvancesinEtiology,PathogenesisandTherapeutics EditedbyKhalidIqbal,SangramS.SisodiaandBengtWinblad Copyright&2001 JohnWiley&SonsLtd Alzheimer’s Disease ADVANCES IN ETIOLOGY, PATHOGENESIS AND THERAPEUTICS Alzheimer’sDisease:AdvancesinEtiology,PathogenesisandTherapeutics EditedbyKhalidIqbal,SangramS.SisodiaandBengtWinblad Copyright&2001 JohnWiley&SonsLtd This publication was supported by an educational grant from Janssen Pharmaceutica and Janssen Research Foundation Alzheimer’sDisease:AdvancesinEtiology,PathogenesisandTherapeutics EditedbyKhalidIqbal,SangramS.SisodiaandBengtWinblad Copyright&2001 JohnWiley&SonsLtd Alzheimer’s Disease ADVANCES IN ETIOLOGY, PATHOGENESIS AND THERAPEUTICS Edited by KHALID IQBAL New York State Institute for Basic Research, New York, USA SANGRAM S. SISODIA University of Chicago, Chicago, USA BENGT WINBLAD Karolinska Institute, Stockholm, Sweden JOHN WILEY & SONS, LTD Chichester . New York . Weinheim . Brisbane . Singapore . Toronto Alzheimer’sDisease:AdvancesinEtiology,PathogenesisandTherapeutics EditedbyKhalidIqbal,SangramS.SisodiaandBengtWinblad Copyright&2001 JohnWiley&SonsLtd Copyright&2001JohnWiley&SonsLtd. 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Includesbibliographicalreferencesandindex. ISBN0-471-52176-0(cased:alk.paper) 1.Alzheimer’sdisease—Congresses. I.Iqbal,Khalid. II.Sisodia,SangramS. III.Winblad,Bengt. IV.InternationalConferenceonAlzheimer’sDiseasesand RelatedDisorders(7th:2000:Washington,D.C.) [DNLM: 1.AlzheimerDisease—etiology—Congresses. 2.AlzheimerDisease— pathology—Congresses. 3.AlzheimerDisease—therapy—Congresses.WT155A47572001] RC523A37532001 616.8’31—dc21 00–067218 BritishLibraryCataloguinginPublicationData AcataloguerecordforthisbookisavailablefromtheBritishLibrary ISBN0-471-52176-0 Typesetfromauthors’disksin10on12pointPlantinby DobbieTypesettingLimited,Tavistock,Devon PrintedandboundinGreatBritainbyBiddlesLtd,GuildfordandKing’sLynn Thisbookisprintedonacid-freepaperresponsiblymanufacturedfromsustainableforestry, inwhichatleasttwotreesareplantedforeachoneusedforpaperproduction. Alzheimer’sDisease:AdvancesinEtiology,PathogenesisandTherapeutics EditedbyKhalidIqbal,SangramS.SisodiaandBengtWinblad Copyright&2001 JohnWiley&SonsLtd Contents List of Contributors xii Dedications xxvi Scientists HonoredforPioneering Research xxix Preface xxxv Acknowledgments xxxvi I. EPIDEMIOLOGYANDRISKFACTORS 1 1. The Transition from NormalFunctioning to Dementia in theAgingPopulation Laura Fratiglioni, BrentSmall, Bengt Winblad andLarsBa¨ckman 3 2. Epidemiology of Alzheimer’s Diseaseand Dementia: Advances and Challenges Robert Katzman 11 3. Epidemiology of DementiainDown’sSyndrome Nicole Schupf 23 II. GENETICS 31 4. A GenomicSearch forAlzheimer’s Disease Genes Jonathan L.Haines, L.Renee Bailey, Janet M.Grubber, DaleHedges, Jenifer L. Hall,SandraWest, Leonard Santoro, BethKemmerer, AnneM.Saunders, Allen D. Roses,Gary W.Small,William K.Scott, P. Michael Conneally,Jeffery M.VanceandMargaret A. Pericak-Vance 33 5. Candidate Genes ShowingNo Evidenceof Association with Alzheimer’s Disease: Results oftheNIMH-AD GeneticsInitiative Lars Bertram, Deborah Blacker, AdamS. Crystal, Jennifer Jones, Devon Keeney,Laura A. MacKenzie-Ingano, Kristina Mullin,Sanjay Basu, Stephen Yhu, MelvinMcInnis, Rodney C.P.Go,Aleister J.Saunders and RudolphE.Tanzi 45 6. Familial Alzheimer’s Diseasewith SpasticParaparesis Associated with aMutation atCodon 261 ofthePresenilin 1Gene Martin R.Farlow, Jill R.Murrell, Frederick W.Unverzagt, Michael Phillips, Masaki Takao,Christine Hulette andBernardino Ghetti 53 7. Genetic Analysis ofthe PresenilinPathway inDrosophila Izhar Livne-Bar andGabrielle L.Boulianne 61 8. Molecular Geneticsand TransgenicModeling oftheTauopathies Jada Lewis,MattBaker, Marjon VanSlegtenhorst andMike Hutton 71 9. Regulation of Four-repeat tauExpression: Interactions between ExonandIntron Splicing RegulatorySequences Ian D’Souza andGerard D.Schellenberg 87 vi CONTENTS III. DIAGNOSIS ANDCLINICAL COURSE 97 10. Preclinical Prediction ofAD:Relation BetweenNeuropsychological and Neuroimaging Findings Marilyn S. Albert, Ronald J.Killiany,Keith Johnson, RudolphE.Tanzi andKenneth Jones 99 11. Neuropsychological Detectionof Preclinical Alzheimer’s Disease: Results ofa Neuropathological Seriesof‘Normal’ Controls Kathleen A. Welsh-Bohmer, Christine Hulette, Donald Schmechel, James Burkeand AnnSaunders 111 12. Potentially Reversible Conditions inMemory ClinicPatients Anne-Mette Hejl, PeterHøgh andGunhild Waldemar 123 13. The Alzheimer’s Disease Centers’ Neuropsychological Database Initiative: AResource forAlzheimer’s DiseasePrevention Trials Michael Grundman, Hyun T.Kim, David Salmon,Martha Storandt, Glenn Smith, StevenFerris, Richard Mohs, JasonBrandt, Rachelle Doody,Kathleen Welsh-Bohmer, Judith Saxton,Kathy Saine, Frederick Schmitt, Paula Ogrocki, NancyJohnson, DianeHowieson, Michelle Papka,Joanne Green, Anthony Gamst,Walter Kukull and Leon J.Thal, fortheAlzheimer’s Disease Centers’ Neuropsychological Database Initiative 129 14. Mild Cognitive Impairment: Transition from Agingto Alzheimer’s Disease Ronald C. Petersen 141 15. Brain FunctionalImaging inEarlyand Preclinical Alzheimer’s Disease Agneta Nordberg,Vesna Jelic,EvaArna´iz, Bengt La˚ngstro¨m andOveAlmkvist 153 16. Amyloid, PHF-tau, Ubiquitinand Synaptic Markersinthe Progression ofAlzheimer’s Disease: Immunochemical Analyses of FrontalCortex from ProspectivelyStudied Elderly Humans D. S. Wang,E.Cochran, D.Bennett, E.Mufson, C.Eckman andD. W.Dickson 165 17. Imaging theConsequences of Alzheimer’s DiseasePathology Yaakov Stern andScottSmall 181 18. Influence ofapoE Genotype andPET BrainImaging on Preclinical Prediction ofAlzheimer’s Disease Gary W.Small,Linda M.Ercoli, DanielH.S.Silverman, S.-C.Huang, Susan Y.Bookheimer, Helen Lavretsky, KarenMiller, Prabha Siddarth, John C.Mazziotta, AnnM.Saunders, MargaretA. Pericak-Vance, Allen D. Roses,Jorge R.Barrio andMichael E.Phelps 193 19. Overview ofVascular Dementia William R. Markesbery 205 20. Clinical and Imaging Characteristics ofVascular Dementiain a Memory Clinic F. Pasquier, X. Douay,C. Delmaire,F. LebertandJ.P. Pruvo 219 21. MRI ofEntorhinal Cortex andHippocampus inAlzheimer’s Disease, Subcortical Ischemic Vascular Dementiaand Mixed Dementia N. Schuff, A.T. Du,D. Amend,Y. Y. Hsu, M.P.Laakso, W.Jagust, H. C.Chui andM.W.Weiner 229 CONTENTS vii 22. Olfactory Function and Event-related Potentials inAlzheimer’s Disease Claire Murphy andCharlieD. Morgan 237 23. Phenotypic Differences in CholinergicMarkerswithinthe Nucleus BasalisinIndividuals withMild Cognitive Impairment Elliott J.Mufson, Michele Gilmor, Shuang Y.Ma, AlanI.Levey and JeffreyH.Kordower 253 24. Evaluating CNSBiomarkers forAlzheimer’s Disease John H.Growdon 265 25. CSFMarkersfor EarlyAlzheimer’s Disease Kaj Blennow, Pia Davidsson andEugeen Vanmechelen 275 26. CSF-Phospho-tau (181P) asa PromisingMarkerfor Discriminating Alzheimer’s Disease from Dementiawith LewyBodies E.Vanmechelen, E.Van Kerschaver, K.Blennow, P.P. DeDeyn,D. Galasko, L. Parnetti, C.J.M.Sindic,H.Arai, M.Riemenschneider, H. Hampel, H. Pottel, A.Valgaeren, F.Hulstaert andH.Vanderstichele 285 27. Increased Levelsof aMinor Glycoform ofAcetylcholinesterase in Alzheimer’s DiseaseBrain andCerebrospinal Fluid Javier Sa´ez-Valero, SuSan Mok,LisaFodero, Alberto Marcos, Maria-Sagrario Barquero, Catriona McLean andDavidH. Small 293 28. Plasma b-Amyloid asa SurrogateGenetic Marker inLate-onset Alzheimer’s Disease Nilufer Ertekin Taner, Neill Graff-Radford, Linda H. Younkin, Christopher Eckman, Jennifer Adamson,DanielJ.Schaid, John Blangero, Michael Hutton andSteven G.Younkin 303 29. Levels ofTotal and Deposited Abare Correlated with Dementia S. Parvathy, J.Naslund, V.Haroutunian andJ.D. Buxbaum 311 30. WhatShould WeTell PatientsAttendinga Memory Disorders Clinic AboutTheir Diagnosis? Conor P.Maguire andRebecca M.Slinn 319 IV. MECHANISMSOF NEURODEGENERATION 329 31. Innate Immunity,Autotoxicity andDegenerative Neurologies Patrick L.McGeer, KojuYasojima andEdith G. McGeer 331 32. Neuroinflammatory Responses intheAlzheimer’s DiseaseBrain Promote theOxidativePost-translational Modificationof Amyloid Deposits Craig S. Atwood, Xudong Huang,Robert D. Moir, MarkA. Smith, Rudolph E.Tanzi, AlexE.Roher, Ashley I.Bushand GeorgePerry 341 33. Plasma Antioxidantsand OxidativeDNA Damage inLymphocytes from Normal AgedPeople andAlzheimer’s Disease Patients Patrizia Mecocci,MariaCristina Polidori, Tiziana Ingegni, PaolaMattioli, Antonio Cherubini, Marco Catani,Roberta Cecchetti andUmberto Senin 363 34. Oxidative Damageand Antioxidant Responses inAlzheimer’s Disease George Perry, AkihikoNunomura, Jesus Avila, MarPerez, Catherine A.Rottkamp, Craig S. Atwood, Xiongwei Zhu,Gjumrakch Aliev, Adam D.Cashand MarkA. Smith 371 viii CONTENTS 35. Cyclooxygenase (COX)-2 andClinical Progression ofAlzheimer’s Disease Dementia:Implications intheRole ofNeuronal COX-2 in CellCycle Giulio MariaPasinetti 379 36. Parallels betweenthe Redox Propertiesand ToxicityofAb in Alzheimer’s Disease andMutant Cu/Zn-SODin Familial Amyotrophic LateralSclerosis Ashley I.Bush 393 37. b-Amyloid Toxicity:Diverse Biological Activities DriveMultiple Cellular Mechanisms C.W.Cotman, L.Tong, A. Anderson,D. Cribbsand J.Su 407 38. Mechanisms ofAb Production and AbDegradation: Routesto theTreatment ofAlzheimer’s Disease D. J.Selkoe,W.Xia, W.T. Kimberly, K.Vekrellis,D. Walsh, W.P. EslerandM.S. Wolfe 421 39. A HighFat,HighCholesterol DietAccelerates b-Amyloid Accumulation in theCNSof aTransgenic MouseModel of Alzheimer’s Disease Lorenzo M.Refolo, BrianMalester, JohnLaFrancois, Tara Bryant-Thomas, Rong Wang,G.Stephen Tint, Kumar Sambamurti, KarenDuffand Miguel A. Pappolla 433 40. Electron Microscopy and X-rayDiffractionStudies furtherConfirm theEfficacy ofPTI-00703TM1 (Cat’sClaw Derivative)as a Potential InhibitorofAlzheimer’s b-Amyloid Protein Fibrillogenesis Gerardo M.Castillo, DanielA.Kirschner, AnnG.Yee andAlanD. Snow 449 41. Accelerated Ab Generation ina Cell Model ofAlzheimer’s Disease-related Endosomal–Lysosomal SystemUpregulation PaulM.Mathews, Carolyn B. Guerra, Ying Jiang, Benjamin H.Kao, Ravi Dinakar, Pankaj Mehta,AnneM.Cataldo andRalph A.Nixon 461 42. The Amyloid Precursor ProteinV717I MutationIncreases Susceptibility to Cell Deathina Cholesterol-dependent Manner Luigi Puglielli, Laura A.MacKenzie Ingano, RudolphE.Tanzi and Dora M.Kovacs 469 43. Intracellular andSecreted Ab Ratios AreDifferently 42/40 Influenced byAPPMutations Heike S. Grimm, StefanF. Lichtenthaler, Konrad Beyreuther andTobias Hartmann 479 44. Familial BritishDementia Jorge Ghiso, TamasRe´ve´sz,AguedaRostagno, RubenVidal, Gordon Plantand Blas Frangione 487 45. Cellular Metabolism ofFamilialBritishDementia-associated BRI-L Seong-Hun KimandSangram S. Sisodia 495 46. A DecamerDuplication inthe BRIGene Originatesa denovo Amyloid Peptide thatCauses Dementiaina Danish Kindred RubenG. Vidal, TamasRe´ve´sz,AguedaRostagno, Toke Bek, Hans Braendgaard, Gordon Plant, JorgeGhiso andBlas Frangione 507 47. Familial Alzheimer’s Disease-linkedMutant Presenilins Attenuate Capacitative CalciumEntry Isaac Cheng,AndrewS. Yoo,Rudolph E.TanziandTae-Wan Kim 515