Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Acta Neuropathologica Communications
Published in: Acta Neuropathologica Communications 1/2014

Open Access 01-12-2014 | Review

Inconsistencies and Controversies Surrounding the Amyloid Hypothesis of Alzheimer's Disease

Authors: Gary P Morris, Ian A Clark, Bryce Vissel

Published in: Acta Neuropathologica Communications | Issue 1/2014

Login to get access

Abstract

The amyloid hypothesis has driven drug development strategies for Alzheimer's disease for over 20 years. We review why accumulation of amyloid-beta (Aβ) oligomers is generally considered causal for synaptic loss and neurodegeneration in AD. We elaborate on and update arguments for and against the amyloid hypothesis with new data and interpretations, and consider why the amyloid hypothesis may be failing therapeutically. We note several unresolved issues in the field including the presence of Aβ deposition in cognitively normal individuals, the weak correlation between plaque load and cognition, questions regarding the biochemical nature, presence and role of Aβ oligomeric assemblies in vivo, the bias of pre-clinical AD models toward the amyloid hypothesis and the poorly explained pathological heterogeneity and comorbidities associated with AD. We also illustrate how extensive data cited in support of the amyloid hypothesis, including genetic links to disease, can be interpreted independently of a role for Aβ in AD. We conclude it is essential to expand our view of pathogenesis beyond Aβ and tau pathology and suggest several future directions for AD research, which we argue will be critical to understanding AD pathogenesis.
Appendix
Available only for authorised users
Literature
1.
Glenner GG, Wong CW: Alzheimer's disease: initial report of the purification and characterization of a novel cerebrovascular amyloid protein. Biochem Biophys Res Commun 1984, 120: 885–890.PubMed
2.
Masters CL: Etiology and pathogenesis of Alzheimer's disease. Pathology 1984, 16: 233–234.PubMed
3.
Hardy J, Mayer J: The amyloid cascade hypothesis has misled the pharmaceutical industry. Biochem Soc Trans 2011, 39: 920–923.
4.
Masters CL, Gajdusek DC, Gibbs CJ Jr: The familial occurrence of Creutzfeldt-Jakob disease and Alzheimer's disease. Brain 1981, 104: 535–558.PubMed
5.
Prusiner SB, McKinley MP, Bowman KA, Bolton DC, Bendheim PE, Groth DF, Glenner GG: Scrapie prions aggregate to form amyloid-like birefringent rods. Cell 1983, 35: 349–358.PubMed
6.
Alzheimer A: Ueber eine eigenartige Erkrankung der Hirnrinde. Centralblat fur Nervenheilkunde und Psychiatrie 1907, 30: 177–179.
7.
Castellani RJ, Lee HG, Zhu X, Perry G, Smith MA: Alzheimer disease pathology as a host response. J Neuropathol Exp Neurol 2008, 67: 523–531.PubMedPubMedCentral
8.
Allsop D, Landon M, Kidd M: The isolation and amino acid composition of senile plaque core protein. Brain Res 1983, 259: 348–352.PubMed
9.
Masters CL, Simms G, Weinman NA, Multhaup G, McDonald BL, Beyreuther K: Amyloid plaque core protein in Alzheimer disease and Down syndrome. Proc Natl Acad Sci U S A 1985, 82: 4245–4249.PubMedPubMedCentral
10.
Grundke-Iqbal I, Iqbal K, Tung YC, Quinlan M, Wisniewski HM, Binder LI: Abnormal phosphorylation of the microtubule-associated protein tau (tau) in Alzheimer cytoskeletal pathology. Proc Natl Acad Sci U S A 1986, 83: 4913–4917.PubMedPubMedCentral
11.
Yankner BA, Dawes LR, Fisher S, Villa-Komaroff L, Oster-Granite ML, Neve RL: Neurotoxicity of a fragment of the amyloid precursor associated with Alzheimer's disease. Science 1989, 245: 417–420.PubMed
12.
Kang J, Lemaire HG, Unterbeck A, Salbaum JM, Masters CL, Grzeschik KH, Multhaup G, Beyreuther K, Muller-Hill B: The precursor of Alzheimer's disease amyloid A4 protein resembles a cell-surface receptor. Nature 1987, 325: 733–736.PubMed
13.
Zigman WB, Devenny DA, Krinsky-McHale SJ, Jenkins EC, Urv TK, Wegiel J, Schupf N, Silverman W: Alzheimer's Disease in Adults with Down Syndrome. Int Rev Res Mental Retardation 2008, 36: 103–145.
14.
Levy E, Carman M, Fernandez-Madrid I, Power MD, Lieberburg I, van Duinen SG, Bots GT, Luyendijk W, Frangione B: Mutation of the Alzheimer's disease amyloid gene in hereditary cerebral hemorrhage, Dutch type. Science 1990, 248: 1124–1126.PubMed
15.
Levy-Lahad E, Wasco W, Poorkaj P, Romano DM, Oshima J, Pettingell WH, Yu CE, Jondro PD, Schmidt SD, Wang K, Crowley AC, Fu YH, Guenette SY, Galas D, Nemens E, Wijsman EM, Bird TD, Schellenberg GD, Tanzi RE: Candidate gene for the chromosome 1 familial Alzheimer's disease locus. Science 1995, 269: 973–977.PubMed
16.
Sherrington R, Rogaev EI, Liang Y, Rogaeva EA, Levesque G, Ikeda M, Chi H, Lin C, Li G, Holman K, Tsuda T, Mar L, Foncin JF, Bruni AC, Montesi MP, Sorbi S, Rainero I, Pinessi L, Nee L, Chumakov I, Pollen D, Brookes A, Sanseau P, Polinsky RJ, Wasco W, Da Silva HAR, Haines JL, Pericak-Vance MA, Tanzi RE, Roses AD, et al.: Cloning of a gene bearing missense mutations in early-onset familial Alzheimer's disease. Nature 1995, 375: 754–760.PubMed
17.
Dimitrov M, Alattia J-R, Lemmin T, Lehal R, Fligier A, Houacine J, Hussain I, Radtke F, Dal Peraro M, Beher D, Fraering PC: Alzheimer’s disease mutations in APP but not γ-secretase modulators affect epsilon-cleavage-dependent AICD production. Nat Commun 2013, 4: 2246.PubMed
18.
Games D, Adams D, Alessandrini R, Barbour R, Borthelette P, Blackwell C, Carr T, Clemens J, Donaldson T, Gillespie F, Guido T, Hagopian S, Johnson-Wood K, Khan K, Lee M, Leibowitz P, Lieberburg I, Little S, Masliah E, Mcconlogue L, Montoya-Zavala M, Mucke L, Paganini L, Penniman E, Power M, Schenk D, Seubert P, Snyder B, Soriano F, Tan H, et al.: Alzheimer-type neuropathology in transgenic mice overexpressing V717F beta-amyloid precursor protein. Nature 1995, 373: 523–527.PubMed
19.
Pike CJ, Burdick D, Walencewicz AJ, Glabe CG, Cotman CW: Neurodegeneration induced by β-amyloid peptides in vitro: The role of peptide assembly state. J Neurosci 1993, 13: 1676–1687.PubMed
20.
Ittner LM, Gotz J: Amyloid-beta and tau’a toxic pas de deux in Alzheimer's disease. Nat Rev Neurosci 2011, 12: 65–72.PubMed
21.
Thies W, Bleiler L: 2011 Alzheimer's disease facts and figures. Alzheimer's and Dementia 2011, 7: 208–244.
22.
Corder EH, Saunders AM, Strittmatter WJ, Schmechel DE, Gaskell PC, Small GW, Roses AD, Haines JL, Pericak-Vance MA: Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families. Science 1993, 261: 921–923.PubMed
23.
Jonsson T, Atwal JK, Steinberg S, Snaedal J, Jonsson PV, Bjornsson S, Stefansson H, Sulem P, Gudbjartsson D, Maloney J, Hoyte K, Gustafson A, Liu Y, Lu Y, Bhangale T, Graham RR, Huttenlocher J, Bjornsdottir G, Andreassen OA, Jonsson EG, Palotie A, Behrens TW, Magnusson OT, Kong A, Thorsteinsdottir U, Watts RJ, Stefansson K: A mutation in APP protects against Alzheimer/'s disease and age-related cognitive decline. Nature 2012, 488: 96–99.PubMed
24.
Uylings HBM, de Brabander JM: Neuronal Changes in Normal Human Aging and Alzheimer's Disease. Brain Cogn 2002, 49: 268–276.PubMed
25.
Conforti L, Adalbert R, Coleman MP: Neuronal death: where does the end begin? Trends Neurosci 2007, 30: 159–166.PubMed
26.
William CM, Andermann ML, Goldey GJ, Roumis DK, Reid RC, Shatz CJ, Albers MW, Frosch MP, Hyman BT: Synaptic plasticity defect following visual deprivation in Alzheimer's disease model transgenic mice. J Neurosci 2012, 32: 8004–8011.PubMedPubMedCentral
27.
Masliah E, Mallory M, Alford M, De Teresa R, Hansen LA, McKeel DW Jr, Morris JC: Altered expression of synaptic proteins occurs early during progression of Alzheimer's disease. Neurology 2001, 56: 127–129.PubMed
28.
Terry RD, Masliah E, Salmon DP, Butters N, DeTeresa R, Hill R, Hansen LA, Katzman R: Physical basis of cognitive alterations in alzheimer's disease: Synapse loss is the major correlate of cognitive impairment. Ann Neurol 1991, 30: 572–580.PubMed
29.
Davies CA, Mann DM, Sumpter PQ, Yates PO: A quantitative morphometric analysis of the neuronal and synaptic content of the frontal and temporal cortex in patients with Alzheimer's disease. J Neurol Sci 1987, 78: 151–164.PubMed
30.
Mesulam MM: A Plasticity-Based Theory of the Pathogenesis of Alzheimer's Disease. Ann N Y Acad Sci 2000, 924: 42–52.PubMed
31.
Selkoe DJ: Alzheimer's disease is a synaptic failure. Science 2002, 298: 789–791.PubMed
32.
Bittner T, Burgold S, Dorostkar MM, Fuhrmann M, Wegenast-Braun BM, Schmidt B, Kretzschmar H, Herms J: Amyloid plaque formation precedes dendritic spine loss. Acta Neuropathol 2012, 124: 797–807.PubMedPubMedCentral
33.
Lacor PN, Buniel MC, Furlow PW, Clemente AS, Velasco PT, Wood M, Viola KL, Klein WL: Aβ Oligomer-Induced Aberrations in Synapse Composition, Shape, and Density Provide a Molecular Basis for Loss of Connectivity in Alzheimer's Disease. J Neurosci 2007, 27: 796–807.PubMed
34.
Calabrese B, Shaked GM, Tabarean IV, Braga J, Koo EH, Halpain S: Rapid, concurrent alterations in pre- and postsynaptic structure induced by naturally-secreted amyloid-beta protein. Mol Cell Neurosci 2007, 35: 183–193.PubMedPubMedCentral
35.
Evans NA, Facci L, Owen DE, Soden PE, Burbidge SA, Prinjha RK, Richardson JC, Skaper SD: Abeta(1–42) reduces synapse number and inhibits neurite outgrowth in primary cortical and hippocampal neurons: a quantitative analysis. J Neurosci Methods 2008, 175: 96–103.PubMed
36.
Shankar GM, Bloodgood BL, Townsend M, Walsh DM, Selkoe DJ, Sabatini BL: Natural oligomers of the Alzheimer amyloid-beta protein induce reversible synapse loss by modulating an NMDA-type glutamate receptor-dependent signaling pathway. J Neurosci 2007, 27: 2866–2875.PubMed
37.
Shrestha BR, Vitolo OV, Joshi P, Lordkipanidze T, Shelanski M, Dunaevsky A: Amyloid beta peptide adversely affects spine number and motility in hippocampal neurons. Mol Cell Neurosci 2006, 33: 274–282.PubMed
38.
Wei W, Nguyen LN, Kessels HW, Hagiwara H, Sisodia S, Malinow R: Amyloid beta from axons and dendrites reduces local spine number and plasticity. Nat Neurosci 2010, 13: 190–196.PubMed
39.
Westmark CJ: What's hAPPening at synapses? The role of amyloid beta-protein precursor and beta-amyloid in neurological disorders. Mol Psychiatry 2012, 18: 425–434.PubMed
40.
Shankar GM, Li S, Mehta TH, Garcia-Munoz A, Shepardson NE, Smith I, Brett FM, Farrell MA, Rowan MJ, Lemere CA, Regan CM, Walsh DM, Sabatini BL, Selkoe DJ: Amyloid-beta protein dimers isolated directly from Alzheimer's brains impair synaptic plasticity and memory. Nat Med 2008, 14: 837–842.PubMedPubMedCentral
41.
Brouillette J, Caillierez R, Zommer N, Alves-Pires C, Benilova I, Blum D, De Strooper B, Buée L: Neurotoxicity and Memory Deficits Induced by Soluble Low-Molecular-Weight Amyloid-β1-42 Oligomers Are Revealed In Vivo by Using a Novel Animal Model. J Neurosci 2012, 32: 7852–7861.PubMed
42.
Lanz TA, Carter DB, Merchant KM: Dendritic spine loss in the hippocampus of young PDAPP and Tg2576 mice and its prevention by the ApoE2 genotype. Neurobiol Dis 2003, 13: 246–253.PubMed
43.
Boncristiano S, Calhoun ME, Howard V, Bondolfi L, Kaeser SA, Wiederhold KH, Staufenbiel M, Jucker M: Neocortical synaptic bouton number is maintained despite robust amyloid deposition in APP23 transgenic mice. Neurobiol Aging 2005, 26: 607–613.PubMed
44.
Spires TL, Meyer-Luehmann M, Stern EA, McLean PJ, Skoch J, Nguyen PT, Bacskai BJ, Hyman BT: Dendritic spine abnormalities in amyloid precursor protein transgenic mice demonstrated by gene transfer and intravital multiphoton microscopy. J Neurosci 2005, 25: 7278–7287.PubMedPubMedCentral
45.
Counts SE, Alldred MJ, Che S, Ginsberg SD, Mufson EJ: Synaptic gene dysregulation within hippocampal CA1 pyramidal neurons in mild cognitive impairment. Neuropharmacology 2014, 79: 172–179.PubMed
46.
Morris GP, Clark IA, Zinn R, Vissel B: Microglia: A new frontier for synaptic plasticity, learning and memory, and neurodegenerative disease research. Neurobiol Learn Mem 2013, 105: 40–53.PubMed
47.
Schenk D, Barbour R, Dunn W, Gordon G, Grajeda H, Guido T, Hu K, Huang J, Johnson-Wood K, Khan K, Kholodenko D, Lee M, Liao Z, Lieberburg I, Motter R, Mutter L, Soriano F, Shopp G, Vasquez N, Vandevert C, Walker S, Wogulis M, Yednock T, Games D, Seubert P: Immunization with amyloid-[beta] attenuates Alzheimer-disease-like pathology in the PDAPP mouse. Nature 1999, 400: 173–177.PubMed
48.
Lobello K, Ryan JM, Liu E, Rippon G, Black R: Targeting Beta Amyloid: A Clinical Review of Immunotherapeutic Approaches in Alzheimer’s Disease. Int J Alzheimers Dis 2012, 2012: 628070.PubMedPubMedCentral
49.
Boche D, Donald J, Love S, Harris S, Neal JW, Holmes C, Nicoll JA: Reduction of aggregated Tau in neuronal processes but not in the cell bodies after Abeta42 immunisation in Alzheimer's disease. Acta Neuropathol 2010, 120: 13–20.PubMed
50.
Nicoll JA, Wilkinson D, Holmes C, Steart P, Markham H, Weller RO: Neuropathology of human Alzheimer disease after immunization with amyloid-beta peptide: a case report. Nat Med 2003, 9: 448–452.PubMed
51.
Winblad B, Andreasen N, Minthon L, Floesser A, Imbert G, Dumortier T, Maguire RP, Blennow K, Lundmark J, Staufenbiel M, Orgogozo JM, Graf A: Safety, tolerability, and antibody response of active Abeta immunotherapy with CAD106 in patients with Alzheimer's disease: randomised, double-blind, placebo-controlled, first-in-human study. Lancet Neurol 2012, 11: 597–604.PubMed
52.
Arai H, Suzuki H, Yoshiyama T, Lobello K, Peng Y, Liu E, Ketter N, Margolin R, Jackson N, Fujimoto Y: Safety, tolerability and immunogenicity of an immunotherapeutic vaccine (vanutide cridificar [ACC-001]) and the QS-21 adjuvant in Japanese individuals with mild-to-moderate Alzheimer's disease: A phase IIa, multicenter, randomized, adjuvant and placebo clinical trial. Alzheimers Dement 2013, 9: P282.
53.
54.
Doody RS, Thomas RG, Farlow M, Iwatsubo T, Vellas B, Joffe S, Kieburtz K, Raman R, Sun X, Aisen PS, Siemers E, Liu-Seifert H, Mohs R: Phase 3 Trials of Solanezumab for Mild-to-Moderate Alzheimer's Disease. N Engl J Med 2014, 370: 311–321.PubMed
55.
Salloway S, Sperling R, Fox NC, Blennow K, Klunk W, Raskind M, Sabbagh M, Honig LS, Porsteinsson AP, Ferris S, Reichert M, Ketter N, Nejadnik B, Guenzler V, Miloslavsky M, Wang D, Lu Y, Lull J, Tudor IC, Liu E, Grundman M, Yuen E, Black R, Brashear HR: Two Phase 3 Trials of Bapineuzumab in Mild-to-Moderate Alzheimer's disease. N Engl J Med 2014, 370: 322–333.PubMedPubMedCentral
56.
Ostrowitzki S, Deptula D, Thurfjell L, Barkhof F, Bohrmann B, Brooks DJ, Klunk WE, Ashford E, Yoo K, Xu ZX, Loetscher H, Santarelli L: Mechanism of amyloid removal in patients with Alzheimer disease treated with gantenerumab. Arch Neurol 2012, 69: 198–207 D.PubMed
57.
Roche IU: Roche announces phase II clinical results of crenezumab in Alzheimer’s disease. 2014.
58.
La Porte SL, Bollini SS, Lanz TA, Abdiche YN, Rusnak AS, Ho WH, Kobayashi D, Harrabi O, Pappas D, Mina EW, Milici AJ, Kawabe TT, Bales K, Lin JC, Pons J: Structural basis of C-terminal beta-amyloid peptide binding by the antibody ponezumab for the treatment of Alzheimer's disease. J Mol Biol 2012, 421: 525–536.PubMed
59.
Coric V, van Dyck CH, Salloway S, Andreasen N, Brody M, Richter RW, Soininen H, Thein S, Shiovitz T, Pilcher G, Colby S, Rollin L, Dockens R, Pachai C, Portelius E, Andreasson U, Blennow K, Soares H, Albright C, Feldman HH, Berman RM: Safety and tolerability of the gamma-secretase inhibitor avagacestat in a phase 2 study of mild to moderate Alzheimer disease. Arch Neurol 2012, 69: 1430–1440.PubMed
60.
Doody RS, Raman R, Farlow M, Iwatsubo T, Vellas B, Joffe S, Ieburtz K, He F, Sun X, Thomas RG, Aisen PS, Siemers E, Sethuraman G, Mohs R: A phase 3 trial of semagacestat for treatment of Alzheimer's disease. N Engl J Med 2013, 369: 341–350.PubMed
61.
Ross J, Sharma S, Winston J, Nunez M, Bottini G, Franceschi M, Scarpini E, Frigerio E, Fiorentini F, Fernandez M, Sivilia S, Giardino L, Calza L, Norris D, Cicirello H, Casula D, Imbimbo BP: CHF5074 reduces biomarkers of neuroinflammation in patients with mild cognitive impairment: a 12-week, double-blind, placebo-controlled study. Curr Alzheimer Res 2013, 10: 742–753.PubMed
62.
Rogers K, Felsenstein KM, Hrdlicka L, Tu Z, Albayya F, Lee W, Hopp S, Miller MJ, Spaulding D, Yang Z, Hodgdon H, Nolan S, Wen M, Costa D, Blain JF, Freeman E, De Strooper B, Vulsteke V, Scrocchi L, Zetterberg H, Portelius E, Hutter-Paier B, Havas D, Ahlijanian M, Flood D, Leventhal L, Shapiro G, Patzke H, Chesworth R, Koenig G: Modulation of gamma-secretase by EVP-0015962 reduces amyloid deposition and behavioral deficits in Tg2576 mice. Mol Neurodegener 2012, 7: 61.PubMedPubMedCentral
63.
Green RC, Schneider LS, Amato DA, Beelen AP, Wilcock G, Swabb EA, Zavitz KH: Effect of tarenflurbil on cognitive decline and activities of daily living in patients with mild Alzheimer disease: a randomized controlled trial. JAMA 2009, 302: 2557–2564.PubMedPubMedCentral
64.
Forman M, Palcza J, Tseng J, Leempoels J, Ramael S, Han D, Jhee S, Ereshefsky L, Tanen M, Laterza O, Dockendorf M, Krishna G, Ma L, Wagner J, Troyer M: The novel BACE inhibitor MK-8931 dramatically lowers cerebrospinal fluid Aβ peptides in healthy subjects following single- and multiple-dose administration. Alzheimers Dement 2012, 8: P704.
65.
Ghosh AK, Brindisi M, Tang J: Developing beta-secretase inhibitors for treatment of Alzheimer's disease. J Neurochem 2012, 120(Suppl 1):71–83.PubMed
66.
LaFerla FM, Green KN: Animal Models of Alzheimer Disease. Cold Spring Harbor Perspect Med 2012, 1: 2(11).
67.
Mullane K, Williams M: Alzheimer's therapeutics: Continued clinical failures question the validity of the amyloid hypothesis-but what lies beyond? Biochem Pharmacol 2013, 85: 289–305.PubMed
68.
Selkoe DJ: Resolving controversies on the path to Alzheimer's therapeutics. Nat Med 2011, 17: 1060–1065.PubMed
69.
Oddo S, Billings L, Kesslak JP, Cribbs DH, LaFerla FM: Aβ Immunotherapy Leads to Clearance of Early, but Not Late, Hyperphosphorylated Tau Aggregates via the Proteasome. Neuron 2004, 43: 321–332.PubMed
70.
Morris JC, Aisen PS, Bateman RJ, Benzinger TL, Cairns NJ, Fagan AM, Ghetti B, Goate AM, Holtzman DM, Klunk WE, McDade E, Marcus DS, Martins RN, Masters CL, Mayeux R, Oliver A, Quaid K, Ringman JM, Rossor MN, Salloway S, Schofield PR, Selsor NJ, Sperling RA, Weiner MW, Xiong C, Moulder KL, Buckles VD: Developing an international network for Alzheimer research: The Dominantly Inherited Alzheimer Network. Clinical Invest 2012, 2: 975–984.
71.
Reiman EM, Langbaum JB, Fleisher AS, Caselli RJ, Chen K, Ayutyanont N, Quiroz YT, Kosik KS, Lopera F, Tariot PN: Alzheimer's Prevention Initiative: a plan to accelerate the evaluation of presymptomatic treatments. J Alzheimers Dis 2011, 26(Suppl 3):321–329.PubMedPubMedCentral
72.
Sperling RA, Rentz DM, Johnson KA, Karlawish J, Donohue M, Salmon DP, Aisen P: The A4 Study: Stopping AD Before Symptoms Begin? Sci Transl Med 2014, 6: 228fs213.
73.
Watt AD, Crespi GA, Down RA, Ascher DB, Gunn A, Perez KA, McLean CA, Villemagne VL, Parker MW, Barnham KJ, Miles LA: Do current therapeutic anti-Abeta antibodies for Alzheimer's disease engage the target? Acta Neuropathol 2014, 127: 803–810.PubMed
74.
Martins IC, Kuperstein I, Wilkinson H, Maes E, Vanbrabant M, Jonckheere W, Van Gelder P, Hartmann D, D'Hooge R, De Strooper B, Schymkowitz J, Rousseau F: Lipids revert inert Abeta amyloid fibrils to neurotoxic protofibrils that affect learning in mice. EMBO J 2008, 27: 224–233.PubMed
75.
Zakaib GW: Anti-Amyloid Therapies Combine Forces to Knock Out Plaques. 2014.
76.
Smith MA, Atwood CS, Joseph JA, Perry G: Predicting the failure of amyloid-beta vaccine. Lancet 2002, 359: 1864–1865.PubMed
77.
Price JL, McKeel DW Jr, Buckles VD, Roe CM, Xiong C, Grundman M, Hansen LA, Petersen RC, Parisi JE, Dickson DW, Smith CD, Davis DG, Schmitt FA, Markesbery WR, Kaye J, Kurlan R, Hulette C, Kurland BF, Higdon R, Kukull W, Morris JC: Neuropathology of nondemented aging: Presumptive evidence for preclinical Alzheimer disease. Neurobiol Aging 2009, 30: 1026–1036.PubMedPubMedCentral
78.
Fagan AM, Mintun MA, Shah AR, Aldea P, Roe CM, Mach RH, Marcus D, Morris JC, Holtzman DM: Cerebrospinal fluid tau and ptau(181) increase with cortical amyloid deposition in cognitively normal individuals: implications for future clinical trials of Alzheimer's disease. EMBO Mol Med 2009, 1: 371–380.PubMedPubMedCentral
79.
Davis DG, Schmitt FA, Wekstein DR, Markesbery WR: Alzheimer neuropathologic alterations in aged cognitively normal subjects. J Neuropathol Exp Neurol 1999, 58: 376–388.PubMed
80.
Chételat G, La Joie R, Villain N, Perrotin A, de La Sayette V, Eustache F, Vandenberghe R: Amyloid imaging in cognitively normal individuals, at-risk populations and preclinical Alzheimer's disease. Neurol Clin 2013, 2: 356–365.
81.
Perls T: Dementia-free centenarians. Exp Gerontol 2004, 39: 1587–1593.PubMed
82.
Poon LW, Woodard JL, Stephen Miller L, Stephen Miller L, Green R, Gearing M, Davey A, Arnold J, Martin P, Siegler IC, Nahapetyan L, Kim YS, Markesbery W: Understanding dementia prevalence among centenarians. J Gerontol A Biol Sci Med Sci 2012, 67: 358–365.PubMed
83.
Snitz BE, Weissfeld LA, Lopez OL, Kuller LH, Saxton J, Singhabahu DM, Klunk WE, Mathis CA, Price JC, Ives DG, Cohen AD, McDade E, Dekosky ST: Cognitive trajectories associated with beta-amyloid deposition in the oldest-old without dementia. Neurology 2013, 80: 1378–1384.PubMedPubMedCentral
84.
Morris JC, Roe CM, Grant EA, Head D, Storandt M, Goate AM, Fagan AM, Holtzman DM, Mintun MA: Pittsburgh compound B imaging and prediction of progression from cognitive normality to symptomatic Alzheimer disease. Arch Neurol 2009, 66: 1469–1475.PubMedPubMedCentral
85.
Rentz DM, Locascio JJ, Becker JA, Moran EK, Eng E, Buckner RL, Sperling RA, Johnson KA: Cognition, reserve, and amyloid deposition in normal aging. Ann Neurol 2010, 67: 353–364.PubMed
86.
Engler H, Forsberg A, Almkvist O, Blomquist G, Larsson E, Savitcheva I, Wall A, Ringheim A, Långström B, Nordberg A: Two-year follow-up of amyloid deposition in patients with Alzheimer's disease. Brain 2006, 129: 2856–2866.PubMed
87.
Ingelsson M, Fukumoto H, Newell KL, Growdon JH, Hedley-Whyte ET, Frosch MP, Albert MS, Hyman BT, Irizarry MC: Early Abeta accumulation and progressive synaptic loss, gliosis, and tangle formation in AD brain. Neurology 2004, 62: 925–931.PubMed
88.
Chetelat G: Alzheimer disease: A[beta]-independent processes-rethinking preclinical AD. Nat Rev Neurol 2013, 9: 123–124.PubMedPubMedCentral
89.
Tsai J, Grutzendler J, Duff K, Gan WB: Fibrillar amyloid deposition leads to local synaptic abnormalities and breakage of neuronal branches. Nat Neurosci 2004, 7: 1181–1183.PubMed
90.
Dickson TC, Vickers JC: The morphological phenotype of beta-amyloid plaques and associated neuritic changes in Alzheimer's disease. Neuroscience 2001, 105: 99–107.PubMed
91.
Reiman EM, Chen K, Liu X, Bandy D, Yu M, Lee W, Ayutyanont N, Keppler J, Reeder SA, Langbaum JB, Alexander GE, Klunk WE, Mathis CA, Price JC, Aizenstein HJ, DeKosky ST, Caselli RJ: Fibrillar amyloid-beta burden in cognitively normal people at 3 levels of genetic risk for Alzheimer's disease. Proc Natl Acad Sci U S A 2009, 106: 6820–6825.PubMedPubMedCentral
92.
Hedden T, Oh H, Younger AP, Patel TA: Meta-analysis of amyloid-cognition relations in cognitively normal older adults. Neurology 2013, 80: 1341–1348.PubMedPubMedCentral
93.
Savory J, Ghribi O, Herman MM: Is amyloid β-peptide neurotoxic or neuroprotective and what is its role in the binding of metal ions? Neurobiol Aging 2002, 23: 1089–1092.PubMed
94.
95.
Atwood CS, Bowen RL, Smith MA, Perry G: Cerebrovascular requirement for sealant, anti-coagulant and remodeling molecules that allow for the maintenance of vascular integrity and blood supply. Brain Res Rev 2003, 43: 164–178.PubMed
96.
Weller RO, Subash M, Preston SD, Mazanti I, Carare RO: Perivascular drainage of amyloid-beta peptides from the brain and its failure in cerebral amyloid angiopathy and Alzheimer's disease. Brain Pathol 2008, 18: 253–266.PubMed
97.
Yasojima K, Akiyama H, McGeer EG, McGeer PL: Reduced neprilysin in high plaque areas of Alzheimer brain: a possible relationship to deficient degradation of beta-amyloid peptide. Neurosci Lett 2001, 297: 97–100.PubMed
98.
Cook DG, Leverenz JB, McMillan PJ, Kulstad JJ, Ericksen S, Roth RA, Schellenberg GD, Jin LW, Kovacina KS, Craft S: Reduced hippocampal insulin-degrading enzyme in late-onset Alzheimer's disease is associated with the apolipoprotein E-epsilon4 allele. Am J Pathol 2003, 162: 313–319.PubMedPubMedCentral
99.
Deane R, Sagare A, Hamm K, Parisi M, Lane S, Finn MB, Holtzman DM, Zlokovic BV: apoE isoform-specific disruption of amyloid beta peptide clearance from mouse brain. J Clin Invest 2008, 118: 4002–4013.PubMedPubMedCentral
100.
Ferreira ST, Klein WL: The Aβ oligomer hypothesis for synapse failure and memory loss in Alzheimer’s disease. Neurobiol Learn Mem 2011, 96: 529–543.PubMedPubMedCentral
101.
Castellani RJ, Smith MA: Compounding artefacts with uncertainty, and an amyloid cascade hypothesis that is 'too big to fail'. J Pathol 2011, 224: 147–152.PubMed
102.
DaRocha-Souto B, Scotton TC, Coma M, Serrano-Pozo A, Hashimoto T, Sereno L, Rodriguez M, Sanchez B, Hyman BT, Gomez-Isla T: Brain oligomeric beta-amyloid but not total amyloid plaque burden correlates with neuronal loss and astrocyte inflammatory response in amyloid precursor protein/tau transgenic mice. J Neuropathol Exp Neurol 2011, 70: 360–376.PubMedPubMedCentral
103.
McDonald JM, Savva GM, Brayne C, Welzel AT, Forster G, Shankar GM, Selkoe DJ, Ince PG, Walsh DM: The presence of sodium dodecyl sulphate-stable Aβ dimers is strongly associated with Alzheimer-type dementia. Brain 2010, 133: 1328–1341.
104.
Benilova I, Karran E, De Strooper B: The toxic Abeta oligomer and Alzheimer's disease: an emperor in need of clothes. Nat Neurosci 2012, 15: 349–357.PubMed
105.
Larson ME, Lesne SE: Soluble Abeta oligomer production and toxicity. J Neurochem 2012, 120(Suppl 1):125–139.PubMed
106.
Esparza TJ, Zhao H, Cirrito JR, Cairns NJ, Bateman RJ, Holtzman DM, Brody DL: Amyloid-beta oligomerization in Alzheimer dementia versus high-pathology controls. Ann Neurol 2013, 73: 104–119.PubMed
107.
Watt AD, Perez KA, Rembach A, Sherrat NA, Hung LW, Johanssen T, McLean CA, Kok WM, Hutton CA, Fodero-Tavoletti M, Masters CL, Villemagne VL, Barnham KJ: Oligomers, fact or artefact? SDS-PAGE induces dimerization of beta-amyloid in human brain samples. Acta Neuropathol 2013, 125: 549–564.PubMed
108.
Atwood CS, Martins RN, Smith MA, Perry G: Senile plaque composition and posttranslational modification of amyloid-β peptide and associated proteins. Peptides 2002, 23: 1343–1350.PubMed
109.
Kudinova NV, Kudinov AR, Berezov TT: Amyloid beta: functional protein or biological junk? Biomeditsinskaia khimiia 2007, 53: 119–127.PubMed
110.
Pimplikar SW: Reassessing the amyloid cascade hypothesis of Alzheimer's disease. Int J Biochem Cell Biol 2009, 41: 1261–1268.PubMed
111.
Gilbert BJ: The role of amyloid beta in the pathogenesis of Alzheimer's disease. J Clin Pathol 2013, 66: 362–366.PubMed
112.
Farrer LA, Myers RH, Cupples LA, St George-Hyslop PH, Bird TD, Rossor MN, Mullan MJ, Polinsky R, Nee L, Heston L: Transmission and age-at-onset patterns in familial Alzheimer's disease: evidence for heterogeneity. Neurology 1990, 40: 395–403.PubMed
113.
Komarova NL, Thalhauser CJ: High degree of heterogeneity in Alzheimer's disease progression patterns. PLoS Comput Biol 2011, 7: e1002251.PubMedPubMedCentral
114.
Stopford CL, Snowden JS, Thompson JC, Neary D: Variability in cognitive presentation of Alzheimer's disease. Cortex 2008, 44: 185–195.PubMed
115.
Shepherd C, McCann H, Halliday GM: Variations in the neuropathology of familial Alzheimer's disease. Acta Neuropathol 2009, 118: 37–52.PubMed
116.
Koedam EL, Lauffer V, van der Vlies AE, van der Flier WM, Scheltens P, Pijnenburg YA: Early-versus late-onset Alzheimer's disease: more than age alone. J Alzheimers Dis 2010, 19: 1401–1408.PubMed
117.
Mastroeni D, Grover A, Delvaux E, Whiteside C, Coleman PD, Rogers J: Epigenetic mechanisms in Alzheimer's disease. Neurobiol Aging 2011, 32: 1161–1180.PubMedPubMedCentral
118.
Whitehouse PJ, George DR: Uncertain progress on the fuzzy boundaries of Alzheimer's disease: reading between the guidelines. J Alzheimers Dis 2011, 26: 1–5.PubMed
119.
Villemagne VL, Ataka S, Mizuno T, Brooks WS, Wada Y, Kondo M, Jones G, Watanabe Y, Mulligan R, Nakagawa M, Miki T, Shimada H, O'Keefe GJ, Masters CL, Mori H, Rowe CC: High striatal amyloid beta-peptide deposition across different autosomal Alzheimer disease mutation types. Arch Neurol 2009, 66: 1537–1544.PubMed
120.
Thal DR, Rub U, Orantes M, Braak H: Phases of A beta-deposition in the human brain and its relevance for the development of AD. Neurology 2002, 58: 1791–1800.PubMed
121.
Resende R, Marques SC, Ferreiro E, Simoes I, Oliveira CR, Pereira CM: Effect of alpha-synuclein on amyloid beta-induced toxicity: relevance to Lewy body variant of Alzheimer disease. Neurochem Res 2013, 38: 797–806.PubMed
122.
Robakis NK: Mechanisms of AD neurodegeneration may be independent of Abeta and its derivatives. Neurobiol Aging 2011, 32: 372–379.PubMed
123.
Perry G, Castellani RJ, Moreira PI, Lee HG, Zhu X, Smith MA: Pathology's new role: defining disease process and protective responses. Int J Clin Exp Pathol 2008, 1: 1–4.PubMedPubMedCentral
124.
Bryan KJ, Lee H, Perry G, Smith MA, Casadesus G: Transgenic Mouse Models of Alzheimer's Disease: Behavioral Testing and Considerations. In Methods of Behavior Analysis in Neuroscience. 2nd edition. Edited by: Buccafusco JJ. CRC Press, Boca Raton (FL); 2009.
125.
Wright AL, Zinn R, Hohensinn B, Konen LM, Beynon SB, Tan RP, Clark IA, Abdipranoto A, Vissel B: Neuroinflammation and Neuronal Loss Precede Abeta Plaque Deposition in the hAPP-J20 Mouse Model of Alzheimer's Disease. PLoS One 2013, 8: e59586.PubMedPubMedCentral
126.
D'Hooge R, Nagels G, Westland CE, Mucke L, De Deyn PP: Spatial learning deficit in mice expressing human 751-amino acid beta-amyloid precursor protein. Neuroreport 1996, 7: 2807–2811.PubMed
127.
Yamaguchi F, Richards SJ, Beyreuther K, Salbaum M, Carlson GA, Dunnett SB: Transgenic mice for the amyloid precursor protein 695 isoform have impaired spatial memory. Neuroreport 1991, 2: 781–784.PubMed
128.
Rovelet-Lecrux A, Hannequin D, Raux G, Le Meur N, Laquerriere A, Vital A, Dumanchin C, Feuillette S, Brice A, Vercelletto M, Dubas F, Frebourg T, Campion D: APP locus duplication causes autosomal dominant early-onset Alzheimer disease with cerebral amyloid angiopathy. Nat Genet 2006, 38: 24–26.PubMed
129.
Blom ES, Viswanathan J, Kilander L, Helisalmi S, Soininen H, Lannfelt L, Ingelsson M, Glaser A, Hiltunen M: Low prevalence of APP duplications in Swedish and Finnish patients with early-onset Alzheimer's disease. Eur J Hum Genet 2008, 16: 171–175.PubMed
130.
Sleegers K, Brouwers N, Gijselinck I, Theuns J, Goossens D, Wauters J, Del-Favero J, Cruts M, van Duijn CM, Van Broeckhoven C: APP duplication is sufficient to cause early onset Alzheimer's dementia with cerebral amyloid angiopathy. Brain 2006, 129: 2977–2983.PubMed
131.
Westerman MA, Cooper-Blacketer D, Mariash A, Kotilinek L, Kawarabayashi T, Younkin LH, Carlson GA, Younkin SG, Ashe KH: The Relationship between Aβ and Memory in the Tg2576 Mouse Model of Alzheimer's Disease. J Neurosci 2002, 22: 1858–1867.PubMed
132.
Lee KW, Lee SH, Kim H, Song JS, Yang SD, Paik SG, Han PL: Progressive cognitive impairment and anxiety induction in the absence of plaque deposition in C57BL/6 inbred mice expressing transgenic amyloid precursor protein. J Neurosci Res 2004, 76: 572–580.PubMed
133.
Savonenko AV, Xu GM, Price DL, Borchelt DR, Markowska AL: Normal cognitive behavior in two distinct congenic lines of transgenic mice hyperexpressing mutant APP SWE. Neurobiol Dis 2003, 12: 194–211.PubMed
134.
Ruiz-Opazo N, Kosik KS, Lopez LV, Bagamasbad P, Ponce LR, Herrera VL: Attenuated hippocampus-dependent learning and memory decline in transgenic TgAPPswe Fischer-344 rats. Mol Med 2004, 10: 36–44.PubMedPubMedCentral
135.
Kalback W, Watson MD, Kokjohn TA, Kuo Y-M, Weiss N, Luehrs DC, Lopez J, Brune D, Sisodia SS, Staufenbiel M, Emmerling M, Roher AE: APP Transgenic Mice Tg2576 Accumulate Aβ Peptides That Are Distinct from the Chemically Modified and Insoluble Peptides Deposited in Alzheimer's Disease Senile Plaques†. Biochemistry 2001, 41: 922–928.
136.
Kuo Y-M, Kokjohn TA, Beach TG, Sue LI, Brune D, Lopez JC, Kalback WM, Abramowski D, Sturchler-Pierrat C, Staufenbiel M, Roher AE: Comparative Analysis of Amyloid-β Chemical Structure and Amyloid Plaque Morphology of Transgenic Mouse and Alzheimer's Disease Brains. J Biol Chem 2001, 276: 12991–12998.PubMed
137.
Ryman D, Lamb BT: Genetic and environmental modifiers of Alzheimer's disease phenotypes in the mouse. Curr Alzheimer Res 2006, 3: 465–473.PubMed
138.
Dolgin E: Old mice require new experimental tricks to study aging process. Nat Med 2013, 19: 518–519.PubMed
139.
140.
Delerue F, Sjollema G, Whittle B, Kruger S, Andrews D, Gotz J: Single Nucleotide Variants (SNVs) Define Senescence-Accelerated SAMP8 Mice, a Model of a Geriatric Condition. J Alzheimers Dis 2013, 36: 349–363.PubMed
141.
Capsoni S, Ugolini G, Comparini A, Ruberti F, Berardi N, Cattaneo A: Alzheimer-like neurodegeneration in aged antinerve growth factor transgenic mice. Proc Natl Acad Sci U S A 2000, 97: 6826–6831.PubMedPubMedCentral
142.
Yamasaki TR, Blurton-Jones M, Morrissette DA, Kitazawa M, Oddo S, LaFerla FM: Neural Stem Cells Improve Memory in an Inducible Mouse Model of Neuronal Loss. J Neurosci 2007, 27: 11925–11933.PubMed
143.
Krstic D, Madhusudan A, Doehner J, Vogel P, Notter T, Imhof C, Manalastas A, Hilfiker M, Pfister S, Schwerdel C, Riether C, Meyer U, Knuesel I: Systemic immune challenges trigger and drive Alzheimer-like neuropathology in mice. J Neuroinflammation 2012, 9: 151.PubMedPubMedCentral
144.
Saito T, Matsuba Y, Mihira N, Takano J, Nilsson P, Itohara S, Iwata N, Saido TC: Single App knock-in mouse models of Alzheimer's disease. Nat Neurosci 2014, 17: 661–663.PubMed
145.
Tanzi RE: The Genetics of Alzheimer Disease. Cold Spring Harbor Perspect Med 2012, 1: 2(10).
146.
Carvalho C, Machado N, Mota PC, Correia SC, Cardoso S, Santos RX, Santos MS, Oliveira CR, Moreira PI: Type 2 diabetic and Alzheimer's disease mice present similar behavioral, cognitive, and vascular anomalies. J Alzheimers Dis 2013, 35: 623–635.PubMed
147.
Hong X, Bu L, Wang Y, Xu J, Wu J, Huang Y, Liu J, Suo H, Yang L, Shi Y, Lou Y, Sun Z, Zhu G, Behnisch T, Yu M, Jia J, Hai W, Meng H, Liang S, Huang F, Zou Y, Ge J: Increases in the risk of cognitive impairment and alterations of cerebral beta-amyloid metabolism in mouse model of heart failure. PLoS One 2013, 8: e63829.PubMedPubMedCentral
148.
Lambert JC, Ibrahim-Verbaas CA, Harold D, Naj AC, Sims R, Bellenguez C, Jun G, Destefano AL, Bis JC, Beecham GW, Grenier-Boley B, Russo G, Thornton-Wells TA, Jones N, Smith AV, Chouraki V, Thomas C, Ikram MA, Zelenika D, Vardarajan BN, Kamatani Y, Lin CF, Gerrish A, Schmidt H, Kunkle B, Dunstan ML, Ruiz A, Bihoreau MT, Choi SH, Reitz C, et al.: Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer's disease. Nat Genet 2013, 45: 1452–1458.PubMedPubMedCentral
149.
Tanzi RE, Bertram L: Twenty Years of the Alzheimer's Disease Amyloid Hypothesis: A Genetic Perspective. Cell 2005, 120: 545–555.PubMed
150.
Podtelezhnikov AA, Tanis KQ, Nebozhyn M, Ray WJ, Stone DJ, Loboda AP: Molecular insights into the pathogenesis of Alzheimer's disease and its relationship to normal aging. PLoS One 2011, 6: e29610.PubMedPubMedCentral
151.
Borchelt DR, Thinakaran G, Eckman CB, Lee MK, Davenport F, Ratovitsky T, Prada CM, Kim G, Seekins S, Yager D, Slunt HH, Wang R, Seeger M, Levey AI, Gandy SE, Copeland NG, Jenkins NA, Price DL, Younkin SG, Sisodia SS: Familial Alzheimer's disease-linked presenilin 1 variants elevate Abeta1–42/1–40 ratio in vitro and in vivo. Neuron 1996, 17: 1005–1013.PubMed
152.
Citron M, Westaway D, Xia W, Carlson G, Diehl T, Levesque G, Johnson-Wood K, Lee M, Seubert P, Davis A, Kholodenko D, Motter R, Sherrington R, Perry B, Yao H, Strome R, Lieberburg I, Rommens J, Kim S, Schenk D, Fraser P, St George Hyslop P, Selkoe DJ: Mutant presenilins of Alzheimer's disease increase production of 42-residue amyloid beta-protein in both transfected cells and transgenic mice. Nat Med 1997, 3: 67–72.PubMed
153.
Scheuner D, Eckman C, Jensen M, Song X, Citron M, Suzuki N, Bird TD, Hardy J, Hutton M, Kukull W, Larson E, Levy-Lahad E, Viitanen M, Peskind E, Poorkaj P, Schellenberg G, Tanzi R, Wasco W, Lannfelt L, Selkoe D, Younkin S: Secreted amyloid beta-protein similar to that in the senile plaques of Alzheimer's disease is increased in vivo by the presenilin 1 and 2 and APP mutations linked to familial Alzheimer's disease. Nat Med 1996, 2: 864–870.PubMed
154.
Shioi J, Georgakopoulos A, Mehta P, Kouchi Z, Litterst CM, Baki L, Robakis NK: FAD mutants unable to increase neurotoxic Abeta 42 suggest that mutation effects on neurodegeneration may be independent of effects on Abeta. J Neurochem 2007, 101: 674–681.PubMed
155.
Gomez-Isla T, Growdon WB, McNamara MJ, Nochlin D, Bird TD, Arango JC, Lopera F, Kosik KS, Lantos PL, Cairns NJ, Hyman BT: The impact of different presenilin 1 andpresenilin 2 mutations on amyloid deposition, neurofibrillary changes and neuronal loss in the familial Alzheimer's disease brain: evidence for other phenotype-modifying factors. Brain 1999, 122(Pt 9):1709–1719.PubMed
156.
Bentahir M, Nyabi O, Verhamme J, Tolia A, Horré K, Wiltfang J, Esselmann H, DeStrooper B: Presenilin clinical mutations can affect γ-secretase activity by different mechanisms. J Neurochem 2006, 96: 732–742.PubMed
157.
Murayama O, Murayama M, Honda T, Sun X, Nihonmatsu N, Takashima A: Twenty-nine missense mutations linked with familial Alzheimer's disease alter the processing of presenilin 1. Prog Neuro-Psychopharmacol Biol Psychiatry 1999, 23: 905–913.
158.
Walker ES, Martinez M, Brunkan AL, Goate A: Presenilin 2 familial Alzheimer's disease mutations result in partial loss of function and dramatic changes in Aβ 42/40 ratios. J Neurochem 2005, 92: 294–301.PubMed
159.
Potter H: The involvement of astrocytes and an acute phase response in the amyloid deposition of Alzheimer's disease. Prog Brain Res 1992, 94: 447–458.PubMed
160.
Saito T, Suemoto T, Brouwers N, Sleegers K, Funamoto S, Mihira N, Matsuba Y, Yamada K, Nilsson P, Takano J, Nishimura M, Iwata N, Van Broeckhoven C, Ihara Y, Saido TC: Potent amyloidogenicity and pathogenicity of Abeta43. Nat Neurosci 2011, 14: 1023–1032.PubMed
161.
Benilova I, De Strooper B: An overlooked neurotoxic species in Alzheimer's disease. Nat Neurosci 2011, 14: 949–950.PubMed
162.
Bernardi L, Tomaino C, Anfossi M, Gallo M, Geracitano S, Costanzo A, Colao R, Puccio G, Frangipane F, Curcio SAM, Mirabelli M, Smirne N, Iapaolo D, Maletta RG, Bruni AC: Novel PSEN1 and PGRN mutations in early-onset familial frontotemporal dementia. Neurobiol Aging 2009, 30: 1825–1833.PubMed
163.
Ishikawa A, Piao YS, Miyashita A, Kuwano R, Onodera O, Ohtake H, Suzuki M, Nishizawa M, Takahashi H: A mutant PSEN1 causes dementia with Lewy bodies and variant Alzheimer's disease. Ann Neurol 2005, 57: 429–434.PubMed
164.
Sitek EJ, Narozanska E, Peplonska B, et al.: A patient with posterior cortical atrophy possesses a novel mutation in the presenilin 1 gene. PLoS One 2013, 8: e61074.PubMedPubMedCentral
165.
Binetti G, Signorini S, Squitti R, Alberici A, Benussi L, Cassetta E, Frisoni GB, Barbiero L, Feudatari E, Nicosia F, Testa C, Zanetti O, Gennarelli M, Perani D, Anchisi D, Ghidoni R, Rossini PM: Atypical dementia associated with a novel presenilin-2 mutation. Ann Neurol 2003, 54: 832–836.PubMed
166.
Boeve BF, Baker M, Dickson DW, Parisi JE, Giannini C, Josephs KA, Hutton M, Pickering-Brown SM, Rademakers R, Tang-Wai D, Jack CR Jr, Kantarci K, Shiung MM, Golde T, Smith GE, Geda YE, Knopman DS, Petersen RC: Frontotemporal dementia and parkinsonism associated with the IVS1 + 1G- > A mutation in progranulin: a clinicopathologic study. Brain 2006, 129: 3103–3114.PubMed
167.
Pickering-Brown SM, Baker M, Gass J, Theuns J, Rademakers R, Saerens J, Pickut BA, Peeters K, van den Broeck M, Vennekens K, Claes S, Cruts M, Cras P, Martin JJ, Van Broeckhoven C, De Deyn PP: Mutations in progranulin explain atypical phenotypes with variants in MAPT. Brain 2006, 129: 3124–3126.PubMed
168.
Dermaut B, Kumar-Singh S, Engelborghs S, et al.: A novel presenilin 1 mutation associated with Pick's disease but not beta-amyloid plaques. Ann Neurol 2004, 55: 617–626.PubMed
169.
Shen J, Kelleher RJ 3rd: The presenilin hypothesis of Alzheimer's disease: evidence for a loss-of-function pathogenic mechanism. Proc Natl Acad Sci U S A 2007, 104: 403–409.PubMed
170.
Beglopoulos V, Sun X, Saura CA, Lemere CA, Kim RD, Shen J: Reduced β-Amyloid Production and Increased Inflammatory Responses in Presenilin Conditional Knock-out Mice. J Biol Chem 2004, 279: 46907–46914.PubMed
171.
Wang H, Megill A, He K, Kirkwood A, Lee H-K: Consequences of Inhibiting Amyloid Precursor Protein Processing Enzymes on Synaptic Function and Plasticity. Neural Plast 2012, 2012: 24.
172.
Castellano JM, Kim J, Stewart FR, Jiang H, DeMattos RB, Patterson BW, Fagan AM, Morris JC, Mawuenyega KG, Cruchaga C, Goate AM, Bales KR, Paul SM, Bateman RJ, Holtzman DM: Human apoE isoforms differentially regulate brain amyloid-beta peptide clearance. Sci Transl Med 2011, 3: 89ra57.PubMedPubMedCentral
173.
Laskowitz DT, Goel S, Bennett ER, Matthew WD: Apolipoprotein E suppresses glial cell secretion of TNF-alpha. J Neuroimmunol 1997, 76: 70–74.PubMed
174.
Vitek MP, Brown CM, Colton CA: APOE genotype-specific differences in the innate immune response. Neurobiol Aging 2009, 30: 1350–1360.PubMed
175.
Hoane MR, Kaufman N, Vitek MP, McKenna SE: COG1410 improves cognitive performance and reduces cortical neuronal loss in the traumatically injured brain. J Neurotrauma 2009, 26: 121–129.PubMedPubMedCentral
176.
Tukhovskaya EA, Yukin AY, Khokhlova ON, Murashev AN, Vitek MP: COG1410, a novel apolipoprotein-E mimetic, improves functional and morphological recovery in a rat model of focal brain ischemia. J Neurosci Res 2009, 87: 677–682.PubMedPubMedCentral
177.
Vitek MP, Christensen DJ, Wilcock D, Davis J, Van Nostrand WE, Li FQ, Colton CA: APOE-mimetic peptides reduce behavioral deficits, plaques and tangles in Alzheimer's disease transgenics. Neurodegener Dis 2012 2012, 10(1-4):122–126.
178.
Ghosal K, Vogt DL, Liang M, Shen Y, Lamb BT, Pimplikar SW: Alzheimer's disease-like pathological features in transgenic mice expressing the APP intracellular domain. Proc Natl Acad Sci U S A 2009, 106: 18367–18372.PubMedPubMedCentral
179.
Tamayev R, Matsuda S, Giliberto L, Arancio O, D'Adamio L: APP heterozygosity averts memory deficit in knockin mice expressing the Danish dementia BRI2 mutant. EMBO J 2011, 30: 2501–2509.PubMedPubMedCentral
180.
Kuhn PH, Wang H, Dislich B, Colombo A, Zeitschel U, Ellwart JW, Kremmer E, Rossner S, Lichtenthaler SF: ADAM10 is the physiologically relevant, constitutive alpha-secretase of the amyloid precursor protein in primary neurons. EMBO J 2010, 29: 3020–3032.PubMedPubMedCentral
181.
Epis R, Marcello E, Gardoni F, Vastagh C, Malinverno M, Balducci C, Colombo A, Borroni B, Vara H, Dell'Agli M, Cattabeni F, Giustetto M, Borsello T, Forloni G, Padovani A, Di Luca M: Blocking ADAM10 synaptic trafficking generates a model of sporadic Alzheimer's disease. Brain 2010, 133: 3323–3335.PubMed
182.
Turner PR, O'Connor K, Tate WP, Abraham WC: Roles of amyloid precursor protein and its fragments in regulating neural activity, plasticity and memory. Prog Neurobiol 2003, 70: 1–32.PubMed
183.
Craft S: Insulin resistance syndrome and Alzheimer's disease: Age- and obesity-related effects on memory, amyloid, and inflammation. Neurobiol Aging 2005, 26: 65–69.PubMed
184.
Liu Y, Liu F, Grundke Iqbal I, Iqbal K, Gong CX: Deficient brain insulin signalling pathway in Alzheimer's disease and diabetes. J Pathol 2011, 225: 54–62.PubMedPubMedCentral
185.
Talbot K, Wang HY, Kazi H, Han LY, Bakshi KP, Stucky A, Fuino RL, Kawaguchi KR, Samoyedny AJ, Wilson RS, Arvanitakis Z, Schneider JA, Wolf BA, Bennett DA, Trojanowski JQ, Arnold SE: Demonstrated brain insulin resistance in Alzheimer's disease patients is associated with IGF-1 resistance, IRS-1 dysregulation, and cognitive decline. J Clin Invest 2012, 122: 1316–1338.PubMedPubMedCentral
186.
de Alvaro C, Teruel T, Hernandez R, Lorenzo M: Tumor Necrosis Factor α Produces Insulin Resistance in Skeletal Muscle by Activation of Inhibitor κB Kinase in a p38 MAPK-dependent Manner. J Biol Chem 2004, 279: 17070–17078.PubMed
187.
Clark I, Atwood C, Bowen R, Paz-Filho G, Vissel B: Tumor necrosis factor-induced cerebral insulin resistance in Alzheimer's disease links numerous treatment rationales. Pharmacol Rev 2012, 64: 1004–1026.PubMed
188.
Tweedie D, Ferguson RA, Fishman K, Frankola KA, Van Praag H, Holloway HW, Luo W, Li Y, Caracciolo L, Russo I, Barlati S, Ray B, Lahiri DK, Bosetti F, Greig NH, Rosi S: Tumor necrosis factor-alpha synthesis inhibitor 3,6'-dithiothalidomide attenuates markers of inflammation, Alzheimer pathology and behavioral deficits in animal models of neuroinflammation and Alzheimer's disease. J Neuroinflammation 2012, 9: 106.PubMedPubMedCentral
189.
McClean PL, Holscher C: Liraglutide can reverse memory impairment, synaptic loss and reduce plaque load in aged APP/PS1 mice, a model of Alzheimer's disease. Neuropharmacology 2014, 76: 57–67.PubMed
190.
Bomfim TR, Forny-Germano L, Sathler LB, Brito-Moreira J, Houzel JC, Decker H, Silverman MA, Kazi H, Melo HM, McClean PL, Holscher C, Arnold SE, Talbot K, Klein WL, Munoz DP, Ferreira ST, De Felice FG: An anti-diabetes agent protects the mouse brain from defective insulin signaling caused by Alzheimer's disease- associated Abeta oligomers. J Clin Invest 2012, 122: 1339–1353.PubMedPubMedCentral
191.
Akiyama H, Barger S, Barnum S, Bradt B, Bauer J, Cole GM, Cooper NR, Eikelenboom P, Emmerling M, Fiebich BL, Finch CE, Frautschy S, Griffin WS, Hampel H, Hull M, Landreth G, Lue L, Mrak R, Mackenzie IR, McGeer PL, O'Banion MK, Pachter J, Pasinetti G, Plata-Salaman C, Rogers J, Rydel R, Shen Y, Streit W, Strohmeyer R, Tooyoma I: Inflammation and Alzheimer's disease. Neurobiol Aging 2000, 21: 383–421.PubMedPubMedCentral
192.
Goldgaber D, Harris HW, Hla T, Maciag T, Donnelly RJ, Jacobsen JS, Vitek MP, Gajdusek DC: Interleukin 1 regulates synthesis of amyloid beta-protein precursor mRNA in human endothelial cells. Proc Natl Acad Sci U S A 1989, 86: 7606–7610.PubMedPubMedCentral
193.
Lourenco MV, Clarke JR, Frozza RL, Bomfim TR, Forny-Germano L, Batista AF, Sathler LB, Brito-Moreira J, Amaral OB, Silva CA, Freitas-Correa L, Espirito-Santo S, Campello-Costa P, Houzel JC, Klein WL, Holscher C, Carvalheira JB, Silva AM, Velloso LA, Munoz DP, Ferreira ST, De Felice FG: TNF-alpha mediates PKR-dependent memory impairment and brain IRS-1 inhibition induced by Alzheimer's beta-amyloid oligomers in mice and monkeys. Cell Metab 2013, 18: 831–843.PubMed
194.
Russo I, Caracciolo L, Tweedie D, Choi SH, Greig NH, Barlati S, Bosetti F: 3,6'-Dithiothalidomide, a new TNF-alpha synthesis inhibitor, attenuates the effect of Abeta1–42 intracerebroventricular injection on hippocampal neurogenesis and memory deficit. J Neurochem 2012, 122: 1181–1192.PubMedPubMedCentral
195.
Rao JS, Kellom M, Kim HW, Rapoport SI, Reese EA: Neuroinflammation and synaptic loss. Neurochem Res 2012, 37: 903–910.PubMedPubMedCentral
196.
Detrait ER, Danis B, Lamberty Y, Foerch P: Peripheral administration of an anti-TNF-alpha receptor fusion protein counteracts the amyloid induced elevation of hippocampal TNF-alpha levels and memory deficits in mice. Neurochem Int 2014, 72C: 10–13.
197.
Goedert M: Tau protein and neurodegeneration. Semin Cell Dev Biol 2004, 15: 45–49.PubMed
198.
Vishnu VY: Can tauopathy shake the amyloid cascade hypothesis? Nat Rev Neurol 2013, 9: 356–356.PubMed
199.
Arendt T, Stieler J, Strijkstra AM, Hut RA, Rudiger J, Van der Zee EA, Harkany T, Holzer M, Hartig W: Reversible paired helical filament-like phosphorylation of tau is an adaptive process associated with neuronal plasticity in hibernating animals. J Neurosci 2003, 23: 6972–6981.PubMed
200.
Kettenmann H, Kirchhoff F, Verkhratsky A: Microglia: New Roles for the Synaptic Stripper. Neuron 2013, 77: 10–18.PubMed
201.
Chung W-S, Clarke LE, Wang GX, Lee SH, Kim JS, Jung YS Hwang SH, Ha NC, Seol WG, Lee J, Park BJ: Astrocytes mediate synapse elimination through MEGF10 and MERTK pathways. Nature 2013, 504: 394–400.PubMedPubMedCentral
202.
Tremblay ME, Lowery RL, Majewska AK: Microglial interactions with synapses are modulated by visual experience. PLoS Biol 2010, 8: e1000527.PubMedPubMedCentral
203.
Diniz LP, Almeida JC, Tortelli V, Vargas Lopes C, Setti-Perdigao P, Stipursky J, Kahn SA, Romao LF, de Miranda J, Alves-Leon SV, de Souza JM, Castro NG, Panizzutti R, Gomes FCA: Astrocyte-induced synaptogenesis is mediated by transforming growth factor beta signaling through modulation of D-serine levels in cerebral cortex neurons. J Biol Chem 2012, 287: 41432–41445.PubMedPubMedCentral
204.
Parkhurst CN, Yang G, Ninan I, Savas JN, Yates IJR, Lafaille JJ, Hempstead BL, Littman DR, Gan W-B: Microglia Promote Learning-Dependent Synapse Formation through Brain-Derived Neurotrophic Factor. Cell 2013, 155: 1596–1609.PubMedPubMedCentral
205.
Perea G, Navarrete M, Araque A: Tripartite synapses: astrocytes process and control synaptic information. Trends Neurosci 2009, 32: 421–431.PubMed
206.
Wake H, Moorhouse AJ, Jinno S, Kohsaka S, Nabekura J: Resting Microglia Directly Monitor the Functional State of Synapses In Vivo and Determine the Fate of Ischemic Terminals. J Neurosci 2009, 29: 3974–3980.PubMed
207.
208.
Button KS, Ioannidis JPA, Mokrysz C, Nosek BA, Flint J, Robinson ESJ, Munafo MR: Power failure: why small sample size undermines the reliability of neuroscience. Nat Rev Neurosci 2013, 14: 365–376.PubMed
209.
Tsilidis KK, Panagiotou OA, Sena ES, Aretouli E, Evangelou E, Howells DW, Al-Shahi SR, Macleod MR, Ioannidis JP: Evaluation of excess significance bias in animal studies of neurological diseases. PLoS Biol 2013, 11: e1001609.PubMedPubMedCentral
210.
Crusio WE, Goldowitz D, Holmes A, Wolfer D: Standards for the publication of mouse mutant studies. Genes Brain Behav 2009, 8: 1–4.PubMed
211.
Richter SH, Garner JP, Wurbel H: Environmental standardization: cure or cause of poor reproducibility in animal experiments? Nat Methods 2009, 6: 257–261.PubMed
Metadata
Title
Inconsistencies and Controversies Surrounding the Amyloid Hypothesis of Alzheimer's Disease
Authors
Gary P Morris
Ian A Clark
Bryce Vissel
Publication date
01-12-2014
Publisher
BioMed Central
Published in
Acta Neuropathologica Communications / Issue 1/2014
Electronic ISSN: 2051-5960
DOI
https://doi.org/10.1186/s40478-014-0135-5

Other articles of this Issue 1/2014

Acta Neuropathologica Communications 1/2014 Go to the issue

Research

Behavioral deficits, early gliosis, dysmyelination and synaptic dysfunction in a mouse model of mucolipidosis IV

Research

Tau accumulation in the nucleus accumbens in tangle-predominant dementia

Research

Deregulation of subcellular biometal homeostasis through loss of the metal transporter, Zip7, in a childhood neurodegenerative disorder

Review

Angiogenesis in multiple sclerosis and experimental autoimmune encephalomyelitis

Research

α4-integrins control viral meningoencephalitis through differential recruitment of T helper cell subsets

Research

Overcoming multiple drug resistance mechanisms in medulloblastoma