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Immunotherapy Against Amyloid-β in Alzheimer’s Disease: An Overview

  • Niels D. PrinsEmail author
Protocol
Part of the Methods in Pharmacology and Toxicology book series (MIPT)

Abstract

Therapeutic options in Alzheimer’s disease (AD) are limited to symptomatic treatments that show only modest clinical effects. Disease-modifying treatments are urgently needed, and the amyloid cascade hypothesis thus far provides the best basis for the development of such therapies. Preclinical studies in mouse models of AD showed that immunization with amyloid-β (Aβ) as well as passive vaccination with monoclonal antibodies against Aβ may be effective in preventing and treating AD. This has led to the development and testing of immunotherapeutic agents in patients with prodromal AD or AD dementia. Passive immunotherapy with monoclonal antibodies against several Aβ species has been tested in phase 3 clinical trials, with thus far disappointing results. Whether the dosage level, target specificity, and/or stage of the disease is to be blamed for these failures is not fully clear. New mAbs specifically aimed at protofibrils of Aβ species that are thought to be most toxic have been developed and are currently being tested in phase 1 and 2 clinical trials. The first active immunotherapy with AN1792 was halted because of severe side effects. New-generation active vaccination programs with compounds avoiding inflammatory T cell activation are in clinical development. Amyloid-related imaging abnormalities (ARIA) consisting of cerebral edema (ARIA-E) or hemorrhage (ARIA-H) are side effects associated with immunotherapy. It has been suggested that immunotherapy may be most effective when administered early in the disease course, and several studies with mAbs in subjects with preclinical AD are now being performed.

Key words

Immunotherapy Monoclonal antibody Active vaccination Alzheimer’s disease Mild cognitive impairment Amyloid-related imaging abnormalities 

References

  1. 1.
    World Alzheimer Report (2014) World Alzheimer Report 2014Google Scholar
  2. 2.
    Hansen RA, Gartlehner G, Webb AP, Morgan LC, Moore CG, Jonas DE (2008) Efficacy and safety of donepezil, galantamine, and rivastigmine for the treatment of Alzheimer’s disease: a systematic review and meta-analysis. Clin Interv Aging 3(2):211–225PubMedPubMedCentralGoogle Scholar
  3. 3.
    Kaduszkiewicz H, Zimmermann T, Beck-Bornholdt HP, van den Bussche H (2005) Cholinesterase inhibitors for patients with Alzheimer’s disease: systematic review of randomised clinical trials. BMJ 331(7512):321–327CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Hardy J (2009) The amyloid hypothesis for Alzheimer’s disease: a critical reappraisal. J Neurochem 110(4):1129–1134CrossRefPubMedGoogle Scholar
  5. 5.
    Hardy J, Bogdanovic N, Winblad B, Portelius E, Andreasen N, Cedazo-Minguez A, Zetterberg H (2014) Pathways to Alzheimer’s disease. J Intern Med 275(3):296–303CrossRefPubMedGoogle Scholar
  6. 6.
    Selkoe DJ (2008) Soluble oligomers of the amyloid β-protein impair synaptic plasticity and behavior. Behav Brain Res 192(1):106–113, Accessed from http://www.sciencedirect.com/science/article/pii/S0166432808000831
  7. 7.
    Walsh DM, Selkoe DJ (2007) A? Oligomers ? a decade of discovery. J Neurochem 101(5):1172–1184CrossRefPubMedGoogle Scholar
  8. 8.
    Lannfelt L, Relkin NR, Siemers ER (2014) Amyloid-ß-directed immunotherapy for Alzheimer’s disease. J Intern Med 275(3):284–295CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Winblad B, Graf A, Riviere ME, Andreasen N, Ryan JM (2014) Active immunotherapy options for Alzheimer’s disease. Alzheimers Res Ther 6(1):7CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Wisniewski T, Goñi F (2014) Immunotherapy for Alzheimer’s disease. Biochem Pharmacol 88(4):499–507CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
  12. 12.
    Mayeux R, Stern Y (2012) Epidemiology of Alzheimer disease. Cold Spring Harbor Perspect Med 2(8):a006239Google Scholar
  13. 13.
    Cummings JL, Cole G (2002) Alzheimer disease. JAMA 287(18):2335–2338CrossRefPubMedGoogle Scholar
  14. 14.
    Lopez OL (2011) The growing burden of Alzheimer’s disease. Am J Manag Care 17(Suppl 13):S339–45PubMedGoogle Scholar
  15. 15.
    Bateman RJ, Xiong C, Benzinger TL, Fagan AM, Goate A, Fox NC, Marcus DS, Cairns NJ, Xie X, Blazey TM, Holtzman DM, Santacruz A, Buckles V, Oliver A, Moulder K, Aisen PS, Ghetti B, Klunk WE, McDade E, Martins RN, Masters CL, Mayeux R, Ringman JM, Rossor MN, Schofield PR, Sperling RA, Salloway S, Morris JC, Dominantly Inherited Alzheimer Network (2012) Clinical and biomarker changes in dominantly inherited Alzheimer’s disease. N Engl J Med 367(9):795–804CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Sperling RA, Aisen PS, Beckett LA, Bennett DA, Craft S, Fagan AM, Iwatsubo T, Jack CR, Kaye J, Montine TJ, Park DC, Reiman EM, Rowe CC, Siemers E, Stern Y, Yaffe K, Carrillo MC, Thies B, Morrison-Bogorad M, Wagster MV, Phelps CH (2011) Toward defining the preclinical stages of Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement 7(3):280–292CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Albert MS, DeKosky ST, Dickson D, Dubois B, Feldman HH, Fox NC, Gamst A, Holtzman DM, Jagust WJ, Petersen RC, Snyder PJ, Carrillo MC, Thies B, Phelps CH (2011) The diagnosis of mild cognitive impairment due to Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement 7(3):270–279CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    McKhann GM, Knopman DS, Chertkow H, Hyman BT, Jack CR, Kawas CH, Klunk WE, Koroshetz WJ, Manly JJ, Mayeux R, Mohs RC, Morris JC, Rossor MN, Scheltens P, Carrillo MC, Thies B, Weintraub S, Phelps CH (2011) The diagnosis of dementia due to Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement 7(3):263–269CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Association A’s (2014) 2014 Alzheimer’s disease facts and figures. Alzheimers Dement 10(2):e47–e92CrossRefGoogle Scholar
  20. 20.
    Loy CT, Schofield PR, Turner AM, Kwok JB (2014) Genetics of dementia. Lancet 383(9919):828–840CrossRefPubMedGoogle Scholar
  21. 21.
    Benilova I, Karran E, De Strooper B (2012) The toxic Aβ oligomer and Alzheimer’s disease: an emperor in need of clothes. Nat Neurosci 15(3):349–357CrossRefPubMedGoogle Scholar
  22. 22.
    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, Jönsson EG, Palotie A, Behrens TW, Magnusson OT, Kong A, Thorsteinsdottir U, Watts RJ, Stefansson K (2012) A mutation in APP protects against Alzheimer’s disease and age-related cognitive decline. Nature 488(7409):96–99CrossRefPubMedGoogle Scholar
  23. 23.
    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 (1999) Immunization with amyloid-beta attenuates Alzheimer-disease-like pathology in the PDAPP mouse. Nature 400(6740):173–177CrossRefPubMedGoogle Scholar
  24. 24.
    Janus C, Pearson J, McLaurin J, Mathews PM, Jiang Y, Schmidt SD, Chishti MA, Horne P, Heslin D, French J, Mount HT, Nixon RA, Mercken M, Bergeron C, Fraser PE, St George-Hyslop P, Westaway D (2000) A beta peptide immunization reduces behavioural impairment and plaques in a model of Alzheimer’s disease. Nature 408(6815):979–982CrossRefPubMedGoogle Scholar
  25. 25.
    Lemere CA, Beierschmitt A, Iglesias M, Spooner ET, Bloom JK, Leverone JF, Zheng JB, Seabrook TJ, Louard D, Li D, Selkoe DJ, Palmour RM, Ervin FR (2004) Alzheimer’s disease abeta vaccine reduces central nervous system abeta levels in a non-human primate, the Caribbean vervet. Am J Pathol 165(1):283–297CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Bard F, Cannon C, Barbour R, Burke RL, Games D, Grajeda H, Guido T, Hu K, Huang J, Johnson-Wood K, Khan K, Kholodenko D, Lee M, Lieberburg I, Motter R, Nguyen M, Soriano F, Vasquez N, Weiss K, Welch B, Seubert P, Schenk D, Yednock T (2000) Peripherally administered antibodies against amyloid beta-peptide enter the central nervous system and reduce pathology in a mouse model of Alzheimer disease. Nat Med 6(8):916–919CrossRefPubMedGoogle Scholar
  27. 27.
    Das P, Howard V, Loosbrock N, Dickson D, Murphy MP, Golde TE (2003) Amyloid-beta immunization effectively reduces amyloid deposition in FcRgamma −/− knock-out mice. J Neurosci 23(24):8532–8538PubMedGoogle Scholar
  28. 28.
    DeMattos RB, Bales KR, Cummins DJ, Dodart JC, Paul SM, Holtzman DM (2001) Peripheral anti-A beta antibody alters CNS and plasma A beta clearance and decreases brain A beta burden in a mouse model of Alzheimer’s disease. Proc Natl Acad Sci U S A 98(15):8850–5CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Morgan D, Diamond DM, Gottschall PE, Ugen KE, Dickey C, Hardy J, Duff K, Jantzen P, DiCarlo G, Wilcock D, Connor K, Hatcher J, Hope C, Gordon M, Arendash GW (2000) A beta peptide vaccination prevents memory loss in an animal model of Alzheimer’s disease. Nature 408(6815):982–985CrossRefPubMedGoogle Scholar
  30. 30.
    Nitsch RM, Hock C (2008) Targeting beta-amyloid pathology in Alzheimer’s disease with Abeta immunotherapy. Neurotherapeutics 5(3):415–420CrossRefPubMedGoogle Scholar
  31. 31.
    Bales KR, Tzavara ET, Wu S, Wade MR, Bymaster FP, Paul SM, Nomikos GG (2006) Cholinergic dysfunction in a mouse model of Alzheimer disease is reversed by an anti-A beta antibody. J Clin Invest 116(3):825–832CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Morgan D (2011) Immunotherapy for Alzheimer’s disease. J Intern Med 269(1):54–63CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Nelson AL, Dhimolea E, Reichert JM (2010) Development trends for human monoclonal antibody therapeutics. Nat Rev Drug Discov 9(10):767–774CrossRefPubMedGoogle Scholar
  34. 34.
    Salloway S et al (2012) A randomized, double-blind, placebo-controlled clinical trial of intravenous bapineuzumab in patients with Alzheimer’s disease who are apolipoprotein E e4 non-carriers. Eur J Neurol 19(Suppl 1):70Google Scholar
  35. 35.
    Sperling R et al (2012) A randomized, double-blind, placebo-controlled clinical trial of intravenous bapineuzumab in patients with Alzheimer’s disease who are apolipoprotein E e4 carriers. Eur J Neurol 19(Suppl 1):70Google Scholar
  36. 36.
    Tayeb HO, Murray ED, Price BH, Tarazi FI (2013) Bapineuzumab and solanezumab for Alzheimer’s disease: is the ‘amyloid cascade hypothesis’ still alive? Expert Opin Biol Ther 13(7):1075–1084CrossRefPubMedGoogle Scholar
  37. 37.
    Delrieu J, Ousset PJ, Vellas B (2012) Gantenerumab for the treatment of Alzheimer’s disease. Expert Opin Biol Ther 12(8):1077–1086CrossRefPubMedGoogle Scholar
  38. 38.
    Moreth J, Mavoungou C, Schindowski K (2013) Passive anti-amyloid immunotherapy in Alzheimer’s disease: what are the most promising targets? Immun Ageing 10(1):18CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Zlokovic BV (2004) Clearing amyloid through the blood-brain barrier. J Neurochem 89(4):807–811CrossRefPubMedGoogle Scholar
  40. 40.
    Schenk D (2002) Amyloid-beta immunotherapy for Alzheimer’s disease: the end of the beginning. Nat Rev Neurosci 3(10):824–828CrossRefPubMedGoogle Scholar
  41. 41.
    Gilman S, Koller M, Black RS, Jenkins L, Griffith SG, Fox NC, Eisner L, Kirby L, Rovira MB, Forette F, Orgogozo JM, AN1792(QS-21)-201 Study Team (2005) Clinical effects of Abeta immunization (AN1792) in patients with AD in an interrupted trial. Neurology 64(9):1553–62CrossRefPubMedGoogle Scholar
  42. 42.
    Holmes C, Boche D, Wilkinson D, Yadegarfar G, Hopkins V, Bayer A, Jones RW, Bullock R, Love S, Neal JW, Zotova E, Nicoll JA (2008) Long-term effects of Abeta42 immunisation in Alzheimer’s disease: follow-up of a randomised, placebo-controlled phase I trial. Lancet 372(9634):216–223CrossRefPubMedGoogle Scholar
  43. 43.
    Nicoll JA, Wilkinson D, Holmes C, Steart P, Markham H, Weller RO (2003) Neuropathology of human Alzheimer disease after immunization with amyloid-beta peptide: a case report. Nat Med 9(4):448–452CrossRefPubMedGoogle Scholar
  44. 44.
    Vellas B, Black R, Thal LJ, Fox NC, Daniels M, McLennan G, Tompkins C, Leibman C, Pomfret M, Grundman M, AN1792 (QS-21)-251 Study Team (2009) Long-term follow-up of patients immunized with AN1792: reduced functional decline in antibody responders. Curr Alzheimer Res 6(2):144–51CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Farlow MR, Andreasen N, Riviere ME, Vostiar I, Vitaliti A, Sovago J, Caputo A, Winblad B, Graf A (2015) Long-term treatment with active Aβ immunotherapy with CAD106 in mild Alzheimer’s disease. Alzheimers Res Ther 7(1):23CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
  47. 47.
  48. 48.
  49. 49.
    Sperling RA, Jack CR, Black SE, Frosch MP, Greenberg SM, Hyman BT, Scheltens P, Carrillo MC, Thies W, Bednar MM, Black RS, Brashear HR, Grundman M, Siemers ER, Feldman HH, Schindler RJ (2011) Amyloid-related imaging abnormalities in amyloid-modifying therapeutic trials: recommendations from the Alzheimer’s Association Research Roundtable Workgroup. Alzheimers Dement 7(4):367–385CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Barkhof F, Daams M, Scheltens P, Brashear HR, Arrighi HM, Bechten A, Morris K, McGovern M, Wattjes MP (2013) An MRI rating scale for amyloid-related imaging abnormalities with edema or effusion. AJNR Am J Neuroradiol 34:1550–1555CrossRefPubMedGoogle Scholar
  51. 51.
    Salloway S, Sperling R, Gilman S, Fox NC, Blennow K, Raskind M, Sabbagh M, Honig LS, Doody R, van Dyck CH, Mulnard R, Barakos J, Gregg KM, Liu E, Lieberburg I, Schenk D, Black R, Grundman M, Bapineuzumab 201 Clinical Trial Investigators (2009) A phase 2 multiple ascending dose trial of bapineuzumab in mild to moderate Alzheimer disease. Neurology 73(24):2061–70CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Miller G (2012) Alzheimer’s research. Stopping Alzheimer’s before it starts. Science 337(6096):790–2CrossRefPubMedGoogle Scholar
  53. 53.
    (2015). Accessed from: http://synapse-pi.com/epad/
  54. 54.
    Crespi GA, Ascher DB, Parker MW, Miles LA (2014) Crystallization and preliminary X-ray diffraction analysis of the Fab portion of the Alzheimer’s disease immunotherapy candidate bapineuzumab complexed with amyloid-β. Acta Crystallogr F Struct Biol Commun 70(Pt 3):374–7CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Single ascending dose study of BIIB037 in subjects with Alzheimer’s disease [Internet]. Retrieved from: http://www.clinicaltrials.gov/ct2/show/NCT01397539?term=BIIB037&rank=2
  56. 56.
    Lannfelt L, Möller C, Basun H, Osswald G, Sehlin D, Satlin A, Logovinsky V, Gellerfors P (2014) Perspectives on future Alzheimer therapies: amyloid-β protofibrils - a new target for immunotherapy with BAN2401 in Alzheimer’s disease. Alzheimers Res Ther 6(2):16CrossRefPubMedPubMedCentralGoogle Scholar
  57. 57.
    Adolfsson O, Pihlgren M, Toni N, Varisco Y, Buccarello AL, Antoniello K, Lohmann S, Piorkowska K, Gafner V, Atwal JK, Maloney J, Chen M, Gogineni A, Weimer RM, Mortensen DL, Friesenhahn M, Ho C, Paul R, Pfeifer A, Muhs A, Watts RJ (2012) An effector-reduced anti-β-amyloid (Aβ) antibody with unique aβ binding properties promotes neuroprotection and glial engulfment of Aβ. J Neurosci 32(28):9677–9689CrossRefPubMedGoogle Scholar
  58. 58.
    Garber K (2012) Genentech’s Alzheimer’s antibody trial to study disease prevention. Nat Biotechnol 30(8):731–732CrossRefPubMedGoogle Scholar
  59. 59.
    Relkin N (2014) Clinical trials of intravenous immunoglobulin for Alzheimer’s disease. J Clin Immunol 34(Suppl 1):S74–9CrossRefPubMedGoogle Scholar
  60. 60.
    Bohrmann B, Baumann K, Benz J, Gerber F, Huber W, Knoflach F, Messer J, Oroszlan K, Rauchenberger R, Richter WF, Rothe C, Urban M, Bardroff M, Winter M, Nordstedt C, Loetscher H (2012) Gantenerumab: a novel human anti-Aβ antibody demonstrates sustained cerebral amyloid-β binding and elicits cell-mediated removal of human amyloid-β. J Alzheimers Dis; 28(1):49–69PubMedGoogle Scholar
  61. 61.
    Ostrowitzki S, Deptula D, Thurfjell L, Barkhof F, Bohrmann B, Brooks DJ, Klunk WE, Ashford E, Yoo K, Xu ZX, Loetscher H, Santarelli L (2012) Mechanism of amyloid removal in patients with Alzheimer disease treated with gantenerumab. Arch Neurol 69(2):198–207CrossRefPubMedGoogle Scholar
  62. 62.
    Andreasen N, Simeoni M, Ostlund H, Lisjo PI, Fladby T, Loercher AE, Byrne GJ, Murray F, Scott-Stevens PT, Wallin A, Zhang YY, Bronge LH, Zetterberg H, Nordberg AK, Yeo AJ, Khan SA, Hilpert J, Mistry PC (2015) First administration of the Fc-attenuated anti-β amyloid antibody GSK933776 to patients with mild Alzheimer’s disease: a randomized, placebo-controlled study. PLoS One 10(3):e0098153CrossRefPubMedPubMedCentralGoogle Scholar
  63. 63.
    A study of single and multiple doses of KHK6640 in subjects with prodromal or mild to moderate Alzheimer’s disease [Internet]. [cited 2015]. Retrieved from: https://clinicaltrials.gov/ct2/show/NCT02127476
  64. 64.
    Demattos RB, Lu J, Tang Y, Racke MM, Delong CA, Tzaferis JA, Hole JT, Forster BM, McDonnell PC, Liu F, Kinley RD, Jordan WH, Hutton ML (2012) A plaque-specific antibody clears existing β-amyloid plaques in Alzheimer’s disease mice. Neuron 76(5):908–920CrossRefPubMedGoogle Scholar
  65. 65.
  66. 66.
    Burstein AH, Zhao Q, Ross J, Styren S, Landen JW, Ma WW, McCush F, Alvey C, Kupiec JW, Bednar MM (2013) Safety and pharmacology of ponezumab (PF-04360365) after a single 10-minute intravenous infusion in subjects with mild to moderate Alzheimer disease. Clin Neuropharmacol 36(1):8–13CrossRefPubMedGoogle Scholar
  67. 67.
    Landen JW, Zhao Q, Cohen S, Borrie M, Woodward M, Billing CB, Bales K, Alvey C, McCush F, Yang J, Kupiec JW, Bednar MM (2013) Safety and pharmacology of a single intravenous dose of ponezumab in subjects with mild-to-moderate Alzheimer disease: a phase I, randomized, placebo-controlled, double-blind, dose-escalation study. Clin Neuropharmacol 36(1):14–23CrossRefPubMedGoogle Scholar
  68. 68.
    Single and repeated dosing study to assess the safety and the concentration-time profile of SAR228810 in Alzheimer’s patients [Internet]. Retrieved from: http://www.clinicaltrials.gov/ct2/show/NCT01485302?term=SAR228810&rank=1
  69. 69.
    Farlow M, Arnold SE, van Dyck CH, Aisen PS, Snider BJ, Porsteinsson AP, Friedrich S, Dean RA, Gonzales C, Sethuraman G, DeMattos RB, Mohs R, Paul SM, Siemers ER (2012) Safety and biomarker effects of solanezumab in patients with Alzheimer’s disease. Alzheimers Dement 8(4):261–271CrossRefPubMedGoogle Scholar
  70. 70.
    Hickman DT, López-Deber MP, Ndao DM, Silva AB, Nand D, Pihlgren M, Giriens V, Madani R, St-Pierre A, Karastaneva H, Nagel-Steger L, Willbold D, Riesner D, Nicolau C, Baldus M, Pfeifer A, Muhs A (2011) Sequence-independent control of peptide conformation in liposomal vaccines for targeting protein misfolding diseases. J Biol Chem 286(16):13966–13976CrossRefPubMedPubMedCentralGoogle Scholar
  71. 71.
    Schneeberger A, Mandler M, Otawa O, Zauner W, Mattner F, Schmidt W (2009) Development of AFFITOPE vaccines for Alzheimer’s disease (AD)--from concept to clinical testing. J Nutr Health Aging 13(3):264–267CrossRefPubMedGoogle Scholar
  72. 72.
    Kingwell K (2012) Alzheimer disease: amyloid-β immunotherapy CAD106 passes first safety test in patients with Alzheimer disease. Nat Rev Neurol 8(8):414PubMedGoogle Scholar
  73. 73.
    Ryan JM, Grundman M (2009) Anti-amyloid-beta immunotherapy in Alzheimer’s disease: ACC-001 clinical trials are ongoing. J Alzheimers Dis. 243Google Scholar

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© Springer Science+Business Media New York 2016

Authors and Affiliations

  1. 1.Alzheimer Center and Department of Neurology, Neuroscience Campus Amsterdam, Vrije Universiteit Medical CenterAmsterdamThe Netherlands
  2. 2.Alzheimer Research CenterAmsterdamThe Netherlands

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