Alzheimer's Disease: Lessons Learned from Amyloidocentric Clinical Trials

CNS Drugs

Volumn 29, Issue 6, 2015, Pages 487-502

  Soejitno, Andreas ^a   Tjan, Anastasia ^b   Purwata, Thomas Eko ^c  

^a National Hospital   (Indonesia)

^b PELITA HARAPAN UNIVERSITY   (Indonesia)

^c UDAYANA UNIVERSITY   (Indonesia)

Author keywords

[No Author keywords available]

Indexed keywords

ALZHEIMER DISEASE VACCINE; AMYLOID BETA PROTEIN; BAPINEUZUMAB; BETA SECRETASE INHIBITOR; GAMMA SECRETASE INHIBITOR; SOLANEZUMAB; TAU PROTEIN; AMYLOID;

ALZHEIMER DISEASE; ARTICLE; CLINICAL TRIAL (TOPIC); COGNITIVE DEFECT; FUNCTIONAL MAGNETIC RESONANCE IMAGING; HUMAN; IMMUNOTHERAPY; NONHUMAN; POSITRON EMISSION TOMOGRAPHY; PRIORITY JOURNAL; PROTEIN INTERACTION; SENSITIVITY AND SPECIFICITY; TAUOPATHY; ANIMAL; METABOLISM;

ALZHEIMER DISEASE; AMYLOID; ANIMALS; CLINICAL TRIALS AS TOPIC; HUMANS;

EID: 84938205301     PISSN: 11727047     EISSN: 11791934     Source Type: Journal    
DOI: 10.1007/s40263-015-0257-8     Document Type: Article

References (126)

1. Klein WL, Krafft GA, Finch CE. Targeting small Abeta oligomers: the solution to an Alzheimer's disease conundrum? Trends Neurosci. 2001;24(4):219-24.
2. Lue LF, Kuo YM, Roher AE, Brachova L, Shen Y, Sue L, et al. Soluble amyloid beta peptide concentration as a predictor of synaptic change in Alzheimer's disease. Am J Pathol. 1999;155(3):853-62.
3. Dahlgren KN, Manelli AM, Stine WB Jr, Baker LK, Krafft GA, LaDu MJ. Oligomeric and fibrillar species of amyloid-beta peptides differentially affect neuronal viability. J Biol Chem. 2002;277(35):32046-53.
4. Hoshi M, Sato M, Matsumoto S, Noguchi A, Yasutake K, Yoshida N, et al. Spherical aggregates of beta-amyloid (amylospheroid) show high neurotoxicity and activate tau protein kinase I/glycogen synthase kinase-3beta. Proc Natl Acad Sci. 2003;100(11):6370-5.
5. Cuajungco MP, Goldstein LE, Nunomura A, Smith MA, Lim JT, Atwood CS, et al. Evidence that the beta-amyloid plaques of Alzheimer's disease represent the redox-silencing and entombment of abeta by zinc. J Biol Chem. 2000;275(26):19439-42.
6. 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(3):349-57.
7. Terry RD, Masliah E, Salmon DP, Butters N, DeTeresa R, Hill R, et al. Physical basis of cognitive alterations in Alzheimer's disease: synapse loss is the major correlate of cognitive impairment. Ann Neurol. 1991;30(4):572-80.
8. Arriagada PV, Growdon JH, Hedley-Whyte ET, Hyman BT. Neurofibrillary tangles but not senile plaques parallel duration and severity of Alzheimer's disease. Neurology. 1992;42(3 Pt 1):631-9.
9. Giannakopoulos P, Herrmann FR, Bussiere T, Bouras C, Kovari E, Perl DP, et al. Tangle and neuron numbers, but not amyloid load, predict cognitive status in Alzheimer's disease. Neurology. 2003;60(9):1495-500.
10. Giacobini E, Gold G. Alzheimer disease therapy-moving from amyloid-beta to tau. Nat Rev Neurol. 2013;9(12):677-86.
11. Stancu IC, Ris L, Vasconcelos B, Marinangeli C, Goeminne L, Laporte V, et al. Tauopathy contributes to synaptic and cognitive deficits in a murine model for Alzheimer's disease. FASEB J. 2014;28(6):2620-31.
12. Pievani M, de Haan W, Wu T, Seeley WW, Frisoni GB. Functional network disruption in the degenerative dementias. Lancet Neurol. 2011;10(9):829-43.
13. Desikan RS, McEvoy LK, Thompson WK, Holland D, Brewer JB, Aisen PS, et al. Amyloid-beta-associated clinical decline occurs only in the presence of elevated P-tau. Arch Neurol. 2012;69(6):709-13.
14. Corrada MM, Berlau DJ, Kawas CH. A population-based clinicopathological study in the oldest-old: the 90+ study. Curr Alzheimer Res. 2012;9(6):709-17.
15. Jack CR Jr, Knopman DS, Jagust WJ, Shaw LM, Aisen PS, Weiner MW, et al. Hypothetical model of dynamic biomarkers of the Alzheimer's pathological cascade. Lancet Neurol. 2010;9(1):119-28.
16. Villemagne VL, Burnham S, Bourgeat P, Brown B, Ellis KA, Salvado O, et al. Amyloid beta deposition, neurodegeneration, and cognitive decline in sporadic Alzheimer's disease: a prospective cohort study. Lancet Neurol. 2013;12(4):357-67.
17. Hutton M, Lendon CL, Rizzu P, Baker M, Froelich S, Houlden H, et al. Association of missense and 5'-splice-site mutations in tau with the inherited dementia FTDP-17. Nature. 1998;393(6686):702-5.
18. Lee VM, Goedert M, Trojanowski JQ. Neurodegenerative tauopathies. Annu Rev Neurosci. 2001;24:1121-59.
19. Ballatore C, Lee VM, Trojanowski JQ. Tau-mediated neurodegeneration in Alzheimer's disease and related disorders. Nat Rev Neurosci. 2007;8(9):663-72.
20. Brunden KR, Trojanowski JQ, Lee VM. Advances in tau-focused drug discovery for Alzheimer's disease and related tauopathies. Nat Rev Drug Discov. 2009;8(10):783-93.
21. Reddy PH. Abnormal tau, mitochondrial dysfunction, impaired axonal transport of mitochondria, and synaptic deprivation in Alzheimer's disease. Brain Res. 2011;1415:136-48.
22. Cosman KM, Boyle LL, Porsteinsson AP. Memantine in the treatment of mild-to-moderate Alzheimer's disease. Expert Opin Pharmacother. 2007;8(2):203-14.
23. Georgievska B, Sandin J, Doherty J, Mortberg A, Neelissen J, Andersson A, et al. AZD1080, a novel GSK3 inhibitor, rescues synaptic plasticity deficits in rodent brain and exhibits peripheral target engagement in humans. J Neurochem. 2013;125(3):446-56.
24. Karran E, Mercken M, De Strooper B. The amyloid cascade hypothesis for Alzheimer's disease: an appraisal for the development of therapeutics. Nat Rev Drug Discov. 2011;10(9):698-712.
25. Nelson PT, Braak H, Markesbery WR. Neuropathology and cognitive impairment in Alzheimer disease: a complex but coherent relationship. J Neuropathol Exp Neurol. 2009;68(1):1-14.
26. Jin M, Shepardson N, Yang T, Chen G, Walsh D, Selkoe DJ. Soluble amyloid beta-protein dimers isolated from Alzheimer cortex directly induce Tau hyperphosphorylation and neuritic degeneration. Proc Natl Acad Sci. 2011;108(14):5819-24.
27. Mawuenyega KG, Sigurdson W, Ovod V, Munsell L, Kasten T, Morris JC, et al. Decreased clearance of CNS beta-amyloid in Alzheimer's disease. Science. 2010;330(6012):1774.
28. Blennow K, Hampel H, Weiner M, Zetterberg H. Cerebrospinal fluid and plasma biomarkers in Alzheimer disease. Nat Rev Neurol. 2010;6(3):131-44.
29. Fagan AM. CSF biomarkers of Alzheimer's disease: impact on disease concept, diagnosis, and clinical trial design. Adv Geriatr. 2014;2014:14.
30. Hampel H, Blennow K, Shaw LM, Hoessler YC, Zetterberg H, Trojanowski JQ. Total and phosphorylated tau protein as biological markers of Alzheimer's disease. Exp Gerontol. 2010;45(1):30-40.
31. Irwin DJ, Trojanowski JQ, Grossman M. Cerebrospinal fluid biomarkers for differentiation of frontotemporal lobar degeneration from Alzheimer's disease. Front Aging Neurosci. 2013;5:6.
32. Stomrud E, Hansson O, Blennow K, Minthon L, Londos E. Cerebrospinal fluid biomarkers predict decline in subjective cognitive function over 3 years in healthy elderly. Dement Geriatr Cogn Disord. 2007;24(2):118-24.
33. Gustafson DR, Skoog I, Rosengren L, Zetterberg H, Blennow K. Cerebrospinal fluid beta-amyloid 1-42 concentration may predict cognitive decline in older women. J Neurol Neurosurg Psychiatry. 2007;78(5):461-4.
34. Skoog I, Davidsson P, Aevarsson O, Vanderstichele H, Vanmechelen E, Blennow K. Cerebrospinal fluid beta-amyloid 42 is reduced before the onset of sporadic dementia: a population-based study in 85-year-olds. Dement Geriatr Cogn Disord. 2003;15(3):169-76.
35. Fagan AM, Roe CM, Xiong C, Mintun MA, Morris JC, Holtzman DM. Cerebrospinal fluid tau/beta-amyloid(42) ratio as a prediction of cognitive decline in nondemented older adults. Arch Neurol. 2007;64(3):343-9.
36. Li G, Sokal I, Quinn JF, Leverenz JB, Brodey M, Schellenberg GD, et al. CSF tau/Abeta42 ratio for increased risk of mild cognitive impairment: a follow-up study. Neurology. 2007;69(7):631-9.
37. Clark CM, Pontecorvo MJ, Beach TG, Bedell BJ, Coleman RE, Doraiswamy PM, et al. Cerebral PET with florbetapir compared with neuropathology at autopsy for detection of neuritic amyloid-beta plaques: a prospective cohort study. Lancet Neurol. 2012;11(8):669-78.
38. Kobylecki C, Langheinrich T, Hinz R, Vardy ER, Brown G, Martino ME, et al. 18F-florbetapir PET in patients with frontotemporal dementia and Alzheimer disease. J Nucl Med. 2015;56(3):386-91.
39. Hatashita S, Yamasaki H, Suzuki Y, Tanaka K, Wakebe D, Hayakawa H. [18F]Flutemetamol amyloid-beta PET imaging compared with [11C]PIB across the spectrum of Alzheimer's disease. Eur J Nucl Med Mol Imaging. 2014;41(2):290-300.
40. Fagan AM, Mintun MA, Shah AR, Aldea P, Roe CM, Mach RH, et al. 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(8-9):371-80.
41. Landau SM, Lu M, Joshi AD, Pontecorvo M, Mintun MA, Trojanowski JQ, et al. Comparing positron emission tomography imaging and cerebrospinal fluid measurements of beta-amyloid. Ann Neurol. 2013;74(6):826-36.
42. Mattsson N, Insel PS, Landau S, Jagust W, Donohue M, Shaw LM, et al. Diagnostic accuracy of CSF Ab42 and florbetapir PET for Alzheimer's disease. Ann Clin Transl Neurol. 2014;1(8):534-43.
43. Dubois B, Feldman HH, Jacova C, Cummings JL, Dekosky ST, Barberger-Gateau P, et al. Revising the definition of Alzheimer's disease: a new lexicon. Lancet Neurol. 2010;9(11):1118-27.
44. McKhann GM, Knopman DS, Chertkow H, Hyman BT, Jack CR Jr, Kawas CH, et al. 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. Alzheimer's Dement J Alzheimer's Assoc. 2011;7(3):263-9.
45. Hemming ML, Elias JE, Gygi SP, Selkoe DJ. Identification of beta-secretase (BACE1) substrates using quantitative proteomics. PLoS One. 2009;4(12):e8477.
46. Kuhn PH, Koroniak K, Hogl S, Colombo A, Zeitschel U, Willem M, et al. Secretome protein enrichment identifies physiological BACE1 protease substrates in neurons. EMBO J. 2012;31(14):3157-68.
47. May PC, Dean RA, Lowe SL, Martenyi F, Sheehan SM, Boggs LN, et al. Robust central reduction of amyloid-beta in humans with an orally available, non-peptidic beta-secretase inhibitor. J Neurosci. 2011;31(46):16507-16.
48. Vassar R, Kuhn PH, Haass C, Kennedy ME, Rajendran L, Wong PC, et al. Function, therapeutic potential and cell biology of BACE proteases: current status and future prospects. J Neurochem. 2014;130(1):4-28.
49. Hu X, Hicks CW, He W, Wong P, Macklin WB, Trapp BD, et al. Bace1 modulates myelination in the central and peripheral nervous system. Nat Neurosci. 2006;9(12):1520-5.
50. Willem M, Garratt AN, Novak B, Citron M, Kaufmann S, Rittger A, et al. Control of peripheral nerve myelination by the beta-secretase BACE1. Science. 2006;314(5799):664-6.
51. Lahiri DK, Maloney B, Long JM, Greig NH. Lessons from a BACE1 inhibitor trial: off-site but not off base. Alzheimer's Dement. 2014;10:S411-9.
52. Alzforum. LY2886721. 2013. Available from: http://www.alzforum.org/therapeutics/ly2886721. Accessed 19 June 2015.
53. An Efficacy and Safety Trial of MK-8931 in Mild to Moderate Alzheimer's Disease (P07738) (EPOCH) [database on the Internet]. Clinicaltrials.gov. 2015. Available from: https://clinicaltrials.gov/ct2/show/NCT01739348. Accessed 19 June 2015.
54. Efficacy and Safety Trial of MK-8931 in Participants With Prodromal Alzheimer's Disease (MK-8931-019) (APECS) [database on the Internet]. Clinicaltrials.gov. 2015. Available from: https://clinicaltrials.gov/ct2/show/NCT01953601. Accessed 19 June 2015.
55. Morgan D, Gitter BD. Evidence supporting a role for anti-Abeta antibodies in the treatment of Alzheimer's disease. Neurobiol Aging. 2004;25(5):605-8.
56. May PC, Yang Z, Li W-Y, Hyslop PA, Siemers E, Boggs LN. O3-06-07 Multi-compartmental pharmacodynamic assessment of the functional gamma-secretase inhibitor LY450139 in PDAPP transgenic mice and non-transgenic mice. Neurobiol Aging. 2004;25:S65.
57. Hyslop PA, May PC, Audia JE, Calligaro DO, McMillian CL, Garner CO, et al. P1-180 Reduction in a-beta(1-40) and A-beta(1-42) in CSF and plasma in the beagle dog following acute oral dosing of the gamma secretase inhibitor, LY450139. Neurobiol Aging. 2004;25:S147.
58. Henley DB, May PC, Dean RA, Siemers ER. Development of semagacestat (LY450139), a functional gamma-secretase inhibitor, for the treatment of Alzheimer's disease. Expert Opin Pharmacother. 2009;10(10):1657-64.
59. Lanz TA, Karmilowicz MJ, Wood KM, Pozdnyakov N, Du P, Piotrowski MA, et al. Concentration-dependent modulation of amyloid-beta in vivo and in vitro using the gamma-secretase inhibitor, LY-450139. J Pharmacol Exp Ther. 2006;319(2):924-33.
60. Li T, Huang Y, Jin S, Ye L, Rong N, Yang X, et al. Gamma-secretase modulators do not induce Abeta-rebound and accumulation of beta-C-terminal fragment. J Neurochem. 2012;121(2):277-86.
61. Chavez-Gutierrez L, Bammens L, Benilova I, Vandersteen A, Benurwar M, Borgers M, et al. The mechanism of gamma-Secretase dysfunction in familial Alzheimer disease. EMBO J. 2012;31(10):2261-74.
62. Krop I, Demuth T, Guthrie T, Wen PY, Mason WP, Chinnaiyan P, et al. Phase I pharmacologic and pharmacodynamic study of the gamma secretase (Notch) inhibitor MK-0752 in adult patients with advanced solid tumors. J Clin Oncol. 2012;30(19):2307-13.
63. Weng AP, Ferrando AA, Lee W, Morris JP, Silverman LB, Sanchez-Irizarry C, et al. Activating mutations of NOTCH1 in human T cell acute lymphoblastic leukemia. Science. 2004;306(5694):269-71.
64. Phng LK, Gerhardt H. Angiogenesis: a team effort coordinated by notch. Dev Cell. 2009;16(2):196-208.
65. Siemers ER, Dean RA, Friedrich S, Ferguson-Sells L, Gonzales C, Farlow MR, et al. Safety, tolerability, and effects on plasma and cerebrospinal fluid amyloid-beta after inhibition of gamma-secretase. Clin Neuropharmacol. 2007;30(6):317-25.
66. Coric V, van Dyck CH, Salloway S, Andreasen N, Brody M, Richter RW, et al. Safety and tolerability of the gamma-secretase inhibitor avagacestat in a phase 2 study of mild to moderate Alzheimer disease. Arch Neurol. 2012;69(11):1430-40.
67. Dockens R, Wang JS, Castaneda L, Sverdlov O, Huang SP, Slemmon R, et al. A placebo-controlled, multiple ascending dose study to evaluate the safety, pharmacokinetics and pharmacodynamics of avagacestat (BMS-708163) in healthy young and elderly subjects. Clin Pharmacokinet. 2012;51(10):681-93.
68. Tong G, Wang JS, Sverdlov O, Huang SP, Slemmon R, Croop R, et al. A contrast in safety, pharmacokinetics and pharmacodynamics across age groups after a single 50 mg oral dose of the gamma-secretase inhibitor avagacestat. Br J Clin Pharmacol. 2013;75(1):136-45.
69. Albright CF, Dockens RC, Meredith JE Jr, Olson RE, Slemmon R, Lentz KA, et al. Pharmacodynamics of selective inhibition of gamma-secretase by avagacestat. J Pharmacol Exp Ther. 2013;344(3):686-95.
70. Tong G, Castaneda L, Wang JS, Sverdlov O, Huang SP, Slemmon R, et al. Effects of single doses of avagacestat (BMS-708163) on cerebrospinal fluid Abeta levels in healthy young men. Clin Drug Investig. 2012;32(11):761-9.
71. Portelius E, Price E, Brinkmalm G, Stiteler M, Olsson M, Persson R, et al. A novel pathway for amyloid precursor protein processing. Neurobiol Aging. 2011;32(6):1090-8.
72. Broersen K, Rousseau F, Schymkowitz J. The culprit behind amyloid beta peptide related neurotoxicity in Alzheimer's disease: oligomer size or conformation? Alzheimers Res Ther. 2010;2(4):12.
73. Weggen S, Eriksen JL, Sagi SA, Pietrzik CU, Ozols V, Fauq A, et al. Evidence that nonsteroidal anti-inflammatory drugs decrease amyloid beta 42 production by direct modulation of gamma-secretase activity. J Biol Chem. 2003;278(34):31831-7.
74. Eriksen JL, Sagi SA, Smith TE, Weggen S, Das P, McLendon DC, et al. NSAIDs and enantiomers of flurbiprofen target gamma-secretase and lower Abeta 42 in vivo. J Clin Investig. 2003;112(3):440-9.
75. Townsend KP, Pratico D. Novel therapeutic opportunities for Alzheimer's disease: focus on nonsteroidal anti-inflammatory drugs. FASEB J. 2005;19(12):1592-601.
76. Selkoe DJ. The therapeutics of Alzheimer's disease: where we stand and where we are heading. Ann Neurol. 2013;74(3):328-36.
77. Imbimbo BP, Del Giudice E, Cenacchi V, Volta R, Villetti G, Facchinetti F, et al. In vitro and in vivo profiling of CHF5022 and CHF5074 Two beta-amyloid1-42 lowering agents. Pharmacol Res. 2007;55(4):318-28.
78. Peretto I, Radaelli S, Parini C, Zandi M, Raveglia LF, Dondio G, et al. Synthesis and biological activity of flurbiprofen analogues as selective inhibitors of beta-amyloid(1)(-)(42) secretion. J Med Chem. 2005;48(18):5705-20.
79. Lanz TA, Fici GJ, Merchant KM. Lack of specific amyloid-beta(1-42) suppression by nonsteroidal anti-inflammatory drugs in young, plaque-free Tg2576 mice and in guinea pig neuronal cultures. J Pharmacol Exp Ther. 2005;312(1):399-406.
80. Galasko DR, Graff-Radford N, May S, Hendrix S, Cottrell BA, Sagi SA, et al. Safety, tolerability, pharmacokinetics, and Abeta levels after short-term administration of R-flurbiprofen in healthy elderly individuals. Alzheimer Dis Assoc Disord. 2007;21(4):292-9.
81. Wilcock GK, Black SE, Hendrix SB, Zavitz KH, Swabb EA, Laughlin MA. Efficacy and safety of tarenflurbil in mild to moderate Alzheimer's disease: a randomised phase II trial. Lancet Neurol. 2008;7(6):483-93.
82. Green RC, Schneider LS, Amato DA, Beelen AP, Wilcock G, Swabb EA, et al. Effect of tarenflurbil on cognitive decline and activities of daily living in patients with mild Alzheimer disease: a randomized controlled trial. JAMA. 2009;302(23):2557-64.
83. Schenk D, Barbour R, Dunn W, Gordon G, Grajeda H, Guido T, et al. Immunization with amyloid-beta attenuates Alzheimer-disease-like pathology in the PDAPP mouse. Nature. 1999;400(6740):173-7.
84. Morgan D, Diamond DM, Gottschall PE, Ugen KE, Dickey C, Hardy J, et al. A beta peptide vaccination prevents memory loss in an animal model of Alzheimer's disease. Nature. 2000;408(6815):982-5.
85. Janus C, Pearson J, McLaurin J, Mathews PM, Jiang Y, Schmidt SD, et al. A[beta] peptide immunization reduces behavioural impairment and plaques in a model of Alzheimer's disease. Nature. 2000;408(6815):979-82.
86. Bayer AJ, Bullock R, Jones RW, Wilkinson D, Paterson KR, Jenkins L, et al. Evaluation of the safety and immunogenicity of synthetic Abeta42 (AN1792) in patients with AD. Neurology. 2005;64(1):94-101.
87. Wisniewski T, Frangione B. Immunological and anti-chaperone therapeutic approaches for Alzheimer disease. Brain Pathol. 2005;15(1):72-7.
88. Orgogozo JM, Gilman S, Dartigues JF, Laurent B, Puel M, Kirby LC, et al. Subacute meningoencephalitis in a subset of patients with AD after Abeta42 immunization. Neurology. 2003;61(1):46-54.
89. Pride M, Seubert P, Grundman M, Hagen M, Eldridge J, Black RS. Progress in the active immunotherapeutic approach to Alzheimer's disease: clinical investigations into AN1792-associated meningoencephalitis. Neurodegener Dis. 2008;5(3-4):194-6.
90. 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(4):448-52.
91. Nicoll JA, Barton E, Boche D, Neal JW, Ferrer I, Thompson P, et al. Abeta species removal after abeta42 immunization. J Neuropathol Exp Neurol. 2006;65(11):1040-8.
92. Masliah E, Hansen L, Adame A, Crews L, Bard F, Lee C, et al. Abeta vaccination effects on plaque pathology in the absence of encephalitis in Alzheimer disease. Neurology. 2005;64(1):129-31.
93. Bombois S, Maurage CA, Gompel M, Deramecourt V, Mackowiak-Cordoliani MA, Black RS, et al. Absence of beta-amyloid deposits after immunization in Alzheimer disease with Lewy body dementia. Arch Neurol. 2007;64(4):583-7. doi: 10.1001/archneur.64.4.583.
94. Davtyan H, Petrushina I, Ghochikyan A. Immunotherapy for Alzheimer's disease: DNA- and protein-based epitope vaccines. Methods Mol Biol. 2014;1143:259-81.
95. Petrushina I, Ghochikyan A, Mktrichyan M, Mamikonyan G, Movsesyan N, Davtyan H, et al. Alzheimer's disease peptide epitope vaccine reduces insoluble but not soluble/oligomeric Abeta species in amyloid precursor protein transgenic mice. J Neurosci. 2007;27(46):12721-31.
96. Patton RL, Kalback WM, Esh CL, Kokjohn TA, Van Vickle GD, Luehrs DC, et al. Amyloid-β Peptide Remnants in AN-1792-Immunized Alzheimer's Disease Patients. Am J Pathol. 2006;169(3):1048-63.
97. Ferrer I, Boada Rovira M, Sanchez Guerra ML, Rey MJ, Costa-Jussa F. Neuropathology and pathogenesis of encephalitis following amyloid-beta immunization in Alzheimer's disease. Brain Pathol. 2004;14(1):11-20.
98. Hock C, Konietzko U, Streffer JR, Tracy J, Signorell A, Muller-Tillmanns B, et al. Antibodies against beta-amyloid slow cognitive decline in Alzheimer's disease. Neuron. 2003;38(4):547-54.
99. Vellas B, Black R, Thal LJ, Fox NC, Daniels M, McLennan G, et al. Long-term follow-up of patients immunized with AN1792: reduced functional decline in antibody responders. Curr Alzheimer Res. 2009;6(2):144-51.
100. Robinson SR, Bishop GM, Lee HG, Munch G. Lessons from the AN 1792 Alzheimer vaccine: lest we forget. Neurobiol Aging. 2004;25(5):609-15.
101. Wisniewski T, Konietzko U. Amyloid-beta immunisation for Alzheimer's disease. Lancet Neurol. 2008;7(9):805-11.
102. Winblad B, Graf A, Riviere ME, Andreasen N, Ryan JM. Active immunotherapy options for Alzheimer's disease. Alzheimers Res Ther. 2014;6(1):7.
103. Arai H, Suzuki H, Yoshiyama T, Lobello K, Peng Y, Liu E, et al. 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. Alzheimer's Dement. 9(4):P282.
104. Karran E, Hardy J. A critique of the drug discovery and phase 3 clinical programs targeting the amyloid hypothesis for Alzheimer disease. Ann Neurol. 2013;76(2):185-205.
105. Bard F, Cannon C, Barbour R, Burke RL, Games D, Grajeda H, et al. Peripherally administered antibodies against amyloid beta-peptide enter the central nervous system and reduce pathology in a mouse model of Alzheimer disease. Nat Med. 2000;6(8):916-9.
106. Demattos RB, Lu J, Tang Y, Racke MM, Delong CA, Tzaferis JA, et al. A plaque-specific antibody clears existing beta-amyloid plaques in Alzheimer's disease mice. Neuron. 2012;76(5):908-20.
107. Black RS, Sperling RA, Safirstein B, Motter RN, Pallay A, Nichols A, et al. A single ascending dose study of bapineuzumab in patients with Alzheimer disease. Alzheimer Dis Assoc Disord. 2010;24(2):198-203.
108. Salloway S, Sperling R, Gilman S, Fox NC, Blennow K, Raskind M, et al. A phase 2 multiple ascending dose trial of bapineuzumab in mild to moderate Alzheimer disease. Neurology. 2009;73(24):2061-70.
109. Salloway S, Sperling R, Fox NC, Blennow K, Klunk W, Raskind M, et al. Two phase 3 trials of bapineuzumab in mild-to-moderate Alzheimer's disease. N Engl J Med. 2014;370(4):322-33.
110. Racke MM, Boone LI, Hepburn DL, Parsadainian M, Bryan MT, Ness DK, et al. Exacerbation of cerebral amyloid angiopathy-associated microhemorrhage in amyloid precursor protein transgenic mice by immunotherapy is dependent on antibody recognition of deposited forms of amyloid beta. J Neurosci. 2005;25(3):629-36.
111. DeMattos RB, Bales KR, Cummins DJ, Dodart JC, Paul SM, Holtzman DM. 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. 2001;98(15):8850-5.
112. Seubert P, Barbour R, Khan K, Motter R, Tang P, Kholodenko D, et al. Antibody capture of soluble Abeta does not reduce cortical Abeta amyloidosis in the PDAPP mouse. Neurodegener Dis. 2008;5(2):65-71.
113. Imbimbo BP, Ottonello S, Frisardi V, Solfrizzi V, Greco A, Seripa D, et al. Solanezumab for the treatment of mild-to-moderate Alzheimer's disease. Expert Rev Clin Immunol. 2012;8(2):135-49.
114. Doody RS, Thomas RG, Farlow M, Iwatsubo T, Vellas B, Joffe S, et al. Phase 3 trials of solanezumab for mild-to-moderate Alzheimer's disease. N Engl J Med. 2014;370(4):311-21.
115. Bohrmann B, Baumann K, Benz J, Gerber F, Huber W, Knoflach F, et al. Gantenerumab: a novel human anti-Abeta antibody demonstrates sustained cerebral amyloid-beta binding and elicits cell-mediated removal of human amyloid-beta. J Alzheimers Dis. 2012;28(1):49-69.
116. Ostrowitzki S, Deptula D, Thurfjell L, Barkhof F, Bohrmann B, Brooks DJ, et al. Mechanism of amyloid removal in patients with Alzheimer disease treated with gantenerumab. Arch Neurol. 2012;69(2):198-207.
117. Lannfelt L, Moller C, Basun H, Osswald G, Sehlin D, Satlin A, et al. Perspectives on future Alzheimer therapies: amyloid-beta protofibrils - a new target for immunotherapy with BAN2401 in Alzheimer's disease. Alzheimers Res Ther. 2014;6(2):16.
118. Moreth J, Mavoungou C, Schindowski K. Passive anti-amyloid immunotherapy in Alzheimer's disease: what are the most promising targets? Immun Ageing. 2013;10(1):18.
119. Adolfsson O, Pihlgren M, Toni N, Varisco Y, Buccarello AL, Antoniello K, et al. An effector-reduced anti-beta-amyloid (Abeta) antibody with unique abeta binding properties promotes neuroprotection and glial engulfment of Abeta. J Neurosci. 2012;32(28):9677-89.
120. Watt AD, Crespi GA, Down RA, Ascher DB, Gunn A, Perez KA, et al. Do current therapeutic anti-Abeta antibodies for Alzheimer's disease engage the target? Acta Neuropathol. 2014;127(6):803-10.
121. Melville NA. Crenezumab fails in Alzheimer's but is there a silver lining? WebMD. 2014. http://www.medscape.com/viewarticle/828883. Accessed 26 Aug 2014.
122. Skoog I, Nilsson L, Persson G, Lernfelt B, Landahl S, Palmertz B, et al. 15-year longitudinal study of blood pressure and dementia. Lancet. 347(9009):1141-5.
123. Kivipelto M, Helkala EL, Laakso MP, Hanninen T, Hallikainen M, Alhainen K, et al. Midlife vascular risk factors and Alzheimer's disease in later life: longitudinal, population based study. BMJ. 2001;322(7300):1447-51.
124. Breteler MMB. Vascular risk factors for Alzheimer's disease. Neurobiol Aging. 1996;21(2):153-60.
125. Richard E, Van den Heuvel E, Moll van Charante EP, Achthoven L, Vermeulen M, Bindels PJ, et al. Prevention of dementia by intensive vascular care (PreDIVA): a cluster-randomized trial in progress. Alzheimer Dis Assoc Disord. 2009;23(3):198-204.
126. Kivipelto M, Solomon A, Ahtiluoto S, Ngandu T, Lehtisalo J, Antikainen R, et al. The Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER): study design and progress. Alzheimer's Dement J Alzheimer's Assoc. 2000;9(6):657-65.