Skip to main content
Erschienen in: CNS Drugs 6/2015

01.06.2015 | Review Article

Alzheimer’s Disease: Lessons Learned from Amyloidocentric Clinical Trials

verfasst von: Andreas Soejitno, Anastasia Tjan, Thomas Eko Purwata

Erschienen in: CNS Drugs | Ausgabe 6/2015

Einloggen, um Zugang zu erhalten

Abstract

Alzheimer’s disease (AD) is one of the most debilitating neurodegenerative diseases and is predicted to affect 1 in 85 people by 2050. Despite much effort to discover a therapeutic strategy to prevent progression or to cure AD, to date no effective disease-modifying agent is available that can prevent, halt, or reverse the cognitive and functional decline of patients with AD. Several underlying etiologies to this failure are proposed. First, accumulating evidence from past trials suggests a preventive as opposed to therapeutic paradigm, and the precise temporal and mechanistic relationship of β-amyloid (Aβ) and tau protein should be elucidated to confirm this hypothesis. Second, we are in urgent need of revised diagnostic criteria to support future trials. Third, various technical and methodological improvements are required, based on the lessons learned from previous failed trials.
Literatur
1.
Zurück zum Zitat 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.PubMed 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.PubMed
2.
Zurück zum Zitat 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.PubMedCentralPubMed 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.PubMedCentralPubMed
3.
Zurück zum Zitat 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.PubMed 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.PubMed
4.
Zurück zum Zitat 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.PubMedCentralPubMed 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.PubMedCentralPubMed
5.
Zurück zum Zitat 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.PubMed 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.PubMed
6.
Zurück zum Zitat 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.PubMed 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.PubMed
7.
Zurück zum Zitat 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.PubMed 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.PubMed
8.
Zurück zum Zitat 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.PubMed 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.PubMed
9.
Zurück zum Zitat 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.PubMed 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.PubMed
10.
Zurück zum Zitat Giacobini E, Gold G. Alzheimer disease therapy–moving from amyloid-beta to tau. Nat Rev Neurol. 2013;9(12):677–86.PubMed Giacobini E, Gold G. Alzheimer disease therapy–moving from amyloid-beta to tau. Nat Rev Neurol. 2013;9(12):677–86.PubMed
11.
Zurück zum Zitat 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.PubMed 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.PubMed
12.
Zurück zum Zitat 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.PubMedCentralPubMed 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.PubMedCentralPubMed
13.
Zurück zum Zitat 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.PubMedCentralPubMed 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.PubMedCentralPubMed
14.
Zurück zum Zitat 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.PubMedCentralPubMed 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.PubMedCentralPubMed
15.
Zurück zum Zitat 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.PubMedCentralPubMed 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.PubMedCentralPubMed
16.
Zurück zum Zitat 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.PubMed 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.PubMed
17.
Zurück zum Zitat 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.PubMed 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.PubMed
18.
Zurück zum Zitat Lee VM, Goedert M, Trojanowski JQ. Neurodegenerative tauopathies. Annu Rev Neurosci. 2001;24:1121–59.PubMed Lee VM, Goedert M, Trojanowski JQ. Neurodegenerative tauopathies. Annu Rev Neurosci. 2001;24:1121–59.PubMed
19.
Zurück zum Zitat Ballatore C, Lee VM, Trojanowski JQ. Tau-mediated neurodegeneration in Alzheimer’s disease and related disorders. Nat Rev Neurosci. 2007;8(9):663–72.PubMed Ballatore C, Lee VM, Trojanowski JQ. Tau-mediated neurodegeneration in Alzheimer’s disease and related disorders. Nat Rev Neurosci. 2007;8(9):663–72.PubMed
20.
Zurück zum Zitat 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.PubMedCentralPubMed 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.PubMedCentralPubMed
21.
Zurück zum Zitat Reddy PH. Abnormal tau, mitochondrial dysfunction, impaired axonal transport of mitochondria, and synaptic deprivation in Alzheimer’s disease. Brain Res. 2011;1415:136–48.PubMedCentralPubMed Reddy PH. Abnormal tau, mitochondrial dysfunction, impaired axonal transport of mitochondria, and synaptic deprivation in Alzheimer’s disease. Brain Res. 2011;1415:136–48.PubMedCentralPubMed
22.
Zurück zum Zitat 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.PubMed 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.PubMed
23.
Zurück zum Zitat 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.PubMed 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.PubMed
24.
Zurück zum Zitat 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.PubMed 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.PubMed
25.
Zurück zum Zitat 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.PubMedCentralPubMed 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.PubMedCentralPubMed
26.
Zurück zum Zitat 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.PubMedCentralPubMed 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.PubMedCentralPubMed
27.
Zurück zum Zitat 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.PubMedCentralPubMed 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.PubMedCentralPubMed
28.
Zurück zum Zitat Blennow K, Hampel H, Weiner M, Zetterberg H. Cerebrospinal fluid and plasma biomarkers in Alzheimer disease. Nat Rev Neurol. 2010;6(3):131–44.PubMed Blennow K, Hampel H, Weiner M, Zetterberg H. Cerebrospinal fluid and plasma biomarkers in Alzheimer disease. Nat Rev Neurol. 2010;6(3):131–44.PubMed
29.
Zurück zum Zitat Fagan AM. CSF biomarkers of Alzheimer’s disease: impact on disease concept, diagnosis, and clinical trial design. Adv Geriatr. 2014;2014:14. Fagan AM. CSF biomarkers of Alzheimer’s disease: impact on disease concept, diagnosis, and clinical trial design. Adv Geriatr. 2014;2014:14.
30.
Zurück zum Zitat 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.PubMedCentralPubMed 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.PubMedCentralPubMed
31.
Zurück zum Zitat 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.PubMedCentralPubMed 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.PubMedCentralPubMed
32.
Zurück zum Zitat 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.PubMed 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.PubMed
33.
Zurück zum Zitat 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.PubMedCentralPubMed 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.PubMedCentralPubMed
34.
Zurück zum Zitat 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.PubMed 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.PubMed
35.
Zurück zum Zitat 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.PubMed 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.PubMed
36.
Zurück zum Zitat 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.PubMed 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.PubMed
37.
Zurück zum Zitat 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.PubMed 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.PubMed
38.
Zurück zum Zitat 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.PubMed 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.PubMed
39.
Zurück zum Zitat 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.PubMed 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.PubMed
40.
Zurück zum Zitat 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.PubMedCentralPubMed 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.PubMedCentralPubMed
41.
Zurück zum Zitat 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.PubMedCentralPubMed 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.PubMedCentralPubMed
42.
Zurück zum Zitat 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.PubMedCentralPubMed 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.PubMedCentralPubMed
43.
Zurück zum Zitat 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.PubMed 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.PubMed
44.
Zurück zum Zitat 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. 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.
Zurück zum Zitat Hemming ML, Elias JE, Gygi SP, Selkoe DJ. Identification of beta-secretase (BACE1) substrates using quantitative proteomics. PLoS One. 2009;4(12):e8477.PubMedCentralPubMed Hemming ML, Elias JE, Gygi SP, Selkoe DJ. Identification of beta-secretase (BACE1) substrates using quantitative proteomics. PLoS One. 2009;4(12):e8477.PubMedCentralPubMed
46.
Zurück zum Zitat 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.PubMedCentralPubMed 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.PubMedCentralPubMed
47.
Zurück zum Zitat 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.PubMed 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.PubMed
48.
Zurück zum Zitat 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.PubMedCentralPubMed 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.PubMedCentralPubMed
49.
Zurück zum Zitat 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.PubMed 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.PubMed
50.
Zurück zum Zitat 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.PubMed 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.PubMed
51.
Zurück zum Zitat 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. 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.
55.
Zurück zum Zitat 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.PubMed 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.PubMed
56.
Zurück zum Zitat 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. 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.
Zurück zum Zitat 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. 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.
Zurück zum Zitat 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.PubMed 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.PubMed
59.
Zurück zum Zitat 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.PubMed 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.PubMed
60.
Zurück zum Zitat 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.PubMed 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.PubMed
61.
Zurück zum Zitat 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.PubMedCentralPubMed 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.PubMedCentralPubMed
62.
Zurück zum Zitat 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.PubMed 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.PubMed
63.
Zurück zum Zitat 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.PubMed 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.PubMed
64.
Zurück zum Zitat Phng LK, Gerhardt H. Angiogenesis: a team effort coordinated by notch. Dev Cell. 2009;16(2):196–208.PubMed Phng LK, Gerhardt H. Angiogenesis: a team effort coordinated by notch. Dev Cell. 2009;16(2):196–208.PubMed
65.
Zurück zum Zitat 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.PubMed 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.PubMed
66.
Zurück zum Zitat 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.PubMed 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.PubMed
67.
Zurück zum Zitat 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.PubMed 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.PubMed
68.
Zurück zum Zitat 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.PubMedCentralPubMed 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.PubMedCentralPubMed
69.
Zurück zum Zitat 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.PubMed 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.PubMed
70.
Zurück zum Zitat 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.PubMed 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.PubMed
71.
Zurück zum Zitat 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.PubMed 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.PubMed
72.
Zurück zum Zitat 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.PubMedCentralPubMed 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.PubMedCentralPubMed
73.
Zurück zum Zitat 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.PubMed 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.PubMed
74.
Zurück zum Zitat 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.PubMedCentralPubMed 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.PubMedCentralPubMed
75.
Zurück zum Zitat Townsend KP, Pratico D. Novel therapeutic opportunities for Alzheimer’s disease: focus on nonsteroidal anti-inflammatory drugs. FASEB J. 2005;19(12):1592–601.PubMed Townsend KP, Pratico D. Novel therapeutic opportunities for Alzheimer’s disease: focus on nonsteroidal anti-inflammatory drugs. FASEB J. 2005;19(12):1592–601.PubMed
76.
Zurück zum Zitat Selkoe DJ. The therapeutics of Alzheimer’s disease: where we stand and where we are heading. Ann Neurol. 2013;74(3):328–36.PubMed Selkoe DJ. The therapeutics of Alzheimer’s disease: where we stand and where we are heading. Ann Neurol. 2013;74(3):328–36.PubMed
77.
Zurück zum Zitat 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.PubMed 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.PubMed
78.
Zurück zum Zitat 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.PubMed 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.PubMed
79.
Zurück zum Zitat 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.PubMed 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.PubMed
80.
Zurück zum Zitat 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.PubMed 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.PubMed
81.
Zurück zum Zitat 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.PubMed 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.PubMed
82.
Zurück zum Zitat 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.PubMedCentralPubMed 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.PubMedCentralPubMed
83.
Zurück zum Zitat 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.PubMed 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.PubMed
84.
Zurück zum Zitat 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.PubMed 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.PubMed
85.
Zurück zum Zitat 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.PubMed 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.PubMed
86.
Zurück zum Zitat 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.PubMed 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.PubMed
87.
Zurück zum Zitat Wisniewski T, Frangione B. Immunological and anti-chaperone therapeutic approaches for Alzheimer disease. Brain Pathol. 2005;15(1):72–7.PubMed Wisniewski T, Frangione B. Immunological and anti-chaperone therapeutic approaches for Alzheimer disease. Brain Pathol. 2005;15(1):72–7.PubMed
88.
Zurück zum Zitat 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.PubMed 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.PubMed
89.
Zurück zum Zitat 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.PubMed 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.PubMed
90.
Zurück zum Zitat 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.PubMed 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.PubMed
91.
Zurück zum Zitat 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.PubMed 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.PubMed
92.
Zurück zum Zitat 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.PubMed 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.PubMed
93.
Zurück zum Zitat 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.PubMed 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.PubMed
94.
Zurück zum Zitat Davtyan H, Petrushina I, Ghochikyan A. Immunotherapy for Alzheimer’s disease: DNA- and protein-based epitope vaccines. Methods Mol Biol. 2014;1143:259–81.PubMed Davtyan H, Petrushina I, Ghochikyan A. Immunotherapy for Alzheimer’s disease: DNA- and protein-based epitope vaccines. Methods Mol Biol. 2014;1143:259–81.PubMed
95.
Zurück zum Zitat 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.PubMedCentralPubMed 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.PubMedCentralPubMed
96.
Zurück zum Zitat 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.PubMedCentralPubMed 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.PubMedCentralPubMed
97.
Zurück zum Zitat 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.PubMed 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.PubMed
98.
Zurück zum Zitat 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.PubMed 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.PubMed
99.
Zurück zum Zitat 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.PubMedCentralPubMed 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.PubMedCentralPubMed
100.
Zurück zum Zitat 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.PubMed 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.PubMed
101.
Zurück zum Zitat Wisniewski T, Konietzko U. Amyloid-beta immunisation for Alzheimer’s disease. Lancet Neurol. 2008;7(9):805–11.PubMedCentralPubMed Wisniewski T, Konietzko U. Amyloid-beta immunisation for Alzheimer’s disease. Lancet Neurol. 2008;7(9):805–11.PubMedCentralPubMed
102.
Zurück zum Zitat Winblad B, Graf A, Riviere ME, Andreasen N, Ryan JM. Active immunotherapy options for Alzheimer’s disease. Alzheimers Res Ther. 2014;6(1):7.PubMedCentralPubMed Winblad B, Graf A, Riviere ME, Andreasen N, Ryan JM. Active immunotherapy options for Alzheimer’s disease. Alzheimers Res Ther. 2014;6(1):7.PubMedCentralPubMed
103.
Zurück zum Zitat 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. 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.
Zurück zum Zitat 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. 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.
Zurück zum Zitat 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.PubMed 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.PubMed
106.
Zurück zum Zitat 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.PubMed 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.PubMed
107.
Zurück zum Zitat 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.PubMedCentralPubMed 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.PubMedCentralPubMed
108.
Zurück zum Zitat 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.PubMedCentralPubMed 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.PubMedCentralPubMed
109.
Zurück zum Zitat 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.PubMedCentralPubMed 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.PubMedCentralPubMed
110.
Zurück zum Zitat 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.PubMed 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.PubMed
111.
Zurück zum Zitat 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.PubMedCentralPubMed 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.PubMedCentralPubMed
112.
Zurück zum Zitat 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.PubMed 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.PubMed
113.
Zurück zum Zitat 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.PubMed 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.PubMed
114.
Zurück zum Zitat 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.PubMed 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.PubMed
115.
Zurück zum Zitat 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.PubMed 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.PubMed
116.
Zurück zum Zitat 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.PubMed 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.PubMed
117.
Zurück zum Zitat 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.PubMedCentralPubMed 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.PubMedCentralPubMed
118.
Zurück zum Zitat 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.PubMedCentralPubMed 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.PubMedCentralPubMed
119.
Zurück zum Zitat 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.PubMed 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.PubMed
120.
Zurück zum Zitat 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.PubMed 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.PubMed
122.
Zurück zum Zitat 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. 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.
Zurück zum Zitat 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.PubMedCentralPubMed 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.PubMedCentralPubMed
124.
Zurück zum Zitat Breteler MMB. Vascular risk factors for Alzheimer’s disease. Neurobiol Aging. 1996;21(2):153–60. Breteler MMB. Vascular risk factors for Alzheimer’s disease. Neurobiol Aging. 1996;21(2):153–60.
125.
Zurück zum Zitat 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.PubMed 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.PubMed
126.
Zurück zum Zitat 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. 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.
Metadaten
Titel
Alzheimer’s Disease: Lessons Learned from Amyloidocentric Clinical Trials
verfasst von
Andreas Soejitno
Anastasia Tjan
Thomas Eko Purwata
Publikationsdatum
01.06.2015
Verlag
Springer International Publishing
Erschienen in
CNS Drugs / Ausgabe 6/2015
Print ISSN: 1172-7047
Elektronische ISSN: 1179-1934
DOI
https://doi.org/10.1007/s40263-015-0257-8

Weitere Artikel der Ausgabe 6/2015

CNS Drugs 6/2015 Zur Ausgabe

Leitlinien kompakt für die Neurologie

Mit medbee Pocketcards sicher entscheiden.

Seit 2022 gehört die medbee GmbH zum Springer Medizin Verlag

Sind Frauen die fähigeren Ärzte?

30.04.2024 Gendermedizin Nachrichten

Patienten, die von Ärztinnen behandelt werden, dürfen offenbar auf bessere Therapieergebnisse hoffen als Patienten von Ärzten. Besonders gilt das offenbar für weibliche Kranke, wie eine Studie zeigt.

Akuter Schwindel: Wann lohnt sich eine MRT?

28.04.2024 Schwindel Nachrichten

Akuter Schwindel stellt oft eine diagnostische Herausforderung dar. Wie nützlich dabei eine MRT ist, hat eine Studie aus Finnland untersucht. Immerhin einer von sechs Patienten wurde mit akutem ischämischem Schlaganfall diagnostiziert.

Niedriger diastolischer Blutdruck erhöht Risiko für schwere kardiovaskuläre Komplikationen

25.04.2024 Hypotonie Nachrichten

Wenn unter einer medikamentösen Hochdrucktherapie der diastolische Blutdruck in den Keller geht, steigt das Risiko für schwere kardiovaskuläre Ereignisse: Darauf deutet eine Sekundäranalyse der SPRINT-Studie hin.

Frühe Alzheimertherapie lohnt sich

25.04.2024 AAN-Jahrestagung 2024 Nachrichten

Ist die Tau-Last noch gering, scheint der Vorteil von Lecanemab besonders groß zu sein. Und beginnen Erkrankte verzögert mit der Behandlung, erreichen sie nicht mehr die kognitive Leistung wie bei einem früheren Start. Darauf deuten neue Analysen der Phase-3-Studie Clarity AD.

Update Neurologie

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.