Review
Amyloid-β immunotherapy for alzheimer disease: Is it now a long shot?
Francesco Panza MD, PhD,
Madia Lozupone MD, PhD,
Davide Seripa PhD,
Bruno P. Imbimbo PhD,
Corresponding Author
Francesco Panza MD, PhD
Neurodegenerative Disease Unit, Department of Basic Medicine, Neuroscience, and Sense Organs, University of Bari Aldo Moro, Bari, Italy
Neurodegenerative Disease Unit, Department of Clinical Research in Neurology, University of Bari Aldo Moro, Cardinal G. Panico Pious Foundation, Tricase, Italy
Geriatric Unit, Home Relief of Suffering, Institute of Hospitalization and Scientific Care Foundation, San Giovanni Rotondo, Italy
F.P. and B.P.I. contributed equally to this work.Address correspondence to Dr Panza, Neurodegenerative Disease Unit, Department of Basic Medicine, Neuroscience, and Sense Organs, University of Bari Aldo Moro, Bari, Italy. Email: [email protected]
Search for more papers by this authorMadia Lozupone MD, PhD
Neurodegenerative Disease Unit, Department of Basic Medicine, Neuroscience, and Sense Organs, University of Bari Aldo Moro, Bari, Italy
Search for more papers by this authorDavide Seripa PhD
Geriatric Unit, Home Relief of Suffering, Institute of Hospitalization and Scientific Care Foundation, San Giovanni Rotondo, Italy
Search for more papers by this authorBruno P. Imbimbo PhD
Department of Research and Development, Chiesi Pharmaceuticals, Parma, Italy
F.P. and B.P.I. contributed equally to this work.Search for more papers by this authorFrancesco Panza MD, PhD,
Madia Lozupone MD, PhD,
Davide Seripa PhD,
Bruno P. Imbimbo PhD,
Corresponding Author
Francesco Panza MD, PhD
Neurodegenerative Disease Unit, Department of Basic Medicine, Neuroscience, and Sense Organs, University of Bari Aldo Moro, Bari, Italy
Neurodegenerative Disease Unit, Department of Clinical Research in Neurology, University of Bari Aldo Moro, Cardinal G. Panico Pious Foundation, Tricase, Italy
Geriatric Unit, Home Relief of Suffering, Institute of Hospitalization and Scientific Care Foundation, San Giovanni Rotondo, Italy
F.P. and B.P.I. contributed equally to this work.Address correspondence to Dr Panza, Neurodegenerative Disease Unit, Department of Basic Medicine, Neuroscience, and Sense Organs, University of Bari Aldo Moro, Bari, Italy. Email: [email protected]
Search for more papers by this authorMadia Lozupone MD, PhD
Neurodegenerative Disease Unit, Department of Basic Medicine, Neuroscience, and Sense Organs, University of Bari Aldo Moro, Bari, Italy
Search for more papers by this authorDavide Seripa PhD
Geriatric Unit, Home Relief of Suffering, Institute of Hospitalization and Scientific Care Foundation, San Giovanni Rotondo, Italy
Search for more papers by this authorBruno P. Imbimbo PhD
Department of Research and Development, Chiesi Pharmaceuticals, Parma, Italy
F.P. and B.P.I. contributed equally to this work.Search for more papers by this authorAbstract
The amyloid-β (Aβ) cascade hypothesis of Alzheimer disease (AD) holds that brain accumulation of Aβ initiates the disease process. Accordingly, drug research has targeted Aβ production, clearance, and deposition as therapeutic strategies. Unfortunately, candidate drugs have failed to show clinical benefit in established, early, or prodromal disease, or in those with high AD risk. Currently, monoclonal antibodies specifically directed against the most neurotoxic Aβ forms are undergoing large-scale trials to confirm initially encouraging results. However, recent findings on the normal physiology of Aβ suggest that accumulation may be compensatory rather than the pathological initiator. If this is true, alternative strategies will be needed to defeat this devastating disease. ANN NEUROL 2019;85:303–315.
Potential Conflicts of Interest
Nothing to report.
References
- 1Panza F, Lozupone M, Logroscino G, Imbimbo, BP. A critical appraisal of amyloid-β-targeting therapies for Alzheimer disease. Nat Rev Neurol 2019 Jan. https://doi.org/10.1038/s41582-018-0116-6. [Epub ahead of print].
- 2Wang J, Logovinsky V, Hendrix SB, et al. ADCOMS: a composite clinical outcome for prodromal Alzheimer's disease trials. J Neurol Neurosurg Psychiatry 2016; 87: 993–999.
- 3Donohue MC, Sperling RA, Salmon DP, et al. The preclinical Alzheimer cognitive composite: measuring amyloid-related decline. JAMA Neurol 2014; 71: 961–970.
- 4Ayutyanont N, Langbaum JB, Hendrix SB, et al. The Alzheimer's prevention initiative composite cognitive test score: sample size estimates for the evaluation of preclinical Alzheimer's disease treatments in presenilin 1 E280A mutation carriers. J Clin Psychiatry 2014; 75: 652–660.
- 5Honig LS, Vellas B, Woodward M, et al. Trial of solanezumab for mild dementia due to Alzheimer's disease. N Engl J Med 2018; 378: 321–330.
- 6Rogers SL, Farlow MR, Doody RS, et al. A 24-week, double-blind, placebo-controlled trial of donepezil in patients with Alzheimer's disease. Donepezil Study Group. Neurology 1998; 50: 136–145.
- 7Thal DR, Rüb U, Orantes M, Braak H. Phases of Aβ-deposition in the human brain and its relevance for the development of AD. Neurology 2002; 58: 1791–1800.
- 8Grothe MJ, Barthel H, Sepulcre J, et al. In vivo staging of regional amyloid deposition. Neurology 2017; 89: 2031–2038.
- 9Beyreuther K, Masters CL. Amyloid precursor protein (APP) and βA4 amyloid in the etiology of Alzheimer's disease: precursor-product relationships in the derangement of neuronal function. Brain Pathol 1991; 1: 241–251.
- 10Hardy J, Allsop D. Amyloid deposition as the central event in the aetiology of Alzheimer's disease. Trends Pharmacol Sci 1991; 12: 383–388.
- 11Jonsson T, Bainbridge T, Gustafson A, et al. A mutation in APP protects against Alzheimer's disease and age-related cognitive decline. Nature 2012; 488: 96–99.
- 12Mawuenyega KG, Sigurdson W, Ovod V, et al. Decreased clearance of CNS β-amyloid in Alzheimer's disease. Science 2010; 330: 1774.
- 13Yang LB, Lindholm K, Yan R, et al. Elevated β-secretase expression and enzymatic activity detected in sporadic Alzheimer disease. Nat Med 2003; 9: 3–4.
- 14Liu CC, Kanekiyo T, Xu H, Bu G. Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy. Nat Rev Neurol 2013; 9: 106–118.
- 15Lim YY, Mormino EC. Alzheimer's Disease Neuroimaging Initiative. APOE genotype and early β-amyloid accumulation in older adults without dementia. Neurology 2017; 89: 1028–1034.
- 16Jack CR Jr, Knopman DS, Jagust WJ, et al. Tracking pathophysiological processes in Alzheimer's disease: an updated hypothetical model of dynamic biomarkers. Lancet Neurol 2013; 12: 207–216.
- 17Bennett DA, Schneider JA, Arvanitakis Z, et al. Neuropathology of older persons without cognitive impairment from two community-based studies. Neurology 2006; 66: 1837–1844.
- 18Jansen WJ, Ossenkoppele R, Knol DL, et al. Prevalence of cerebral amyloid pathology in persons without dementia: a meta-analysis. JAMA 2015; 313: 1924–1938.
- 19Donohue MC, Sperling RA, Petersen R, et al. Association between elevated brain amyloid and subsequent cognitive decline among cognitively normal persons. JAMA 2017; 317: 2305–2316.
- 20Villemagne VL, Burnham S, Bourgeat P, et al; Australian Imaging Biomarkers and Lifestyle (AIBL) Research Group. Amyloid β deposition, neurodegeneration, and cognitive decline in sporadic Alzheimer's disease: a prospective cohort study. Lancet Neurol 2013; 12: 357–367.
- 21Gordon BA, Blazey TM, Su Y, et al. Spatial patterns of neuroimaging biomarker change in individuals from families with autosomal dominant Alzheimer's disease: a longitudinal study. Lancet Neurol 2018; 17: 241–250.
- 22Polanco JC, Li C, Bodea LG, et al. Amyloid-β and tau complexity—towards improved biomarkers and targeted therapies. Nat Rev Neurol 2018; 14: 22–39.
- 23Tijms BM, Visser PJ. Capturing the Alzheimer's disease pathological cascade. Lancet Neurol 2018; 1: 199–200.
- 24Selkoe DJ, Hardy J. The amyloid hypothesis of Alzheimer's disease at 25 years. EMBO Mol Med 2016; 8: 595–608.
- 25Giannakopoulos P, Herrmann FR, Bussière T, et al. Tangle and neuron numbers, but not amyloid load, predict cognitive status in Alzheimer's disease. Neurology 2003; 60: 1495–1500.
- 26Holmes C, Boche D, Wilkinson D, et al. Long-term effects of Aβ42 immunisation in Alzheimer's disease: follow-up of a randomised, placebo-controlled phase I trial. Lancet 2008; 372: 216–223.
- 27Kuo YM, Emmerling MR, Vigo-Pelfrey C, et al. Water-soluble Aβ (N-40, N-42) oligomers in normal and Alzheimer disease brains. J Biol Chem 1996; 271: 4077–4081.
- 28Lesné S, Koh MT, Kotilinek L, et al. A specific amyloid-β protein assembly in the brain impairs memory. Nature 2006; 440: 352–357.
- 29Lesné SE, Sherman MA, Grant M, et al. Brain amyloid-β oligomers in ageing and Alzheimer's disease. Brain 2013; 136: 1383–1398.
- 30Yang T, Li S, Xu H, et al. Large soluble oligomers of amyloid β-protein from Alzheimer brain are far less neuroactive than the smaller oligomers to which they dissociate. J Neurosci 2017; 37: 152–163.
- 31Amar F, Sherman MA, Rush T, et al. The amyloid-β oligomer Aβ*56 induces specific alterations in neuronal signaling that lead to tau phosphorylation and aggregation. Sci Signal 2017; 10. pii: eaal2021.
- 32Hong W, Wang Z, Liu W, et al. Diffusible, highly bioactive oligomers represent a critical minority of soluble Aβ in Alzheimer's disease brain. Acta Neuropathol 2018; 136: 19–40.
- 33Sperling RA, Jack CR Jr, Aisen PS. Testing the right target and right drug at the right stage. Sci Transl Med 2011; 3: 111cm33.
- 34Cummings J. APECS trial of the BACE1 inhibitor verubecestat for prodromal Alzheimer's disease. J Prev Alzheimers Dis 2018; 5(suppl 1): S1.
- 35Sur C, Kost J, Scott D, et al. BACE inhibition by verubecestat produces a rapid, non-progressive reduction in brain and hippocampal volume in Alzheimer's disease. J Prev Alzheimers Dis 2018; 5(suppl 1): S18–S19 OC13.
- 36Doody RS, Raman R, Farlow M, et al. A phase 3 trial of semagacestat for treatment of Alzheimer's disease. N Engl J Med 2013; 369: 341–350.
- 37Coric V, Salloway S, van Dyck CH, et al. Targeting prodromal Alzheimer disease with avagacestat: a randomized clinical trial. JAMA Neurol 2015; 72: 1324–1333.
- 38Coric V, van Dyck CH, Salloway S, et al. Safety and tolerability of the γ-secretase inhibitor avagacestat in a phase 2 study of mild to moderate Alzheimer disease. Arch Neurol 2012; 69: 1430–1440.
- 39Green RC, Schneider LS, Amato DA, 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: 2557–2564.
- 40Winblad B, Andreasen N, Minthon L, et al. Safety, tolerability, and antibody response of active Aβ immunotherapy with CAD106 in patients with Alzheimer's disease: randomised, double-blind, placebo-controlled, first-in-human study. Lancet Neurol 2012; 11: 597–604.
- 41Schneeberger A, Hendrix S, Mandler M, et al. Results from a phase II study to assess the clinical and immunological activity of AFFITOPE® AD02 in patients with early Alzheimer's disease. J Prev Alzheimers Dis 2015; 2: 103–114.
- 42Salloway S, Sperling R, Keren R, et al. A phase 2 randomized trial of ELND005, scyllo-inositol, in mild to moderate Alzheimer disease. Neurology 2011; 77: 1253–1262.
- 43Townsend M, Cleary JP, Mehta T, et al. Orally available compound prevents deficits in memory caused by the Alzheimer amyloid-β oligomers. Ann Neurol 2006; 60: 668–676.
- 44Zhao J, Nussinov R, Ma B. Mechanisms of recognition of amyloid-β (Aβ) monomer, oligomer, and fibril by homologous antibodies. J Biol Chem 2017; 292: 18325–18343.
- 45Bohrmann B, Baumann K, Benz J, et al. 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 2012; 28: 49–69.
- 46Relkin RN. Natural human antibodies targeting amyloid aggregates in intravenous immunoglobulin. Alzheimers Dement 2008; 4(suppl): T10.
- 47Du Y, Wei X, Dodel R, et al. Human anti-β-amyloid antibodies block β-amyloid fibril formation and prevent β-amyloid-induced neurotoxicity. Brain 2003; 126(pt 9): 1935–1939.
- 48Garde D. Series of setbacks raises doubt on the drug industry's next big idea to treat Alzheimer's. StatNews May 23, 2018.
- 49Panza F, Lozupone M, Solfrizzi V, et al. BACE inhibitors in clinical development for the treatment of Alzheimer's disease. Expert Rev Neurother 2018; 18: 847–857.
- 50Congdon EE, Sigurdsson EM. Tau-targeting therapies for Alzheimer disease. Nat Rev Neurol 2018; 14: 399–415.
- 51Hara Y, McKeehan N, Fillit HM. Translating the biology of aging into novel therapeutics for Alzheimer disease. Neurology 2019; 92: 84–93.
- 52Gilman S, Koller M, Black RS, et al. Clinical effects of Aβ immunization (AN1792) in patients with AD in an interrupted trial. Neurology 2005; 64: 1553–1562.
- 53Bouter Y, Lopez Noguerola JS, Tucholla P, et al. Aβ targets of the biosimilar antibodies of bapineuzumab, crenezumab, solanezumab in comparison to an antibody against N truncated Aβ in sporadic Alzheimer disease cases and mouse models. Acta Neuropathol 2015; 130: 713–729.
- 54Dodart JC, Bales KR, Gannon KS, et al. Immunization reverses memory deficits without reducing brain Aβ burden in Alzheimer's disease model. Nat Neurosci 2002; 5: 452–457.
- 55Mably AJ, Liu W, Mc Donald JM, et al. Anti-Aβ antibodies incapable of reducing cerebral Aβ oligomers fail to attenuate spatial reference memory deficits in J20 mice. Neurobiol Dis 2015; 82: 372–384.
- 56Farlow M, Arnold SE, van Dyck CH, et al. Safety and biomarker effects of solanezumab in patients with Alzheimer's disease. Alzheimers Dement 2012; 8: 261–271.
- 57Doody RS, Thomas RG, Farlow M, et al. Phase 3 trials of solanezumab for mild-to-moderate Alzheimer's disease. N Engl J Med 2014; 370: 311–321.
- 58Ostrowitzki S, Lasser RA, Dorflinger E, et al. A phase III randomized trial of gantenerumab in prodromal Alzheimer's disease. Alzheimers Res Ther 2017; 9: 95.
- 59Abi-Saab D, Andjelkovic M, Delmar P, et al. The effect of 6-month dosing on the rate of amyloid-related imaging abnormalities (ARIA) in the Marguerite RoAD study. Alzheimers Dement 2017; 13(suppl): P252–P253.
10.1016/j.jalz.2017.06.112 Google Scholar
- 60Ultsch M, Li B, Maurer T, et al. Structure of crenezumab complex with Aβ shows loss of β-hairpin. Sci Rep 2016; 6: 39374.
- 61Cummings J, Cho W, Ward M, et al. A randomized, double-blind, placebo-controlled phase 2 study to evaluate the efficacy and safety of crenezumab in patients with mild to moderate Alzheimer's disease. Alzheimers Dement 2014; 10(suppl):P275.
- 62Mackey H, Cho W, Ward M, et al. Exploratory analyses of cognitive effects of crenezumab in a mild Alzheimer's disease subpopulation of randomized, double-blind, placebo-controlled, parallel-group phase 2 study (ABBY). Alzheimers Dement 2016; 12(suppl): P610.
10.1016/j.jalz.2016.06.1210 Google Scholar
- 63Asnaghi V, Lin H, Hu N, et al. Safety and tolerability of crenezumab in mild-to-moderate AD patients treated with escalating doses for up to 25 months. Alzheimers Dement 2017; 13(suppl): P602.
10.1016/j.jalz.2017.07.246 Google Scholar
- 64Blaettler T. Clinical trial design of CREAD: a randomized, double-blind, placebo-controlled, parallel-group phase-3 study to evaluate crenezumab treatment in patients with prodromal-to-mild Alzheimer's disease. Alzheimers Dement 2016; 12(suppl): P609.
10.1016/j.jalz.2016.06.1207 Google Scholar
- 65Langbaum J, Tariot P, Reiman E, et al. The Alzheimer's Prevention Initiative (API) Autosomal Dominant Alzheimer's Disease (ADAD) trial. Neurobiol Aging 2016; 39(suppl 1): S8–S9.
- 66Bussiere T, Weinreb PH, Dunstan RW, et al. Differential in vitro and in vivo binding profiles of BIIB037 and other anti-Aβ clinical antibody candidates. Neurodegener Dis 2013; 11(suppl 1).
- 67Sevigny J, Chiao P, Bussière T, et al. The antibody aducanumab reduces Aβ plaques in Alzheimer's disease. Nature 2016; 537: 50–56.
- 68Budd Haeberlein S, O'Gorman J, Chiao P, et al. Clinical development of aducanumab, an anti-Aβ human monoclonal antibody being investigated for the treatment of early Alzheimer's disease. J Prev Alzheimers Dis 2017; 4: 255–263.
- 69Tucker S, Möller C, Tegerstedt K, et al. The murine version of BAN2401 (mAb158) selectively reduces amyloid-β protofibrils in brain and cerebrospinal fluid of tg-ArcSwe mice. J Alzheimers Dis 2015; 43: 575–588.
- 70Osswald G. BioArctic announces positive topline results of BAN2401 phase 2b at 18 months in early Alzheimer's disease. BioArctic press release, July 6, 2018.
- 71Chételat G. Alzheimer disease: Aβ-independent processes-rethinking preclinical AD. Nat Rev Neurol 2013; 9: 123–124.
- 72Morris GP, Clark IA, Vissel B. Inconsistencies and controversies surrounding the amyloid hypothesis of Alzheimer's disease. Acta Neuropathol Commun 2014; 2: 135.
- 73Musiek ES, Holtzman DM. Three dimensions of the amyloid hypothesis: time, space and 'wingmen'. Nat Neurosci 2015; 18: 800–806.
- 74Braak H, Del Tredici K. The pathological process underlying Alzheimer's disease in individuals under thirty. Acta Neuropathol 2011; 121: 171–181.
- 75Knopman DS, Jack CR Jr, Wiste HJ, et al. Brain injury biomarkers are not dependent on β-amyloid in normal elderly. Ann Neurol 2013; 73: 472–480.
- 76Knopman DS, Jack CR Jr, Wiste HJ, et al. Short-term clinical outcomes for stages of NIA-AA preclinical Alzheimer disease. Neurology 2012; 78: 1576–1582.
- 77Jagust WJ, Landau SM. Apolipoprotein E, not fibrillar β amyloid, reduces cerebral glucose metabolism in normal aging. J Neurosci 2012; 32: 18227–18233.
- 78Bateman RJ, Xiong C, Benzinger TL, et al. Clinical and biomarker changes in dominantly inherited Alzheimer's disease. N Engl J Med 2012; 367: 795–804.
- 79Jack CR Jr, Knopman DS, Jagust WJ, et al. Hypothetical model of dynamic biomarkers of the Alzheimer's pathological cascade. Lancet Neurol 2010; 9: 119–128.
- 80Dubois B, Epelbaum S, Nyasse F, et al. Cognitive and neuroimaging features and brain β-amyloidosis in individuals at risk of Alzheimer's disease (INSIGHT-preAD): a longitudinal observational study. Lancet Neurol 2018; 17: 335–346.
- 81Lumsden AL, Rogers JT, Majd S, et al. Dysregulation of neuronal iron homeostasis as an alternative unifying effect of mutations causing familial Alzheimer's disease. Front Neurosci 2018; 12: 533.
- 82Herrup K. The case for rejecting the amyloid cascade hypothesis. Nat Neurosci 2015; 18: 794–799.
- 83Kamenetz F, Tomita T, Hsieh H, et al. APP processing and synaptic function. Neuron 2003; 37: 925–937.
- 84Puzzo D, Privitera L, Fa' M, et al. Endogenous amyloid-β is necessary for hippocampal synaptic plasticity and memory. Ann Neurol 2011; 69: 819–830.
- 85Palmeri A, Ricciarelli R, Gulisano W, et al. Amyloid-β peptide is needed for cGMP-induced long-term potentiation and memory. J Neurosci 2017; 37: 6926–6937.
- 86Abramov E, Dolev I, Fogel H, et al. Amyloid-β as a positive endogenous regulator of release probability at hippocampal synapses. Nat Neurosci 2009; 12: 1567–1576.
- 87Morley JE, Farr SA, Banks WA, et al. A physiological role for amyloid-β protein: enhancement of learning and memory. J Alzheimers Dis 2010; 19: 441–449.
- 88López-Toledano MA, Shelanski ML. Neurogenic effect of β-amyloid peptide in the development of neural stem cells. J Neurosci 2004; 24: 5439–5444.
- 89Puzzo D, Gulisano W, Arancio O, Palmeri, A. The keystone of Alzheimer pathogenesis might be sought in Aβ physiology. Neuroscience 2015; 307: 26–36.
- 90Plant LD, Boyle JP, Smith IF, et al. The production of amyloid β peptide is a critical requirement for the viability of central neurons. J Neurosci 2003; 23: 5531–5535.
- 91Abrahamson EE, Ikonomovic MD, Dixon CE, DeKosky ST. Simvastatin therapy prevents brain trauma-induced increases in β-amyloid peptide levels. Ann Neurol 2009; 66: 407–414.
- 92Stein TD, Montenigro PH, Alvarez VE, et al. β-amyloid deposition in chronic traumatic encephalopathy. Acta Neuropathol 2015; 130: 21–34.
- 93Dong Y, Zhang G, Zhang B, et al. The common inhalational anesthetic sevoflurane induces apoptosis and increases β-amyloid protein levels. Arch Neurol 2009; 66: 620–631.
- 94Bryson JB, Hobbs C, Parsons MJ, et al. Amyloid precursor protein (APP) contributes to pathology in the SOD1(G93A) mouse model of amyotrophic lateral sclerosis. Hum Mol Genet 2012; 21: 3871–3882.
- 95Coan G, Mitchell CS. An assessment of possible neuropathology and clinical relationships in 46 sporadic amyotrophic lateral sclerosis patient autopsies. Neurodegener Dis 2015; 15: 301–312.
- 96Donovan NJ, Locascio JJ, Marshall GA, et al. Longitudinal association of amyloid β and anxious-depressive symptoms in cognitively normal older adults. Am J Psychiatry 2018; 175: 530–537.
- 97Garcia-Alloza M, Gregory J, Kuchibhotla KV, et al. Cerebrovascular lesions induce transient β-amyloid deposition. Brain 2011; 134: 3697–3707.
- 98Pietroboni AM, Caprioli M, Carandini T, et al. CSF β-amyloid predicts prognosis in patients with multiple sclerosis. Mult Scler 2018 Aug. https://doi.org/10.1177/1352458518791709. [Epub ahead of print].
- 99Palotás A, Reis HJ, Bogáts G, et al. Coronary artery bypass surgery provokes Alzheimer's disease-like changes in the cerebrospinal fluid. J Alzheimers Dis 2010; 21: 1153–1164.
- 100Zetterberg H, Mörtberg E, Song L, et al. Hypoxia due to cardiac arrest induces a time-dependent increase in serum amyloid β levels in humans. PLoS One 2011; 6:e28263.
- 101Hu Y, Shi S, Liu X, et al. Effects of heart bypass surgery on plasma Aβ40 and Aβ42 levels in infants and young children. Medicine 2016; 95:e2684.
- 102Lucey BP, Hicks TJ, McLeland JS, et al. Effect of sleep on overnight CSF amyloid-β kinetics. Ann Neurol 2018; 83: 197–204.
- 103Ju YS, Ooms SJ, Sutphen C, et al. Slow wave sleep disruption increases cerebrospinal fluid amyloid-β levels. Brain 2017; 140: 2104–2111.
- 104Zhao HY, Wu HJ, He JL, et al. Chronic sleep restriction induces cognitive deficits and cortical β-amyloid deposition in mice via BACE1-antisense activation. CNS Neurosci Ther 2017; 23: 233–240.
- 105Kokjohn TA, Maarouf CL, Roher AE. Is Alzheimer's disease amyloidosis the result of a repair mechanism gone astray? Alzheimers Dement 2012; 8: 574–583.
- 106Krstic D, Knuesel I. Deciphering the mechanism underlying late-onset Alzheimer disease. Nat Rev Neurol 2013; 9: 25–34.
- 107Jones DT, Graff-Radford J, Lowe VJ, et al. Tau, amyloid, and cascading network failure across the Alzheimer's disease spectrum. Cortex 2017; 97: 143–159.
- 108Struble RG, Ala T, Patrylo PR, et al. Is brain amyloid production a cause or a result of dementia of the Alzheimer's type? J Alzheimers Dis 2010; 22: 393–399.
- 109Herrup K. Reimagining Alzheimer's disease—an age-based hypothesis. J Neurosci 2010; 30: 16755–16762.
- 110Castellani RJ, Lee HG, Zhu X, et al. Alzheimer disease pathology as a host response. J Neuropathol Exp Neurol 2008; 67: 523–531.
- 111Castello MA, Soriano S. Rational heterodoxy: cholesterol reformation of the amyloid doctrine. Ageing Res Rev 2013; 12: 282–288.
- 112Aisen PS, Gauthier S, Ferris SH, et al. Tramiprosate in mild-to-moderate Alzheimer's disease—a randomized, double-blind, placebo-controlled, multi-centre study (the Alphase Study). Arch Med Sci 2011; 7: 102–111.
- 113Kirk R. Clinical trials in CNS—SMi's eighth annual conference. IDrugs 2010; 13: 66–69.
- 114Burstein AH, Zhao Q, Ross J, et al. Safety and pharmacology of ponezumab (PF-04360365) after a single 10-minute intravenous infusion in subjects with mild to moderate Alzheimer disease. Clin Neuropharmacol 2013; 36: 8–13.
- 115Salloway S, Sperling R, Fox NC, et al. Two phase 3 trials of bapineuzumab in mild-to-moderate Alzheimer's disease. N Engl J Med 2014; 370: 322–333.
- 116Pasquier F, Sadowsky C, Holstein A, et al. Two phase 2 multiple ascending-dose studies of vanutide cridificar (ACC-001) and QS-21 adjuvant in mild-to-moderate Alzheimer's disease. J Alzheimers Dis 2016; 51: 1131–1143.
- 117Relkin NR, Thomas RG, Rissman RA, et al. A phase 3 trial of IV immunoglobulin for Alzheimer disease. Neurology 2017; 88: 1768–1775.
- 118Lahiri DK, Maloney B, Long JM, Greig NH. Lessons from a BACE1 inhibitor trial: off-site but not off base. Alzheimers Dement 2014; 10(5 suppl): S411–S419.
- 119Yan R. Stepping closer to treating Alzheimer's disease patients with BACE1 inhibitor drugs. Transl Neurodegener 2016; 5: 13.
- 120Vandenberghe R, Riviere ME, Caputo A, et al. Active Aβ immunotherapy CAD106 in Alzheimer's disease: a phase 2b study. Alzheimers Dement (N Y) 2016; 3: 10–22.
- 121Villemagne VL, Rowe CC, Barnham KJ, et al. A randomized, exploratory molecular imaging study targeting amyloid β with a novel 8-OH quinoline in Alzheimer's disease: the PBT2-204 IMAGINE study. Alzheimers Dement (N Y) 2017; 3: 622–635.
- 122Ricks D. Eli-Lilly call with analysts. 24 January, 2017.
- 123Egan MF, Kost J, Tariot PN, et al. Randomized trial of verubecestat for mild-to-moderate Alzheimer's Disease. N Engl J Med 2018; 378: 1691–1703.
- 124Update on Janssen's BACE inhibitor program. Janssen press release. 21 January, 2019. Available at: https://www.janssen.com/update-janssens-bace-inhibitor-program.
- 125Update on phase III clinical trials of lanabecestat for Alzheimer's disease. AstraZeneca press release. 21 January, 2019. Available at: https://www.astrazeneca.com/media-centre/press-releases/2018/update-on-phase-iii-clinical-trials-of-lanabecestat-for-alzheimers-disease-12062018.html.
Citing Literature
