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Clarity on the blazing trail: clearing the way for amyloid-removing therapies for Alzheimer’s disease

Molecular Psychiatry (2023)Cite this article

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Abstract

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder with a complex pathogenesis. Senile plaques composed of the amyloid-β (Aβ) peptide in the brain are the core hallmarks of AD and a promising target for the development of disease-modifying therapies. However, over the past 20 years, the failures of clinical trials directed at Aβ clearance have fueled a debate as to whether Aβ is the principal pathogenic factor in AD and a valid therapeutic target. The success of the recent phase 3 trials of lecanemab (Clarity AD) and donanemab (Trailblazer Alz2), and lessons from previous Aβ clearance trials provide critical evidence to support the role of Aβ in AD pathogenesis and suggest that targeting Aβ clearance is heading in the right direction for AD treatment. Here, we analyze key questions relating to the efficacy of Aβ targeting therapies, and provide perspectives on early intervention, adequate Aβ removal, sufficient treatment period, and combinatory therapeutics, which may be required to achieve the best cognitive benefits in future trials in the real world.

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Fig. 1: Perspectives on Aβ clearance therapies.

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References

  1. Selkoe DJ. Alzheimer’s disease: genes, proteins, and therapy. Physiol Rev. 2001;81:741–66.

    Article  CAS  PubMed  Google Scholar 

  2. Glenner GG, Wong CW. Alzheimer’s disease and Down’s syndrome: sharing of a unique cerebrovascular amyloid fibril protein. Biochem Biophys Res Commun. 1984;122:1131–5.

    Article  CAS  PubMed  Google Scholar 

  3. Masters CL, Simms G, Weinman NA, Multhaup G, McDonald BL, Beyreuther K. Amyloid plaque core protein in Alzheimer disease and Down syndrome. Proc Natl Acad Sci USA. 1985;82:4245–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Hampel H, Hardy J, Blennow K, Chen C, Perry G, Kim SH, et al. The Amyloid-beta Pathway in Alzheimer’s Disease. Mol Psychiatry. 2021;26:5481–503.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Selkoe DJ, Hardy J. The amyloid hypothesis of Alzheimer’s disease at 25 years. EMBO Mol Med. 2016;8:595–608.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Beyreuther K, Masters CL. Amyloid precursor protein (APP) and beta A4 amyloid in the etiology of Alzheimer’s disease: precursor-product relationships in the derangement of neuronal function. Brain Pathol. 1991;1:241–51.

    Article  CAS  PubMed  Google Scholar 

  7. Selkoe DJ. The molecular pathology of Alzheimer’s disease. Neuron. 1991;6:487–98.

    Article  CAS  PubMed  Google Scholar 

  8. Hardy J, Allsop D. Amyloid deposition as the central event in the aetiology of Alzheimer’s disease. Trends Pharm Sci. 1991;12:383–8.

    Article  CAS  PubMed  Google Scholar 

  9. Hardy JA, Higgins GA. Alzheimer’s disease: the amyloid cascade hypothesis. Science. 1992;256:184–5.

    Article  CAS  PubMed  Google Scholar 

  10. Kumar M, Cohen D, Eisdorfer C. Serum IgG brain reactive antibodies in Alzheimer disease and Down syndrome. Alzheimer Dis Assoc Disord. 1988;2:50–55.

    Article  CAS  PubMed  Google Scholar 

  11. Solomon B, Koppel R, Hanan E, Katzav T. Monoclonal antibodies inhibit in vitro fibrillar aggregation of the Alzheimer beta-amyloid peptide. Proc Natl Acad Sci USA. 1996;93:452–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Solomon B, Koppel R, Frankel D, Hanan-Aharon E. Disaggregation of Alzheimer beta-amyloid by site-directed mAb. Proc Natl Acad Sci USA. 1997;94:4109–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Schenk D. Hopes remain for an Alzheimer’s vaccine. Nature. 2004;431:398.

    Article  CAS  PubMed  Google Scholar 

  14. 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;61:46–54.

    Article  CAS  PubMed  Google Scholar 

  15. Hartman RE, Izumi Y, Bales KR, Paul SM, Wozniak DF, Holtzman DM. Treatment with an amyloid-beta antibody ameliorates plaque load, learning deficits, and hippocampal long-term potentiation in a mouse model of Alzheimer’s disease. J Neurosci. 2005;25:6213–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. 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;370:322–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Ostrowitzki S, Lasser RA, Dorflinger E, Scheltens P, Barkhof F, Nikolcheva T, et al. A phase III randomized trial of gantenerumab in prodromal Alzheimer’s disease. Alzheimers Res Ther. 2017;9:95.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Ostrowitzki S, Bittner T, Sink KM, Mackey H, Rabe C, Honig LS, et al. Evaluating the Safety and Efficacy of Crenezumab vs Placebo in Adults With Early Alzheimer Disease: Two Phase 3 Randomized Placebo-Controlled Trials. JAMA Neurol. 2022;79:1113–21.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Knopman DS, Jones DT, Greicius MD. Failure to demonstrate efficacy of aducanumab: An analysis of the EMERGE and ENGAGE trials as reported by Biogen, December 2019. Alzheimer’s Dement. 2021;17:696–701.

    Article  Google Scholar 

  20. 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;370:311–21.

    Article  CAS  PubMed  Google Scholar 

  21. Kepp KP, Robakis NK, Høilund-Carlsen PF, Sensi SL, Vissel B. The amyloid cascade hypothesis: an updated critical review. Brain. 2023;146:3969–90.

    Article  PubMed  Google Scholar 

  22. Alexander GC, Knopman DS, Emerson SS, Ovbiagele B, Kryscio RJ, Perlmutter JS, et al. Revisiting FDA Approval of Aducanumab. N. Engl J Med. 2021;385:769–71.

    Article  CAS  PubMed  Google Scholar 

  23. van Dyck CH, Swanson CJ, Aisen P, Bateman RJ, Chen C, Gee M, et al. Lecanemab in Early Alzheimer’s Disease. N. Engl J Med. 2023;388:9–21.

    Article  PubMed  Google Scholar 

  24. Sims JR, Zimmer JA, Evans CD, Lu M, Ardayfio P, Sparks J, et al. Donanemab in Early Symptomatic Alzheimer Disease: The TRAILBLAZER-ALZ 2 Randomized Clinical Trial. JAMA. 2023;330:512–27.

    Article  CAS  PubMed  Google Scholar 

  25. Rosenberg RN, Lambracht-Washington D, Yu G, Xia W. Genomics of Alzheimer Disease: A Review. JAMA Neurol. 2016;73:867–74.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Jonsson T, Atwal JK, Steinberg S, Snaedal J, Jonsson PV, Bjornsson S, et al. A mutation in APP protects against Alzheimer’s disease and age-related cognitive. Nature. 2012;488:96–99.

    Article  CAS  PubMed  Google Scholar 

  27. Liu CC, Liu CC, Kanekiyo T, Xu H, Bu G. Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy. Nat Rev Neurol. 2013;9:106–18.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Bateman RJ, Xiong C, Benzinger TL, Fagan AM, Goate A, Fox NC, et al. Clinical and biomarker changes in dominantly inherited Alzheimer’s disease. N. Engl J Med. 2012;367:795–804.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Wang HF, Shen XN, Li JQ, Suckling J, Tan CC, Wang YJ, et al. Clinical and biomarker trajectories in sporadic Alzheimer’s disease: A longitudinal study. Alzheimers Dement. 2020;12:e12095.

  30. Benilova I, Karran E, De Strooper B. The toxic Abeta oligomer and Alzheimer’s disease: an emperor in need of clothes. Nat Neurosci. 2012;15:349–57.

    Article  CAS  PubMed  Google Scholar 

  31. CLINICAL PHARMACOLOGY AND BIOPHARMACEUTICS REVIEW(S). https://www.accessdata.fda.gov/drugsatfda_docs/nda/2021/761178Orig1s000ClinPharm_Redacted.pdf, 2021, Accessed Date Accessed 2021.

  32. Liu YH, Giunta B, Zhou HD, Tan J, Wang YJ. Immunotherapy for Alzheimer disease: the challenge of adverse effects. Nat Rev Neurol. 2012;8:465–9.

    Article  CAS  PubMed  Google Scholar 

  33. Wang X. A Bridge Between the Innate Immunity System and Amyloid-β Production in Alzheimer’s Disease. Neurosci Bull. 2021;37:898–901.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Bertram L, Tanzi RE. Alzheimer disease risk genes: 29 and counting. Nat Rev Neurol. 2019;15:191–2.

    Article  PubMed  Google Scholar 

  35. Sarlus H, Heneka MT. Microglia in Alzheimer’s disease. J Clin Investig. 2017;127:3240–9.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Franco-Bocanegra DK, McAuley C, Nicoll JAR, Boche D. Molecular Mechanisms of Microglial Motility: Changes in Ageing and Alzheimer’s Disease. Cells. 2019;8:639.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Chen X, Holtzman DM. Emerging roles of innate and adaptive immunity in Alzheimer’s disease. Immunity. 2022;55:2236–54.

    Article  CAS  PubMed  Google Scholar 

  38. Fan DY, Wang YJ. Early Intervention in Alzheimer’s Disease: How Early is Early Enough? Neurosci Bull. 2020;36:195–7.

    Article  CAS  PubMed  Google Scholar 

  39. Scheltens P, De Strooper B, Kivipelto M, Holstege H, Chételat G, Teunissen CE, et al. Alzheimer’s disease. Lancet. 2021;397:1577–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Honig LS, Vellas B, Woodward M, Boada M, Bullock R, Borrie M, et al. Trial of Solanezumab for Mild Dementia Due to Alzheimer’s Disease. N. Engl J Med. 2018;378:321–30.

    Article  CAS  PubMed  Google Scholar 

  41. Swanson CJ, Zhang Y, Dhadda S, Wang J, Kaplow J, Lai RYK, et al. A randomized, double-blind, phase 2b proof-of-concept clinical trial in early Alzheimer’s disease with lecanemab, an anti-Abeta protofibril antibody. Alzheimer’s Res Ther. 2021;13:80.

    Article  CAS  Google Scholar 

  42. Rafii MS, Sperling RA, Donohue MC, Zhou J, Roberts C, Irizarry MC, et al. The AHEAD 3-45 Study: Design of a prevention trial for Alzheimer’s disease. Alzheimer’s Dement. 2023;19:1227–33.

  43. Golde TE, Schneider LS, Koo EH. Anti-abeta therapeutics in Alzheimer’s disease: the need for a paradigm shift. Neuron. 2011;69:203–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. De Strooper B, Karran E. The Cellular Phase of Alzheimer’s Disease. Cell. 2016;164:603–15.

    Article  PubMed  Google Scholar 

  45. Golde TE. Disease-Modifying Therapies for Alzheimer’s Disease: More Questions than Answers. NeuroTherapeutics. 2022;19:209–27.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Izuo N, Murakami K, Sato M, Iwasaki M, Izumi Y, Shimizu T, et al. Non-toxic conformer of amyloid β may suppress amyloid β-induced toxicity in rat primary neurons: implications for a novel therapeutic strategy for Alzheimer’s disease. Biochem Biophys Res Commun. 2013;438:1–5.

    Article  CAS  PubMed  Google Scholar 

  47. Ladiwala AR, Litt J, Kane RS, Aucoin DS, Smith SO, Ranjan S, et al. Conformational differences between two amyloid β oligomers of similar size and dissimilar toxicity. J Biol Chem. 2012;287:24765–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Geula C, Wu CK, Saroff D, Lorenzo A, Yuan M, Yankner BA. Aging renders the brain vulnerable to amyloid beta-protein neurotoxicity. Nat Med. 1998;4:827–31.

    Article  CAS  PubMed  Google Scholar 

  49. Zhao Y, Sivaji S, Chiang MC, Ali H, Zukowski M, Ali S, et al. Amyloid Beta Peptides Block New Synapse Assembly by Nogo Receptor-Mediated Inhibition of T-Type Calcium Channels. Neuron. 2017;96:355–72.e356.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Zott B, Simon MM, Hong W, Unger F, Chen-Engerer HJ, Frosch MP, et al. A vicious cycle of β amyloid-dependent neuronal hyperactivation. Science. 2019;365:559–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Panza F, Lozupone M, Logroscino G, Imbimbo BP. A critical appraisal of amyloid-β-targeting therapies for Alzheimer disease. Nat Rev Neurol. 2019;15:73–88.

    Article  PubMed  Google Scholar 

  52. Karran E, De Strooper B. The amyloid hypothesis in Alzheimer disease: new insights from new therapeutics. Nat Rev Drug Discov. 2022;21:306–18.

    Article  CAS  PubMed  Google Scholar 

  53. Meilandt WJ, Maloney JA, Imperio J, Lalehzadeh G, Earr T, Crowell S, et al. Characterization of the selective in vitro and in vivo binding properties of crenezumab to oligomeric Aβ. Alzheimers Res Ther. 2019;11:97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Salloway S, Farlow M, McDade E, Clifford DB, Wang G, Llibre-Guerra JJ, et al. A trial of gantenerumab or solanezumab in dominantly inherited Alzheimer’s disease. Nat Med. 2021;27:1187–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Swanson CJ, Zhang Y, Dhadda S, Wang J, Kaplow J, Lai RYK, et al. A randomized, double-blind, phase 2b proof-of-concept clinical trial in early Alzheimer’s disease with lecanemab, an anti-Aβ protofibril antibody. Alzheimer’s Res Ther. 2021;13:80.

    Article  CAS  Google Scholar 

  56. Bohrmann B, Baumann K, Benz J, Gerber F, Huber W, Knoflach F, 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 Alzheimer’s Dis. 2012;28:49–69.

    Article  CAS  Google Scholar 

  57. Arndt JW, Qian F, Smith BA, Quan C, Kilambi KP, Bush MW, et al. Structural and kinetic basis for the selectivity of aducanumab for aggregated forms of amyloid-β. Sci Rep. 2018;8:6412.

    Article  PubMed  PubMed Central  Google Scholar 

  58. Alexander GC, Emerson S, Kesselheim AS. Evaluation of Aducanumab for Alzheimer Disease: Scientific Evidence and Regulatory Review Involving Efficacy, Safety, and Futility. JAMA. 2021;325:1717–8.

    Article  PubMed  Google Scholar 

  59. Klein G, Delmar P, Voyle N, Rehal S, Hofmann C, Abi-Saab D, et al. Gantenerumab reduces amyloid-β plaques in patients with prodromal to moderate Alzheimer’s disease: a PET substudy interim analysis. Alzheimers Res Ther. 2019;11:101.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Söderberg L, Johannesson M, Nygren P, Laudon H, Eriksson F, Osswald G, et al. Lecanemab, Aducanumab, and Gantenerumab - Binding Profiles to Different Forms of Amyloid-Beta Might Explain Efficacy and Side Effects in Clinical Trials for Alzheimer’s Disease. Neurotherapeutics. 2023;20:195–206.

  61. Tahami Monfared AA, Tafazzoli A, Ye W, Chavan A, Zhang Q. Long-Term Health Outcomes of Lecanemab in Patients with Early Alzheimer’s Disease Using Simulation Modeling. Neurol Ther. 2022;11:863–80.

    Article  PubMed  PubMed Central  Google Scholar 

  62. Gantenerumab Falls Short in Phase 3. https://www.alzforum.org/news/research-news/gantenerumab-falls-short-phase-3-0, 2022, Accessed Date Accessed 2022 Accessed.

  63. 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-β plaques: a prospective cohort study. Lancet Neurol. 2012;11:669–78.

    Article  CAS  PubMed  Google Scholar 

  64. La Joie R, Ayakta N, Seeley WW, Borys E, Boxer AL, DeCarli C, et al. Multisite study of the relationships between antemortem [(11)C]PIB-PET Centiloid values and postmortem measures of Alzheimer’s disease neuropathology. Alzheimer’s Dement. 2019;15:205–16.

    Article  Google Scholar 

  65. Amadoru S, Doré V, McLean CA, Hinton F, Shepherd CE, Halliday GM, et al. Comparison of amyloid PET measured in Centiloid units with neuropathological findings in Alzheimer’s disease. Alzheimers Res Ther. 2020;12:22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Knopman DS, Lundt ES, Therneau TM, Albertson SM, Gunter JL, Senjem ML, et al. Association of Initial β-Amyloid Levels With Subsequent Flortaucipir Positron Emission Tomography Changes in Persons Without Cognitive Impairment. JAMA Neurol. 2021;78:217–28.

    Article  PubMed  Google Scholar 

  67. Long JM, Holtzman DM. Alzheimer Disease: An Update on Pathobiology and Treatment Strategies. Cell. 2019;179:312–39.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Delor I, Charoin JE, Gieschke R, Retout S, Jacqmin P. Modeling Alzheimer’s Disease Progression Using Disease Onset Time and Disease Trajectory Concepts Applied to CDR-SOB Scores From ADNI. CPT: Pharmacomet Syst Pharmacol. 2013;2:e78.

    CAS  Google Scholar 

  69. Could Benefit of Plaque Removal Grow in Time? https://www.alzforum.org/news/conference-coverage/could-benefit-plaque-removal-grow-time, 2022, Accessed Date Accessed 2022 Accessed.

  70. Andrews JS, Desai U, Kirson NY, Zichlin ML, Ball DE, Matthews BR. Disease severity and minimal clinically important differences in clinical outcome assessments for Alzheimer’s disease clinical trials. Alzheimer’s Dement. 2019;5:354–63.

    Article  Google Scholar 

  71. Liu KY, Schneider LS, Howard R. The need to show minimum clinically important differences in Alzheimer’s disease trials. lancet Psychiatry. 2021;8:1013–6.

    Article  PubMed  Google Scholar 

  72. Nelson PT, Alafuzoff I, Bigio EH, Bouras C, Braak H, Cairns NJ, et al. Correlation of Alzheimer disease neuropathologic changes with cognitive status: a review of the literature. J Neuropathol Exp Neurol. 2012;71:362–81.

    Article  PubMed  Google Scholar 

  73. Liu F, Sun J, Wang X, Jin S, Sun F, Wang T, et al. Focal-type, but not Diffuse-type, Amyloid Beta Plaques are Correlated with Alzheimer’s Neuropathology, Cognitive Dysfunction, and Neuroinflammation in the Human Hippocampus. Neurosci Bull. 2022;38:1125–38.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Consortium AB, Jia YJ, Wang J, Ren JR, Chan P, Chen S, et al. A framework of biomarkers for brain aging: a consensus statement by the Aging Biomarker Consortium. Life Med. 2023;2:lnad017.

  75. Sato C, Barthélemy NR, Mawuenyega KG, Patterson BW, Gordon BA, Jockel-Balsarotti J, et al. Tau Kinetics in Neurons and the Human Central Nervous System. Neuron. 2018;97:1284–98.e1287.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Ying Y, Wang JZ. Illuminating Neural Circuits in Alzheimer’s Disease. Neurosci Bull. 2021;37:1203–17.

    Article  PubMed  PubMed Central  Google Scholar 

  77. Lu MH, Zhao XY, Yao PP, Xu DE, Ma QH. The Mitochondrion: A Potential Therapeutic Target for Alzheimer’s Disease. Neurosci Bull. 2018;34:1127–30.

    Article  PubMed  PubMed Central  Google Scholar 

  78. Hou X, Zhang X, Zou H, Guan M, Fu C, Wang W, et al. Differential and substrate-specific inhibition of γ-secretase by the C-terminal region of ApoE2, ApoE3, and ApoE4. Neuron. 2023;111:1898–913.e1895.

    Article  CAS  PubMed  Google Scholar 

  79. Tsai RM, Miller Z, Koestler M, Rojas JC, Ljubenkov PA, Rosen HJ, et al. Reactions to Multiple Ascending Doses of the Microtubule Stabilizer TPI-287 in Patients With Alzheimer Disease, Progressive Supranuclear Palsy, and Corticobasal Syndrome: A Randomized Clinical Trial. JAMA Neurol. 2020;77:215–24.

    Article  PubMed  Google Scholar 

  80. Vaz M, Silvestre S. Alzheimer’s disease: Recent treatment strategies. Eur J Pharmacol. 2020;887:173554.

    Article  CAS  PubMed  Google Scholar 

  81. Panza F, Lozupone M, Logroscino G, Imbimbo BP. A critical appraisal of amyloid-beta-targeting therapies for Alzheimer disease. Nat Rev Neurol. 2019;15:73–88.

    Article  PubMed  Google Scholar 

  82. Busche MA, Grienberger C, Keskin AD, Song B, Neumann U, Staufenbiel M, et al. Decreased amyloid-β and increased neuronal hyperactivity by immunotherapy in Alzheimer’s models. Nat Neurosci. 2015;18:1725–7.

    Article  CAS  PubMed  Google Scholar 

  83. Liu J, van Beusekom H, Bu XL, Chen G, Henrique Rosado de Castro P, Chen X, et al. Preserving cognitive function in patients with Alzheimer’s disease: The Alzheimer’s disease neuroprotection research initiative (ADNRI). Neuroprotection. 2023.in press.

  84. Bu XL, Jiao SS, Lian Y, Wang YJ. Perspectives on the Tertiary Prevention Strategy for Alzheimer’s Disease. Curr Alzheimer Res. 2016;13:307–16.

    Article  CAS  PubMed  Google Scholar 

  85. Zhang Q, Xie C. Apolipoprotein E Drives Early Blood-Brain Barrier Damage in Alzheimer’s Disease. Neurosci Bull. 2021;37:281–3.

    Article  CAS  PubMed  Google Scholar 

  86. Tolar M, Abushakra S, Hey JA, Porsteinsson A, Sabbagh M. Aducanumab, gantenerumab, BAN2401, and ALZ-801-the first wave of amyloid-targeting drugs for Alzheimer’s disease with potential for near term approval. Alzheimers Res Ther. 2020;12:95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Salloway S, Chalkias S, Barkhof F, Burkett P, Barakos J, Purcell D, et al. Amyloid-Related Imaging Abnormalities in 2 Phase 3 Studies Evaluating Aducanumab in Patients With Early Alzheimer Disease. JAMA Neurol. 2022;79:13–21.

    Article  PubMed  Google Scholar 

  88. Gueorguieva I, Willis BA, Chua L, Chow K, Ernest CS, Shcherbinin S, et al. Donanemab Population Pharmacokinetics, Amyloid Plaque Reduction, and Safety in Participants with Alzheimer’s Disease. Clin Pharmacol Therap. 2023;113:1258–67.

    Article  CAS  Google Scholar 

  89. Winkler DT, Biedermann L, Tolnay M, Allegrini PR, Staufenbiel M, Wiessner C, et al. Thrombolysis induces cerebral hemorrhage in a mouse model of cerebral amyloid angiopathy. Ann Neurol. 2002;51:790–3.

    Article  PubMed  Google Scholar 

  90. Alves F, Kalinowski P, Ayton S. Accelerated Brain Volume Loss Caused by Anti-β-Amyloid Drugs: A Systematic Review and Meta-analysis. Neurology. 2023;100:e2114–24.

    Article  CAS  PubMed  Google Scholar 

  91. Filippi M, Cecchetti G, Spinelli EG, Vezzulli P, Falini A, Agosta F. Amyloid-Related Imaging Abnormalities and β-Amyloid-Targeting Antibodies: A Systematic Review. JAMA Neurol. 2022;79:291–304.

    Article  PubMed  Google Scholar 

  92. Safety and Amyloid Plaque Reduction Effects of Remternetug in Patients with Alzheimer’s Disease: Interim Analysis from a Phase 1 Study. https://assets.ctfassets.net/mpejy6umgthp/51Sv0wOrFxfiHJNqcyuNYu/0c5df804e8a23256262fcb40489ae181/REMIPT3_ADPD2023_JIN_SAFETY_PLAQUE_REDUCTION_Ph1LAKB.pdf, 2023, Accessed Date Accessed 2023 Accessed.

  93. Vandenberghe R, Rinne JO, Boada M, Katayama S, Scheltens P, Vellas B, et al. Bapineuzumab for mild to moderate Alzheimer’s disease in two global, randomized, phase 3 trials. Alzheimers Res Ther. 2016;8:18.

    Article  PubMed  PubMed Central  Google Scholar 

  94. Sperling RA, Donohue MC, Raman R, Rafii MS, Johnson K, Masters CL, et al. Trial of Solanezumab in Preclinical Alzheimer’s Disease. N Engl J Med. 2023;389:1096–107.

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Acknowledgements

This study is supported by Natural Science Foundation of China (Grant No. 82120108010 and 81930028).

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  1. These authors contributed equally: Yan Lian, Yu-Juan Jia.

Authors and Affiliations

  1. Department of Prevention and Health Care, Daping Hospital, Third Military Medical University, Chongqing, China

    Yan Lian

  2. Department of Neurology and Centre for Clinical Neuroscience, Daping Hospital, Third Military Medical University, Chongqing, China

    Yan Lian & Yan-Jiang Wang

  3. Key Laboratory of Ageing and Brain Disease, Chongqing, China

    Yan Lian & Yan-Jiang Wang

  4. Department of Neurology, First Hospital of Shanxi Medical University, Taiyuan, China

    Yu-Juan Jia & Junhong Guo

  5. The Florey Institute, The University of Melbourne, Parkville, VIC, Australia

    Joelyn Wong & Colin L. Masters

  6. School of Pharmacy and Medical Sciences and Sansom Institute, Division of Health Sciences, University of South Australia, Adelaide, SA, Australia

    Xin-Fu Zhou

  7. Institute of Aging, Key Laboratory of Alzheimer’s Disease of Zhejiang Province. Zhejiang Clinical Research Center for Mental Disorders, School of Mental Health and The Affiliated Kangning Hospital, Wenzhou Medical University, Oujiang Laboratory (Zhejiang Laboratory for Regenerative Medicine, Vision and Brain Health), Wenzhou, Zhejiang, China

    Weihong Song

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YJW received research funding from the Natural Science Foundation of China (Grant No. 82120108010 and 81930028). The other authors declare no competing interests.

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Lian, Y., Jia, YJ., Wong, J. et al. Clarity on the blazing trail: clearing the way for amyloid-removing therapies for Alzheimer’s disease. Mol Psychiatry (2023). https://doi.org/10.1038/s41380-023-02324-4

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  • DOI: https://doi.org/10.1038/s41380-023-02324-4

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