Skip to main content

Advertisement

SpringerLink
Log in

Anti-amyloid Antibody Therapies for Alzheimer’s Disease

  • Review
  • Published:
Nuclear Medicine and Molecular Imaging Aims and scope Submit manuscript

Abstract

Alzheimer’s disease (AD) is the most common cause of dementia, which is characterized by a progressive neurodegenerative disorder that is extremely difficult to treat and severely reduces quality of life. Amyloid beta (Aβ) has been the primary target of experimental therapies owing to the neurotoxicity of Aβ and the brain Aβ load detected in humans by amyloid positron emission tomography (PET) imaging. Recently completed phase 2 and 3 trials of third-generation anti-amyloid immunotherapies indicated clinical efficacy in significantly reducing brain Aβ load and inhibiting the progression of cognitive decline. Anti-amyloid immunotherapies are the first effective disease-modifying therapies for AD, and aducanumab and lecanemab were recently approved through the US Food and Drug Administration’s accelerated approval pathway. However, these therapies still exhibit insufficient clinical efficacy and are associated with amyloid-related imaging abnormalities. Further advances in the field of AD therapeutics are required to revolutionize clinical AD treatment, dementia care, and preventive cognitive healthcare.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

Data Availability

For this type of study, data sharing is not applicable as no datasets were generated or analyzed.

References

  1. Prince M, Wimo A, Guerchet M, Ali G, Wu Y, Prina M. World Alzheimer report–the global impact of dementia; 2015

  2. Cummings J, Lee G, Nahed P, Kambar MEZN, Zhong K, Fonseca J, et al. Alzheimer’s disease drug development pipeline: 2022. Alzheimers Dement (N Y). 2022;8:e12295. https://doi.org/10.1002/trc2.12295.

    Article  PubMed  Google Scholar 

  3. 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. https://doi.org/10.1186/s13195-019-0559-z.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Lowe SL, Duggan Evans C, Shcherbinin S, Cheng YJ, Willis BA, Gueorguieva I, et al. Donanemab (LY3002813) phase 1b study in Alzheimer’s disease: rapid and sustained reduction of brain amyloid measured by florbetapir F18 imaging. J Prev Alzheimers Dis. 2021;8:414–24. https://doi.org/10.14283/jpad.2021.56.

    Article  CAS  PubMed  Google Scholar 

  5. Panza F, Lozupone M, Solfrizzi V, Sardone R, Piccininni C, Dibello V, et al. BACE inhibitors in clinical development for the treatment of Alzheimer’s disease. Expert Rev Neurother. 2018;18:847–57. https://doi.org/10.1080/14737175.2018.1531706.

    Article  CAS  PubMed  Google Scholar 

  6. Viola KL, Bicca MA, Bebenek AM, Kranz DL, Nandwana V, Waters EA, et al. The therapeutic and diagnostic potential of amyloid beta oligomers selective antibodies to treat Alzheimer’s disease. Front Neurosci. 2021;15:768646. https://doi.org/10.3389/fnins.2021.768646.

    Article  PubMed  Google Scholar 

  7. De Felice FG, Wu D, Lambert MP, Fernandez SJ, Velasco PT, Lacor PN, et al. Alzheimer’s disease-type neuronal tau hyperphosphorylation induced by Aβ oligomers. Neurobiol Aging. 2008;29:1334–47. https://doi.org/10.1016/j.neurobiolaging.2007.02.029.

    Article  CAS  PubMed  Google Scholar 

  8. Rudinskiy N, Fuerer C, Demurtas D, Zamorano S, De Piano C, Herrmann AG, et al. Amyloid-beta oligomerization is associated with the generation of a typical peptide fragment fingerprint. Alzheimers Dement. 2016;12:996–1013. https://doi.org/10.1016/j.jalz.2016.03.011.

    Article  PubMed  Google Scholar 

  9. Massaad CA, Klann E. Reactive oxygen species in the regulation of synaptic plasticity and memory. Antioxid Redox Signal. 2011;14:2013–54. https://doi.org/10.1089/ars.2010.3208.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Klunk WE, Engler H, Nordberg A, Wang Y, Blomqvist G, Holt DP, et al. Imaging brain amyloid in Alzheimer’s disease with Pittsburgh compound-B. Ann Neurol. 2004;55:306–19. https://doi.org/10.1002/ana.20009.

    Article  CAS  PubMed  Google Scholar 

  11. Wang J, Jin C, Zhou J, Zhou R, Tian M, Lee HJ, et al. PET molecular imaging for pathophysiological visualization in Alzheimer’s disease. Eur J Nucl Med Mol Imaging. 2023;50:765–83. https://doi.org/10.1007/s00259-022-05999-z.

    Article  PubMed  Google Scholar 

  12. Hardy JA, Higgins GA. Alzheimer’s disease: the amyloid cascade hypothesis. Science. 1992;256:184–5. https://doi.org/10.1126/science.166067.

    Article  ADS  CAS  PubMed  Google Scholar 

  13. Selkoe DJ, Hardy J. The amyloid hypothesis of Alzheimer’s disease at 25 years. EMBO Mol Med. 2016;8:595–608. https://doi.org/10.15252/emmm.201606210.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Sperling R, Mormino E, Johnson K. The evolution of preclinical Alzheimer’s disease: implications for prevention trials. Neuron. 2014;84:608–22. https://doi.org/10.1016/j.neuron.2014.10.038.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Jack CR Jr, Bennett DA, Blennow K, Carrillo MC, Dunn B, Haeberlein SB, et al. NIA-AA research framework: toward a biological definition of Alzheimer’s disease. Alzheimers Dement. 2018;14:535–62. https://doi.org/10.1016/j.jalz.2018.02.018.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Wilcock DM, Colton CA. Anti-amyloid-β immunotherapy in Alzheimer’s disease: relevance of transgenic mouse studies to clinical trials. J Alzheimers Dis. 2008;15:555–69. https://doi.org/10.3233/jad-2008-15404.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Orgogozo JM, Gilman S, Dartigues JF, Laurent B, Puel M, Kirby LC, et al. Subacute meningoencephalitis in a subset of patients with AD after Aβ42 immunization. Neurology. 2003;61:46–54. https://doi.org/10.1212/01.wnl.0000073623.84147.a8.

    Article  CAS  PubMed  Google Scholar 

  18. Lacosta AM, Pascual-Lucas M, Pesini P, Casabona D, Pérez-Grijalba V, Marcos-Campos I, et al. Safety, tolerability and immunogenicity of an active anti-Abeta (40) vaccine (ABvac40) in patients with Alzheimer’s disease: a randomised, doubleblind, placebo-controlled, phase I trial. Alzheimers Res Ther. 2018;10:12. https://doi.org/10.1186/s13195-018-0340-8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Wang CY, Wang PN, Chiu MJ, Finstad CL, Lin F, Lynn S, et al. UB-311, a novel UBITh®amyloid beta peptide vaccine for mild Alzheimer’s disease. Alzheimers Dement (N Y). 2017;3:262–72. https://doi.org/10.1016/j.trci.2017.03.005.

    Article  PubMed  Google Scholar 

  20. Wilcock DM, Rojiani A, Rosenthal A, Subbarao S, Freeman MJ, Gordon MN, et al. Passive immunotherapy against Aβ in aged APP-transgenic mice reverses cognitive deficits and depletes parenchymal amyloid deposits in spite of increased vascular amyloid and microhemorrhage. J Neuroinflammation. 2004;1:24. https://doi.org/10.1186/1742-2094-1-24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Bard F, Barbour R, Cannon C, Carretto R, Fox M, Games D, et al. Epitope and isotype specificities of antibodies to beta -amyloid peptide for protection against Alzheimer’s disease-like neuropathology. Proc Natl Acad Sci U S A. 2003;100:2023–8. https://doi.org/10.1073/pnas.0436286100.

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  22. Wilcock DM, Rojiani A, Rosenthal A, Levkowitz G, Subbarao S, Alamed J, et al. Passive amyloid immunotherapy clears amyloid and transiently activates microglia in a transgenic mouse model of amyloid deposition. J Neurosci. 2004;24:6144–51. https://doi.org/10.1523/JNEUROSCI.1090-04.2004.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Hartman RE, Izumi Y, Bales KR, Paul SM, Wozniak DF, Holtzman DM. Treatment with an amyloid-β 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. https://doi.org/10.1523/JNEUROSCI.0664-05.2005.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. 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. https://doi.org/10.1056/NEJMoa1304839.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Chapleau M, Iaccarino L, Soleimani-Meigooni D, Rabinovici GD. The role of amyloid PET in imaging neurodegenerative disorders: a review. J Nucl Med. 2022;63;Suppl 1:13S–9S–S19. https://doi.org/10.2967/jnumed.121.263195

  26. Lendel C, Bjerring M, Dubnovitsky A, Kelly RT, Filippov A, Antzutkin ON, et al. A hexameric peptide barrel as building block of amyloid-β protofibrils. Angew Chem Int Ed Engl. 2014;53:12756–60. https://doi.org/10.1002/anie.201406357.

    Article  CAS  PubMed  Google Scholar 

  27. 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. https://doi.org/10.1056/NEJMoa1705971.

    Article  CAS  PubMed  Google Scholar 

  28. 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. https://doi.org/10.1056/NEJMoa1312889.

    Article  CAS  PubMed  Google Scholar 

  29. Meilandt W, Maloney J, Imperio J, Bainbridge T, Reichelt M, Mandikian D, et al. Characterization of the selective in vivo and in vitro binding properties of crenezumab: insights into crenezumab’s unique mechanism of action. Alzheimers Res Ther. 2019;11:97. https://doi.org/10.1186/s13195-019-0553-5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Cummings JL, Cohen S, van Dyck CH, Brody M, Curtis C, Cho W, et al. ABBY: a phase 2 randomized trial of crenezumab in mild to moderate Alzheimer disease. Neurology. 2018;90:e1889–97. https://doi.org/10.1212/WNL.0000000000005550.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. 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. https://doi.org/10.1001/jamaneurol.2022.2909.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Reiman EM, Pruzin JJ, Rios-Romenets S, Brown C, Giraldo M, Acosta-Baena N, et al. A public resource of baseline data from the Alzheimer’s prevention initiative autosomal-dominant Alzheimer’s disease trial. Alzheimers Dement. 2023;19:1938–46. https://doi.org/10.1002/alz.12843.

    Article  PubMed  Google Scholar 

  33. 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. https://doi.org/10.1186/s13195-017-0318-y.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Bateman RJ, Cummings J, Schobel S, Salloway S, Vellas B, Boada M, et al. Gantenerumab: an anti-amyloid monoclonal antibody with potential disease-modifying effects in early Alzheimer’s disease. Alzheimers Res Ther. 2022;14:178. https://doi.org/10.1186/s13195-022-01110-8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Roche announces results from the GRADUATE Phase III trials of gantenerumab; 2022. https://www.roche.com/media/releases/med-cor-2022-11-14. Accessed 11/08/2023

  36. 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. https://doi.org/10.1038/s41598-018-24501-0.

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  37. Colvin MT, Silvers R, Ni QZ, Can TV, Sergeyev I, Rosay M, et al. Atomic resolution structure of monomorphic Aβ42 amyloid fibrils. J Am Chem Soc. 2016;138:9663–74. https://doi.org/10.1021/jacs.6b05129.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Sevigny J, Chiao P, Bussière T, Weinreb PH, Williams L, Maier M, et al. The antibody aducanumab reduces Aβ plaques in Alzheimer’s disease. Nature. 2016;537:50–6. https://doi.org/10.1038/nature19323.

    Article  ADS  CAS  PubMed  Google Scholar 

  39. Um JW, Kaufman AC, Kostylev M, Heiss JK, Stagi M, Takahashi H, et al. Metabotropic glutamate receptor 5 is a coreceptor for Alzheimer aβ oligomer bound to cellular prion protein. Neuron. 2013;79:887–902. https://doi.org/10.1016/j.neuron.2013.06.036.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Budd Haeberlein S, Aisen PS, Barkhof F, Chalkias S, Chen T, Cohen S, et al. Two randomized phase 3 studies of aducanumab in early Alzheimer’s disease. J Prev Alzheimers Dis. 2022;9:197–210. https://doi.org/10.14283/jpad.2022.30.

    Article  CAS  PubMed  Google Scholar 

  41. 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. https://doi.org/10.1001/jamaneurol.2021.4161.

    Article  PubMed  Google Scholar 

  42. Beshir SA, Aadithsoorya AM, Parveen A, Goh SSL, Hussain N, Menon VB. Aducanumab therapy to treat Alzheimer’s disease: a narrative review. Int J Alzheimers Dis. 2022;2022:9343514. https://doi.org/10.1155/2022/9343514.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Basun H, Bogdanovic N, Ingelsson M, Almkvist O, Näslund J, Axelman K, et al. Clinical and neuropathological features of the arctic APP gene mutation causing early-onset Alzheimer disease. Arch Neurol. 2008;65:499–505. https://doi.org/10.1001/archneur.65.4.499.

    Article  PubMed  PubMed Central  Google Scholar 

  44. Nilsberth C, Westlind-Danielsson A, Eckman CB, Condron MM, Axelman K, Forsell C, et al. The ‘Arctic’ APP mutation (E693G) causes Alzheimer’s disease by enhanced abeta protofibril formation. Nat Neurosci. 2001;4:887–93. https://doi.org/10.1038/nn0901-887.

    Article  CAS  PubMed  Google Scholar 

  45. 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. https://doi.org/10.1056/NEJMoa2212948.

    Article  PubMed  Google Scholar 

  46. Papp KV, Rentz DM, Orlovsky I, Sperling RA, Mormino EC. Optimizing the preclinical Alzheimer’s cognitive composite with semantic processing: the PACC5. Alzheimers Dement (N Y). 2017;3:668–77. https://doi.org/10.1016/j.trci.2017.10.004.

    Article  PubMed  Google Scholar 

  47. Jawhar S, Wirths O, Bayer TA. Pyroglutamate amyloid-beta (Aβ): a hatchet man in Alzheimer disease. J Biol Chem. 2011;286:38825–32. https://doi.org/10.1074/jbc.R111.288308.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Iwatsubo T, Saido TC, Mann DM, Lee VM, Trojanowski JQ. Full-length amyloid-beta (1–42 (43)) and amino-terminally modified and truncated amyloid-beta 42 (43) deposit in diffuse plaques. Am J Pathol. 1996;149:1823–30.

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Demattos RB, Lu J, Tang Y, Racke MM, Delong CA, Tzaferis JA, et al. A plaque-specific antibody clears existing β-amyloid plaques in Alzheimer’s disease mice. Neuron. 2012;76:908–20. https://doi.org/10.1016/j.neuron.2012.10.029.

    Article  CAS  PubMed  Google Scholar 

  50. Espay AJ. Donanemab in early Alzheimer’s disease. N Engl J Med. 2021;385:666–7. https://doi.org/10.1056/NEJMc2109455.

    Article  PubMed  Google Scholar 

  51. Mintun MA, Lo AC, Duggan Evans C, Wessels AM, Ardayfio PA, Andersen SW, et al. Donanemab in early Alzheimer’s disease. N Engl J Med. 2021;384:1691–704. https://doi.org/10.1056/NEJMoa2100708.

    Article  CAS  PubMed  Google Scholar 

  52. Shcherbinin S, Andersen SW, Evans CD, Lo AC, Lu M, Navitsky M, et al. TRAILBLAZER-ALZ Study: dynamics of amyloid reduction after donanemab treatment. Alzheimers Dement. 2021;17:e057492. https://doi.org/10.1002/alz.057492.

    Article  Google Scholar 

  53. 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. https://doi.org/10.1001/jama.2023.13239.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Jin Y. Safety and amyloid plaque reduction effects of remternetug in patients with Alzheimer’s disease: interim analysis from a phase 1 study AD/PD Conference. Sweden: Gothernburg; 2023. p. 2023.

    Google Scholar 

  55. Siemers E, Hitchcock J, Sundell K, Dean R, Jerecic J, Cline E, et al. ACU193, A monoclonal antibody that selectively binds soluble Aβ oligomers: development rationale, phase 1 trial design, and clinical development plan. J Prev Alzheimers Dis. 2023;10:19–24. https://doi.org/10.14283/jpad.2022.93.

    Article  CAS  PubMed  Google Scholar 

  56. ALZFORUM. Trontinemab: AlzForum Foundation Inc.; 2023. https://www.alzforum.org/therapeutics/trontinemab. Accessed 11/08/2023

  57. Yadollahikhales G, Rojas JC. Anti-amyloid immunotherapies for Alzheimer’s disease: a 2023 clinical update. Neurotherapeutics. 2023;20:914–31. https://doi.org/10.1007/s13311-023-01405-0.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The author would like to thank the neurology and nuclear medicine staffs at Dong-A University College of Medicine.

Author information

Authors and Affiliations

  1. Department of Neurology, Dong-A University College of Medicine, 26 Daesingongwon-Ro, Seo-Gu, Busan, 49201, Korea

    Kyung Won Park

  2. Department of Translational Biomedical Sciences, Graduate School, Dong-A University, 26 Daesingongwon-Ro, Seo-Gu, Busan, 49201, Korea

    Kyung Won Park

Authors
  1. Kyung Won Park
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Kyung Won Park contributed to the conceptualization, design, and writing of this review manuscript.

Corresponding author

Correspondence to Kyung Won Park.

Ethics declarations

Conflict of Interest

Kyung Won Park declares no competing interests.

Ethical Approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

Informed Consent

For this type of study, formal consent is not required and informed consent is not applicable.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Park, K.W. Anti-amyloid Antibody Therapies for Alzheimer’s Disease. Nucl Med Mol Imaging (2024). https://doi.org/10.1007/s13139-024-00848-3

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s13139-024-00848-3

Keywords

Search

Navigation