Antiamyloid therapy of Alzheimer’s disease: origins, current state and prospects of development

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Abstract

Over the past historical period, views on Alzheimer’s disease therapy have undergone significant changes. This was facilitated by new research in the framework of studying the mechanisms of its development. Currently, the “amyloid hypothesis” remains prevalent, the central link of which is the accumulation of insoluble beta-amyloid protein, which provokes a subsequent cascade of pathochemical reactions leading to the formation of dementia. The presence of reliable evidence of a significant contribution of β-amyloid in the processes of neurodegeneration contributed to the development of therapeutic strategies aimed at leveling its pathological influence. In this regard, attempts are being made to develop antibodies to β-amyloid, to create β-secretase and γ-secretase inhibitors, α-secretase stimulants, as well as the synthesis of drugs capable of blocking zinc- and copper-induced formation of toxic forms of oligomers and aggregation of β-amyloid. The greatest success was achieved with the introduction of monoclonal antibodies to the protein β-amyloid. It is in this direction that the greatest efforts of scientists are focused on creating a new effective treatment for Alzheimer’s disease.

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About the authors

Sergey V. Vorobev

Almazov National Medical Research Centre; Saint-Petersburg State Pediatric Medical University

Email: sergiognezdo@yandex.ru
ORCID iD: 0000-0002-4830-907X
SPIN-code: 3426-6511

M.D., D. Sci. (Med.), chief researcher, research laboratory of neurology and neurorehabilitation; Prof., Depart. of Clinical Laboratory Diagnostics

Russian Federation, Saint-Petersburg; Saint-Petersburg

Andrey Yu. Emelin

S.M. Kirov Military Medical Academy

Author for correspondence.
Email: emelinand@rambler.ru
ORCID iD: 0000-0002-4723-802X
SPIN-code: 9650-1368
Scopus Author ID: 35773115100
ResearcherId: I-8241-2016

M.D., D. Sci. (Med.), Prof., Assoc. Prof., Depart. of Nervous Diseases

Russian Federation, Saint Petersburg

Stanislav N. Yanishevskij

Almazov National Medical Research Centre; S.M. Kirov Military Medical Academy

Email: stasya71@yandex.ru
ORCID iD: 0000-0002-6484-286X
SPIN-code: 7379-4564
Scopus Author ID: 57200699871
ResearcherId: ABA-5695-2020

M.D., D. Sci. (Med.), Assoc. Prof.; Head, research laboratory of neurology and neurorehabilitation; Assoc. Prof., Depart. of Nervous Diseases

Russian Federation, Saint-Petersburg; Saint-Petersburg

Elena V. Kostina

S.M. Kirov Military Medical Academy

Email: lena241996@gmail.com
ORCID iD: 0000-0002-4760-9927
SPIN-code: 5623-0172

clinical resident, Depart. of Nervous Diseases

Russian Federation, Saint Petersburg

Anna A. Galaeva

S.M. Kirov Military Medical Academy

Email: galaevaanna8@gmail.com
ORCID iD: 0000-0003-2309-9413
SPIN-code: 2929-8342

clinical resident, Depart. of Nervous Diseases

Russian Federation, Saint Petersburg

References

  1. Vorobev SV, Emelin AYu, Kuznetsova RN, Kudryavtsev IV. Role of the immune response in the pathogenesis of Alzheimer’s disease and possibilities of anti-inflammatory therapy. Nevrologicheskij vestnik. 2020;52(3):55–62. (In Russ.) doi: 10.17816/nb34654.
  2. Ricciarelli R, Fedele E. The amyloid cascade hypothesis in Alzheimer’s disease: It’s time to change our mind. Curr Neuropharmacol. 2017;15(6):926–935. doi: 10.2174/1570159X15666170116143743.
  3. Eshchenko ND. Biochemistry of mental and nervous diseases. Saint-Petersburg: Izd-vo S.-Peterb. un-ta; 2004. 200 p. (In Russ.)
  4. Litvinenko IV, Emelin AYu, Lobzin VYu et al. Amyloid hypothesis of Alzheimer’s disease: past and present, hopes and disappointments. Nevrologiya, neyropsikhiatriya, psikhosomatika. 2019;3(11):4–10. (In Russ.) DOI: 1014412/2074-2711-2019-3-4-10.
  5. Emelin AYu, Lobzin VYu, Vorob’ev SV. Cognitive disorders. A guide for doctors. Moscow: T8 Izdatel’skie Tekhnologii; 2019. 416 р. (In Russ.)
  6. Lobzin VYu, Kolmakova KA, Emelin AYu, Lapina AV. Glymphatic brain system and its role in pathogenesis of Alzhei-mer’s disease. Vestnik Rossijskoj voenno-medicinskoj akademii. 2019;1(65):230–236. (In Russ.)
  7. Gilman S, Koller M, Black RS et al. AN1792 (QS-21)-201 study team. Clinical effects of Abeta immunization (AN1792) in patients with AD in an interrupted trial. Neurology. 2005;64(9):1553–1562. doi: 10.1212/01.WNL.0000159740.16984.3C.
  8. Kokjohn TA, Roher AE. Antibody responses, amyloid-beta peptide remnants and clinical effects of AN-1792 immunization in patients with AD in an interrupted trial. CNS Neurol Disord Drug Targets. 2009;8(2):88–97. doi: 10.2174/187152709787847315.
  9. Ketter N, Liu E, Di J et al. A randomized, double-blind, phase 2 study of the effects of the vaccine Vanutide Cridificar with QS-21 adjuvant on immunogenicity, safety and amyloid imaging in patients with mild to moderate Alzheimer’s disease. J Prev Alzheimers Dis. 2016;3(4):192–201. doi: 10.14283/jpad.2016.118.
  10. Pasquier F, Sadowsky C, Holstein A et al. ACC-001 (QS-21) study team. 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(4):1131–1143. doi: 10.3233/JAD-150376.
  11. Landen JW, Andreasen N, Cronenberger CL et al. Ponezumab in mild-to-moderate Alzheimer’s disease: Randomized phase II PET-PIB study. Alzheimers Dement (NY). 2017;3(3):393–401. doi: 10.1016/j.trci.2017.05.003.
  12. Ultsch M, Li B, Maurer T et al. Structure of Crenezumab Complex with Aβ shows loss of β-Hairpin. Sci Rep. 2016;6:39374. doi: 10.1038/srep39374.
  13. Tian Hui Kwan A, Arfaie S, Therriault J et al. Lessons learnt from the second generation of anti-amyloid monoclonal antibodies clinical trials. Dement Geriatr Cogn Disord. 2020;49(4):334–348. doi: 10.1159/000511506.
  14. Farlow 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. doi: 10.1016/j.jalz.2011.09.224.
  15. Siemers ER, Sundell KL, Carlson C et al. Phase 3 solanezumab trials: Secondary outcomes in mild Alzheimer’s disease patients. Alzheimers Dement. 2016;12:110–120. doi: 10.1016/j.jalz.2015.06.1893.
  16. Honig LS, Vellas B, Woodward M et al. Trial of Solanezumab for mild dementia due to Alzheimer’s disease. N Engl J Med. 2018;378(4):321–330. doi: 10.1056/NEJMoa1705971.
  17. Ostrowitzki S, Lasser RA, Dorflinger E et al. SCarlet RoAD Investigators. A phase III randomized trial of gantenerumab in prodromal Alzheimer’s disease. Alzheimers Res Ther. 2017;9(1):95. doi: 10.1186/s13195-017-0318-y.
  18. Klein G, Delmar P, Voyle N 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(1):101. doi: 10.1186/s13195-019-0559-z.
  19. Bard F, Cannon C, Barbour R 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;6:916–919.
  20. Salloway S, Sperling R, Gilman S et al. A phase 2 multiple ascending dose trial of bapineuzumab in mild to moderate Alzheimer disease. Neurology. 2009;73:2061–2070. doi: 10.1212/WNL.0b013e3181c67808.
  21. Abushouk AI, Elmaraezy A, Aglan A et al. Bapineuzumab for mild to moderate Alzheimer’s disease: A meta-analysis of randomized controlled trials. BMC Neurol. 2017;17(1):66. doi: 10.1186/s12883-017-0850-1.
  22. Ferrero J, Williams L, Stella H et al. First-in-human, double-blind, placebo-controlled, single-dose escalation study of aducanumab (BIIB037) in mild-to-moderate Alzheimer’s disease. Alzheimers Dement (NY). 2016;2(3):169–176. doi: 10.1016/j.trci.2016.06.002.
  23. Kuller LH, Lopez OL. ENGAGE and EMERGE: Truth and consequences? Alzheimers Dement. 2021;17(4):692–695. doi: 10.1002/alz.12286.
  24. Haeberlein SB, von Hehn C, Tian Y et al. EMERGE and ENGAGE topline results: two phase 3 studies to evaluate aducanumab in patients with early Alzheimer’s disease. San Diego, CA: 12th Clinical Trials on Alzheimer’s Disease; 2019. 25 р.
  25. Cummings J, Aisen P, Lemere C et al. Aducanumab produced a clinically meaningful benefit in association with amyloid lowering. Alzheimers Res Ther. 2021;13(1):98. doi: 10.1186/s13195-021-00838-z.
  26. Editorial Board. The battle over an Alzheimer’s treatment; Biogen’s promising drug is caught in the FDA’s political and bureaucratic limbo. Wall Street J. 2021. https://www.wsj.com/articles/the-battle-over-an-alzheimers-treatment-11618873596 (access date: 07.04.2022).
  27. Egan MF, Kost J, Tariot PN et al. Randomized Trial of Verubecestat for mild-to-moderate Alzheimer’s disease. N Engl J Med. 2018;378(18):1691–1703. doi: 10.1056/NEJMoa1706441.
  28. Egan MF, Kost J, Voss T et al. Randomized Trial of Verubecestat for prodromal Alzheimer’s disease. N Engl J Med. 2019;380(15):1408–1420. doi: 10.1056/NEJMoa1812840.
  29. Zimmer JA, Shcherbinin S, Devous MDSr et al. Lanabecestat: Neuroimaging results in early symptomatic Alzheimer’s disease. Alzheimers Dement (NY). 2021;7(1):e12123. doi: 10.1002/trc2.12123.
  30. Sperling R, Henley D, Aisen PS et al. Findings of efficacy, safety, and biomarker outcomes of Atabecestat in preclinical Alzheimer disease: a truncated randomized phase 2b/3 clinical trial. JAMA Neurol. 2021;78(3):293–301. doi: 10.1001/jamaneurol.2020.4857.
  31. Vormfelde SV, Pezous N, Lefèvre G et al. A pooled analysis of three randomized phase I/IIa clinical trials confirms absence of a clinically relevant effect on the QTc Interval by Umibecestat. Clin Transl Sci. 2020;13(6):1316–1326. doi: 10.1111/cts.12832.
  32. Lopez Lopez C, Tariot PN, Caputo A et al. The Alzhei-mer’s Prevention Initiative Generation Program: Study design of two randomized controlled trials for individuals at risk for clinical onset of Alzheimer’s disease. Alzheimers Dement (NY). 2019;5:216–227. doi: 10.1016/j.trci.2019.02.005.
  33. Green RC, Schneider LS, Amato DA et al. Tarenflurbil Phase 3 Study Group. 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):2557–2564. doi: 10.1001/jama.2009.1866.
  34. Doody 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(4):341–350. doi: 10.1056/NEJMoa1210951.
  35. Coric V, Salloway S, van Dyck CH et al. Targeting prodromal Alzheimer disease with Avagacestat: A randomized clinical trial. JAMA Neurol. 2015;72(11):1324–1333. doi: 10.1001/jamaneurol.2015.0607.
  36. Zhang X, Li Y, Xu H. The γ-secreatse complex: from structure to function. Front Cell Neurosci. 2014;8:427. doi: 10.3389/fncel.2014.00427.
  37. Marcade M, Bourdin J, Loiseau N et al. Etazolate, a neuroprotective drug linking GABA(A) receptor pharmacology to amyloid precursor protein processing. J Neurochem. 2008;106(1):392–404. doi: 10.1111/j.1471-4159.2008.05396.x.
  38. Vellas B, Sol O, Snyder PJ et al. EHT0202/002 study group. EHT0202 in Alzheimer’s disease: a 3-month, randomized, placebo-controlled, double-blind study. Curr Alzheimer Res. 2011;8(2):203–212. doi: 10.2174/156720511795256053.
  39. Obregon DF, Rezai-Zadeh K, Bai Y et al. ADAM10 activation is required for green tea (–) — epigallocatechin-3-gallate-induced alpha-secretase cleavage of amyloid precursor protein. J Biol Chem. 2006;281(24):16419–16427. doi: 10.1074/jbc.M600617200.
  40. Kulikova AA, Makarov AA, Kozin SA. Roles of zinc ions and structural polymorphism of β-amyloid in the development of Alzheimer’s disease. Molekulyarnaya biologiya. 2015;49(2):249–263. (In Russ.) doi: 10.7868/S002689841502007X.
  41. Ritchie CW, Bush AI, Mackinnon A et al. Metal-protein attenuation with iodochlorhydroxyquin (clioquinol) targeting A beta amyloid deposition and toxicity in Alzheimer disease — A pilot phase 2 clinical trial. Arch Neurol. 2003;60(12):1685–1691. doi: 10.1001/archneur.60.12.1685.
  42. Jenagaratnam L, McShane R. Clioquinol for the treatment of Alzheimer’s Disease. Cochrane Database Syst Rev. 2006;(1):CD005380. doi: 10.1002/14651858.CD005380.pub2.
  43. Lei P, Ayton S, Bush AI. The essential elements of Alzhei-mer’s disease. J Biol Chem. 2021;296:100105. doi: 10.1074/jbc.REV120.008207
  44. Rodin DI, Shvarcman AL, Saranceva SV. Modern approaches to therapy for Alzheimer’s disease: from amyloid to the search for new targets. Uchenye zapiski SPbGMU im IP Pavlova. 2014;21(1):6–10. (In Russ.)
  45. Salloway S, Sperling R, Keren R et al. ELND005-AD201 Investigators. A phase 2 randomized trial of ELND005, scyllo-inositol, in mild to moderate Alzheimer disease. Neurology. 2011;77(13):1253–1262. doi: 10.1212/WNL.0b013e3182309fa5.

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2. Figure 1. Fragment of the pathogenesis of Alzheimer's disease with points of application of drugs in the framework of the anti-amyloid strategy

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Copyright (c) 2022 Vorobev S.V., Emelin A.Y., Yanishevskij S.N., Kostina E.V., Galaeva A.A.

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