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Current Neurology and Neuroscience Reports

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21-10-2022 | Alzheimer's Disease | Dementia (K.S. Marder, Section Editor)

Vascular Considerations for Amyloid Immunotherapy

Authors: Kate E. Foley, Donna M. Wilcock

Published in: Current Neurology and Neuroscience Reports | Issue 11/2022

Abstract

Purpose of Review

Amyloid beta (Aβ) plaque accumulation is a hallmark pathology contributing to Alzheimer’s disease (AD) and is widely hypothesized to lead to cognitive decline. Decades of research into anti-Aβ immunotherapies provide evidence for increased Aβ clearance from the brain; however, this is frequently accompanied by complicated vascular deficits. This article reviews the history of anti-Aβ immunotherapies and clinical findings and provides recommendations moving forward.

Recent Findings

In 20 years of both animal and human studies, anti-Aβ immunotherapies have been a prevalent avenue of reducing hallmark Aβ plaques. In both models and with different anti-Aβ antibody designs, amyloid-related imaging abnormalities (ARIA) indicating severe cerebrovascular compromise have been common and concerning occurrence.

Summary

ARIA caused by anti-Aβ immunotherapy has been noted since the early 2000s, and the mechanisms driving it are still unknown. Recent approval of aducanumab comes with renewed urgency to consider vascular deficits caused by anti-Aβ immunotherapy.

Hippius H, Neundorfer G. The discovery of Alzheimer’s disease. Dialogues Clin Neurosci. 2003;5(1):101–8.CrossRefPubMedPubMedCentral

Goate A, Chartier-Harlin M-C, Mullan M, Brown J, Crawford F, Fidani L, et al. Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer’s disease. Nature. 1991;349(6311):704–6. https://doi.org/10.1038/349704a0.CrossRefPubMed

Hardy JA, Higgins GA. Alzheimer’s disease: the amyloid cascade hypothesis. Science. 1992;256(5054):184–5. https://doi.org/10.1126/science.1566067.CrossRefPubMed

Selkoe DJ. Alzheimer’s disease: a central role for amyloid. J Neuropathol Exp Neurol. 1994;53(5):438–47. https://doi.org/10.1097/00005072-199409000-00003.CrossRefPubMed

Pike CJ, Overman MJ, Cotman CW. Amino-terminal deletions enhance aggregation of β-amyloid peptides in vitro. J Biol Chem. 1995;270(41):23895–8. https://doi.org/10.1074/jbc.270.41.23895.CrossRefPubMed

Iwatsubo T, Odaka A, Suzuki N, Mizusawa H, Nukina N, Ihara Y. Visualization of A beta 42(43) and A beta 40 in senile plaques with end-specific A beta monoclonals: evidence that an initially deposited species is A beta 42(43). Neuron. 1994;13(1):45–53. https://doi.org/10.1016/0896-6273(94)90458-8.CrossRefPubMed

Niwa K, Carlson GA, Iadecola C. Exogenous Aβ1–40 reproduces cerebrovascular alterations resulting from amyloid precursor protein overexpression in mice. J Cereb Blood Flow Metab. 2000;20(12):1659–68. https://doi.org/10.1097/00004647-200012000-00005.CrossRefPubMed

Gomis M, Sobrino TS, Ois A, MilláN MN, RodríGuez-Campello A, De La Ossa NPR, et al. Plasma β-amyloid 1–40 is associated with the diffuse small vessel disease subtype. Stroke. 2009;40(10):3197–201. https://doi.org/10.1161/strokeaha.109.559641.CrossRefPubMed

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. 1996;93(1):452–5. https://doi.org/10.1073/pnas.93.1.452.CrossRefPubMedPubMedCentral

10.

Solomon B, Koppel R, Frankel D, Hanan-Aharon E. Disaggregation of Alzheimer beta-amyloid by site-directed mAb. Proc Natl Acad Sci U S A. 1997;94(8):4109–12. https://doi.org/10.1073/pnas.94.8.4109.CrossRefPubMedPubMedCentral

11.•

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. https://doi.org/10.1038/22124. This paper is the first article showing effective immunization procedures to clear Aβ plaques in mice.CrossRefPubMed

12.

Morgan D, Diamond DM, Gottschall PE, Ugen KE, Dickey C, Hardy J, et al. Aβ peptide vaccination prevents memory loss in an animal model of Alzheimer’s disease. Nature. 2000;408(6815):982–5. https://doi.org/10.1038/35050116.CrossRefPubMed

13.

Janus C, Pearson J, McLaurin J, Mathews PM, Jiang Y, Schmidt SD, et al. Aβ peptide immunization reduces behavioural impairment and plaques in a model of Alzheimer’s disease. Nature. 2000;408(6815):979–82. https://doi.org/10.1038/35050110.CrossRefPubMed

14.

Chishti MA, Yang DS, Janus C, Phinney AL, Horne P, Pearson J, et al. Early-onset amyloid deposition and cognitive deficits in transgenic mice expressing a double mutant form of amyloid precursor protein 695. J Biol Chem. 2001;276(24):21562–70. https://doi.org/10.1074/jbc.M100710200.CrossRefPubMed

15.•

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. https://doi.org/10.1038/78682. The authors show the first murine demonstration that peripheral immunization of anti-Aβ antibodies can cross the cerebrovasculature to mitigate Aβ plaque.CrossRefPubMed

16.

Vidarsson G, Dekkers G, Rispens T. IgG subclasses and allotypes: from structure to effector functions. Front Immunol. 2014;5:520. https://doi.org/10.3389/fimmu.2014.00520.CrossRefPubMedPubMedCentral

17.

De Taeye SW, Rispens T, Vidarsson G. The ligands for human IgG and their effector functions. Antibodies. 2019;8(2):30. https://doi.org/10.3390/antib8020030.CrossRefPubMedCentral

18.

Bacskai BJ, Kajdasz ST, McLellan ME, Games D, Seubert P, Schenk D, et al. Non-Fc-mediated mechanisms are involved in clearance of amyloid-beta in vivo by immunotherapy. J Neurosci. 2002;22(18):7873–8.CrossRefPubMedPubMedCentral

19.

Bard F, Barbour R, Cannon C, Carretto R, Fox M, Games D, et al. Epitope and isotype specificities of antibodies to β-amyloid peptide for protection against Alzheimer’s disease-like neuropathology. Proc Natl Acad Sci. 2003;100(4):2023–8. https://doi.org/10.1073/pnas.0436286100.CrossRefPubMedPubMedCentral

20.

Lightle S, Aykent S, Lacher N, Mitaksov V, Wells K, Zobel J, et al. Mutations within a human IgG2 antibody form distinct and homogeneous disulfide isomers but do not affect Fc gamma receptor or C1q binding. Protein Sci. 2010;19(4):753–62. https://doi.org/10.1002/pro.352.CrossRefPubMedPubMedCentral

21.

Wilcock DM, DiCarlo G, Henderson D, Jackson J, Clarke K, Ugen KE, et al. Intracranially administered anti-Abeta antibodies reduce beta-amyloid deposition by mechanisms both independent of and associated with microglial activation. J Neurosci. 2003;23(9):3745–51.CrossRefPubMedPubMedCentral

22.

Wilcock DM, Munireddy SK, Rosenthal A, Ugen KE, Gordon MN, Morgan D. Microglial activation facilitates Abeta plaque removal following intracranial anti-Abeta antibody administration. Neurobiol Dis. 2004;15(1):11–20. https://doi.org/10.1016/j.nbd.2003.09.015.CrossRefPubMed

23.

DeWitt DA, Perry G, Cohen M, Doller C, Silver J. Astrocytes regulate microglial phagocytosis of senile plaque cores of Alzheimer’s disease. Exp Neurol. 1998;149(2):329–40. https://doi.org/10.1006/exnr.1997.6738.CrossRefPubMed

24.

Wyss-Coray T, Loike JD, Brionne TC, Lu E, Anankov R, Yan F, et al. Adult mouse astrocytes degrade amyloid-beta in vitro and in situ. Nat Med. 2003;9(4):453–7. https://doi.org/10.1038/nm838.CrossRefPubMed

25.

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 U S A. 2001;98(15):8850–5. https://doi.org/10.1073/pnas.151261398.CrossRefPubMedPubMedCentral

26.

DeMattos RB, Bales KR, Cummins DJ, Paul SM, Holtzman DM. Brain to plasma amyloid-beta efflux: a measure of brain amyloid burden in a mouse model of Alzheimer’s disease. Science. 2002;295(5563):2264–7. https://doi.org/10.1126/science.1067568.CrossRefPubMed

27.

Pfeifer M, Boncristiano S, Bondolfi L, Stalder A, Deller T, Staufenbiel M, et al. Cerebral hemorrhage after passive anti-Abeta immunotherapy. Science. 2002;298(5597):1379. https://doi.org/10.1126/science.1078259.CrossRefPubMed

28.

Wilcock DM, Rojiani A, Rosenthal A, Subbarao S, Freeman MJ, Gordon MN, et al. Passive immunotherapy against Abeta 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(1):24. https://doi.org/10.1186/1742-2094-1-24.CrossRefPubMedPubMedCentral

29.

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. https://doi.org/10.1523/JNEUROSCI.4337-04.2005.CrossRefPubMedPubMedCentral

30.

Jellinger KA. Alzheimer disease and cerebrovascular pathology: an update. J Neural Transm. 2002;109(5–6):813–36. https://doi.org/10.1007/s007020200068.CrossRefPubMed

31.

Janota C, Lemere CA, Brito MA. Dissecting the contribution of vascular alterations and aging to Alzheimer’s disease. Mol Neurobiol. 2016;53(6):3793–811. https://doi.org/10.1007/s12035-015-9319-7.CrossRefPubMed

32.

Schenk D. Amyloid-β immunotherapy for Alzheimer’s disease: the end of the beginning. Nat Rev Neurosci. 2002;3(10):824–8. https://doi.org/10.1038/nrn938.CrossRefPubMed

33.

Buckwalter MS, Coleman BS, Buttini M, Barbour R, Schenk D, Games D, et al. Increased T cell recruitment to the CNS after amyloid beta1-42 immunization in Alzheimer’s mice overproducing transforming growth factor-beta1. J Neurosci. 2006;26(44):11437–41. https://doi.org/10.1523/jneurosci.2436-06.2006.CrossRefPubMedPubMedCentral

34.

Ferrer I, Rovira MB, Guerra MLS, Rey MJ, Costa-Jussá F. Neuropathology and pathogenesis of encephalitis following amyloid β immunization in Alzheimer’s disease. Brain Pathol. 2004;14(1):11–20. https://doi.org/10.1111/j.1750-3639.2004.tb00493.x.CrossRefPubMed

35.

Nicoll JAR, Wilkinson D, Holmes C, Steart P, Markham H, Weller RO. Neuropathology of human Alzheimer disease after immunization with amyloid-β peptide: a case report. Nat Med. 2003;9(4):448–52. https://doi.org/10.1038/nm840.CrossRefPubMed

36.

Nicoll JAR, Barton E, Boche D, Neal JW, Ferrer I, Thompson P, et al. Aβ species removal after Aβ<sub>42</sub>immunization. J Neuropathol Exp Neurol. 2006;65(11):1040–8. https://doi.org/10.1097/01.jnen.0000240466.10758.ce.CrossRefPubMed

37.

Boche D, Zotova E, Weller RO, Love S, Neal JW, Pickering RM, et al. Consequence of Abeta immunization on the vasculature of human Alzheimer’s disease brain. Brain. 2008;131(Pt 12):3299–310. https://doi.org/10.1093/brain/awn261.CrossRefPubMed

38.

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. https://doi.org/10.1212/wnl.0b013e3181c67808.CrossRefPubMedPubMedCentral

39.

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. https://doi.org/10.1056/nejmoa1304839.CrossRefPubMedPubMedCentral

40.

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. Alzheimer’s Res Ther. 2016;8(1). https://doi.org/10.1186/s13195-016-0189-7.

41.

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. https://doi.org/10.1097/wad.0b013e3181c53b00.CrossRefPubMedPubMedCentral

42.

Rinne JO, Brooks DJ, Rossor MN, Fox NC, Bullock R, Klunk WE, et al. 11C-PiB PET assessment of change in fibrillar amyloid-beta load in patients with Alzheimer’s disease treated with bapineuzumab: a phase 2, double-blind, placebo-controlled, ascending-dose study. Lancet Neurol. 2010;9(4):363–72. https://doi.org/10.1016/S1474-4422(10)70043-0.CrossRefPubMed

43.

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. https://doi.org/10.1056/nejmoa1312889.CrossRefPubMed

44.

Sperling RA, Jack CR Jr, Black SE, Frosch MP, Greenberg SM, Hyman BT, et al. Amyloid-related imaging abnormalities in amyloid-modifying therapeutic trials: recommendations from the Alzheimer’s Association Research Roundtable Workgroup. Alzheimers Dement. 2011;7(4):367–85. https://doi.org/10.1016/j.jalz.2011.05.2351.CrossRefPubMedPubMedCentral

45.

Tampi RR, Forester BP, Agronin M. Aducanumab: evidence from clinical trial data and controversies. Drugs in Context. 2021;10:1–9. https://doi.org/10.7573/dic.2021-7-3.CrossRef

46.

Food and Drug Administration, Biogen. Peripheral and Central Nervous System (PCNS) Drugs Advisory Committee Meeting. 2020.

47.

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(7618):50–6. https://doi.org/10.1038/nature19323.CrossRefPubMed

48.

Khan TK. Chapter 2 - Clinical diagnosis of Alzheimer’s disease. In: Khan TK, editor. Biomarkers in Alzheimer’s Disease. Academic Press; 2016. p. 27–48.CrossRef

49.••

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. Alzheimers Dement. 2021;17(4):696–701. https://doi.org/10.1002/alz.12213. This paper outlines the timeline of clinical trials for aducanumab and FDA statements as well as highlights the areas where outcome measures fell short statistically and translationally. This subjective piece details the need for a third clinical trial since EMERGE and ENGAGE failed to provide evidence of efficacy.CrossRefPubMed

50.

Haeberlein SB, Von Hehn C, Tian Y, Chalkias S, Muralidharan KK, Chen T, et al. Emerge and Engage topline results: phase 3 studies of aducanumab in early Alzheimer’s disease. Alzheimer's & Dementia. 2020;16(S9). https://doi.org/10.1002/alz.047259.

51.

Cummings J, Aisen P, Apostolova LG, Atri A, Salloway S, Weiner M. Aducanumab: appropriate use recommendations. J Prev Alzheimers Dis. 2021;8(4):398–410. https://doi.org/10.14283/jpad.2021.41.CrossRefPubMedPubMedCentral

52.••

Cummings J, Rabinovici GD, Atri A, Aisen P, Apostolova LG, Hendrix S, et al. Aducanumab: appropriate use recommendations update. J Prev Alzheimers Dis. 2022;9(2):221–30. https://doi.org/10.14283/jpad.2022.34. This article updates the appropriate use of aducanumab in the clinic. The authors outline the recommendations of patient population selection and clinical safety monitoring of ARIA events.CrossRefPubMed

Title: Vascular Considerations for Amyloid Immunotherapy
Authors: Kate E. Foley
Donna M. Wilcock
Publication date: 21-10-2022
Publisher: Springer US
Keywords: Alzheimer's Disease
Alzheimer's Disease
Biomarkers
Published in: Current Neurology and Neuroscience Reports / Issue 11/2022
Print ISSN: 1528-4042
Electronic ISSN: 1534-6293
DOI: https://doi.org/10.1007/s11910-022-01235-1

Keynote webinar | Spotlight on sleep in brain health

Springer Medicine

Vascular Considerations for Amyloid Immunotherapy

Abstract

Purpose of Review

Recent Findings

Summary

Keynote webinar | Spotlight on sleep in brain health

Springer Medicine

Abstract

Purpose of Review

Recent Findings

Summary

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