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image of Structural and Functional Determinants of ARIA-H Risk in Anti-Amyloid Monoclonal Antibodies: A Comparative Mechanistic Framework for 
Alzheimer's Immunotherapy Development
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Abstract

Introduction

Amyloid-beta-targeting monoclonal antibodies (mAbs) for Alzheimer's disease frequently induce amyloid-related imaging abnormalities with hemorrhage (ARIA-H), yet systematic comparisons of ARIA-H incidence across therapeutic agents remain limited. Post-approval research prioritizes dosing over mechanism, leaving unresolved whether ARIA-H variations originate from intrinsic mAb properties. We address two gaps: comparative ARIA-H risk stratification among clinically available/investigational mAbs, and elucidation of structural/functional features influencing ARIA-H susceptibility.

Methods

A systematic comparison of seven mAbs (donanemab, aducanumab, bapineuzumab, lecanemab, gantenerumab, crenezumab, solanezumab) was conducted, analyzing clinical trial data and molecular characteristics.

Results

ARIA-H incidence ranked as follows (highest to lowest): donanemab > aducanumab > bapineuzumab > lecanemab > gantenerumab > crenezumab > solanezumab. Five mAb-specific determinants emerged: (1) Types of Aβ Binding: Enhanced clearance of mature amyloid plaques correlated with elevated ARIA-H risk. (2) Polymer binding Affinity: Reduced small oligomer-binding capacity predicted higher ARIA-H incidence. (3) Epitope location: N-terminal-targeting mAbs showed greater ARIA-H incidence . mid/C-terminal binders. (4) Fc region structure: IgG4-based constructs showed higher ARIA-H incidence than IgG1 analogs. (5) Clearance kinetics: Rapid attainment of amyloid reduction thresholds amplified ARIA-H incidence.

Discussion

We identify a risk hierarchy for ARIA-H among anti-Aβ mAbs and link specific mAb biophysical properties—Aβ binding type, affinity for soluble oligomers, epitope specificity, Fc structure, and plaque clearance dynamics—directly to ARIA-H pathogenesis.

Conclusion

These findings establish a mechanistic framework for ARIA-H risk and provide concrete molecular predictors to guide antibody engineering strategies. Prioritizing mAbs with controlled amyloid clearance, C-terminal binding domains, and IgG1 frameworks may enhance therapeutic safety, advancing precision immunotherapy for Alzheimer's disease.

© 2025 The Author(s). Published by Bentham Science Publisher.
This is an open access article published under CC BY 4.0 https://creativecommons.org/licenses/by/4.0/legalcode
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References

  1. Fatima R. Khan Y. Maqbool M. Ramalingam P.S. Khan M.G. Bisht A.S. Hussain M.S. Amyloid-β clearance with monoclonal antibodies: Transforming Alzheimer’s treatment. Curr. Protein Pept. Sci. 2025 26 10.2174/0113892037362037250205143911 39980294
    [Google Scholar]
  2. van Dyck C.H. Swanson C.J. Aisen P. Bateman R.J. Chen C. Gee M. Kanekiyo M. Li D. Reyderman L. Cohen S. Froelich L. Katayama S. Sabbagh M. Vellas B. Watson D. Dhadda S. Irizarry M. Kramer L.D. Iwatsubo T. Lecanemab in early Alzheimer’s disease. N. Engl. J. Med. 2023 388 1 9 21 10.1056/NEJMoa2212948 36449413
    [Google Scholar]
  3. Jones K.E. Aakre J.A. Castillo A.M. Ramanan V.K. Kremers W.K. Jack C.R. Vemuri P. Schwarz C.G. Lowe V.J. Knopman D.S. Petersen R.C. Graff-Radford J. Vassilaki M. Eligibility for donanemab trial in a population-based study of cognitive aging. J. Prev. Alzheimers Dis. 2025 12 4 100088 10.1016/j.tjpad.2025.100088 39966022
    [Google Scholar]
  4. Yu F.F. Invited commentary: Radiologist’s role in anti-amyloid therapy for Alzheimer disease. Radiographics 2023 43 9 e230205 10.1148/rg.230205 37651274
    [Google Scholar]
  5. Liu K.Y. Howard R. Can we learn lessons from the FDA’s approval of aducanumab? Nat. Rev. Neurol. 2021 17 11 715 722 10.1038/s41582‑021‑00557‑x 34535787
    [Google Scholar]
  6. Boxer A.L. Sperling R. Accelerating Alzheimer’s therapeutic development: The past and future of clinical trials. Cell 2023 186 22 4757 4772 10.1016/j.cell.2023.09.023 37848035
    [Google Scholar]
  7. Jeong S.Y. Suh C.H. Lim J.S. Choi Y. Kim H.S. Kim S.J. Lee J.H. Anti-amyloid imaging abnormality in the era of anti-amyloid beta monoclonal antibodies: Recent updates for the radiologist. J. Korean Soc. Radiol. 2025 86 1 17 33 10.3348/jksr.2024.0140 39958499
    [Google Scholar]
  8. Barakos J. Sperling R. Salloway S. Jack C. Gass A. Fiebach J.B. Tampieri D. Melançon D. Miaux Y. Rippon G. Black R. Lu Y. Brashear H.R. Arrighi H.M. Morris K.A. Grundman M. MR imaging features of amyloid-related imaging abnormalities. AJNR Am. J. Neuroradiol. 2013 34 10 1958 1965 10.3174/ajnr.A3500 23578674
    [Google Scholar]
  9. Sims J.R. Zimmer J.A. Evans C.D. Lu M. Ardayfio P. Sparks J. Wessels A.M. Shcherbinin S. Wang H. Monkul Nery E.S. Collins E.C. Solomon P. Salloway S. Apostolova L.G. Hansson O. Ritchie C. Brooks D.A. Mintun M. Skovronsky D.M. Abreu R. Agarwal P. Aggarwal P. Agronin M. Allen A. Altamirano D. Alva G. Andersen J. Anderson A. Anderson D. Arnold J. Asada T. Aso Y. Atit V. Ayala R. Badruddoja M. Badzio-jagiello H. Bajacek M. Barton D. Bear D. Benjamin S. Bergeron R. Bhatia P. Black S. Block A. Bolouri M. Bond W. Bouthillier J. Brangman S. Brew B. Brisbin S. Brisken T. Brodtmann A. Brody M. Brosch J. Brown C. Brownstone P. Bukowczan S. Burns J. Cabrera A. Capote H. Carrasco A. Cevallos Yepez J. Chavez E. Chertkow H. Chyrchel-paszkiewicz U. Ciabarra A. Clemmons E. Cohen D. Cohen R. Cohen I. Concha M. Costell B. Crimmins D. Cruz-pagan Y. Cueli A. Cupelo R. Czarnecki M. Darby D. Dautzenberg P. De Deyn P. De La Gandara J. Deck K. Dibenedetto D. Dibuono M. Dinnerstein E. Dirican A. Dixit S. Dobryniewski J. Drake R. Drysdale P. Duara R. Duffy J. Ellenbogen A. Faradji V. Feinberg M. Feldman R. Fishman S. Flitman S. Forchetti C. Fraga I. Frank A. Frishberg B. Fujigasaki H. Fukase H. Fumero I. Furihata K. Galloway C. Gandhi R. George K. Germain M. Gitelman D. Goetsch N. Goldfarb D. Goldstein M. Goldstick L. Gonzalez Rojas Y. Goodman I. Greeley D. Griffin C. Grigsby E. Grosz D. Hafner K. Hart D. Henein S. Herskowitz B. Higashi S. Higashi Y. Ho G. Hodgson J. Hohenberg M. Hollenbeck L. Holub R. Hori T. Hort J. Ilkowski J. Ingram K.J. Isaac M. Ishikawa M. Janu L. Johnston M. Julio W. Justiz W. Kaga T. Kakigi T. Kalafer M. Kamijo M. Kaplan J. Karathanos M. Katayama S. Kaul S. Keegan A. Kerwin D. Khan U. Khan A. Kimura N. Kirk G. Klodowska G. Kowa H. Kutz C. Kwentus J. Lai R. Lall A. Lawrence M. Lee E. Leon R. Linker G. Lisewski P. Liss J. Liu C. Losk S. Lukaszyk E. Lynch J. Macfarlane S. Macsweeney J. Mannering N. Markovic O. Marks D. Masdeu J. Matsui Y. Matsuishi K. Mcallister P. Mcconnehey B. Mcelveen A. Mcgill L. Mecca A. Mega M. Mensah J. Mickielewicz A. Minaeian A. Mocherla B. Murphy C. Murphy P. Nagashima H. Nair A. Nair M. Nardandrea J. Nash M. Nasreddine Z. Nishida Y. Norton J. Nunez L. Ochiai J. Ohkubo T. Okamura Y. Okorie E. Olivera E. O’mahony J. Omidvar O. Ortiz-Cruz D. Osowa A. Papka M. Parker A. Patel P. Patel A. Patel M. Patry C. Peckham E. Pfeffer M. Pietras A. Plopper M. Porsteinsson A. Poulin Robitaille R. Prins N. Puente O. Ratajczak M. Rhee M. Ritter A. Rodriguez R. Rodriguez Ables L. Rojas J. Ross J. Royer P. Rubin J. Russell D. Rutgers S.M. Rutrick S. Sadowski M. Safirstein B. Sagisaka T. Scharre D. Schneider L. Schreiber C. Schrift M. Schulz P. Schwartz H. Schwartzbard J. Scott J. Selem L. Sethi P. Sha S. Sharlin K. Sharma S. Shiovitz T. Shiwach R. Sladek M. Sloan B. Smith A. Solomon P. Sorial E. Sosa E. Stedman M. Steen S. Stein L. Stolyar A. Stoukides J. Sudoh S. Sutton J. Syed J. Szigeti K. Tachibana H. Takahashi Y. Tateno A. Taylor J.D. Taylor K. Tcheremissine O. Thebaud A. Thein S. Thurman L. Toenjes S. Toji H. Toma M. Tran D. Trueba P. Tsujimoto M. Turner R. Uchiyama A. Ussorowska D. Vaishnavi S. Valor E. Vandersluis J. Vasquez A. Velez J. Verghese C. Vodickova-borzova K. Watson D. Weidman D. Weisman D. White A. Willingham K. Winkel I. Winner P. Winston J. Wolff A. Yagi H. Yamamoto H. Yathiraj S. Yoshiyama Y. Zboch M. Donanemab in early symptomatic Alzheimer disease. JAMA 2023 330 6 512 527 10.1001/jama.2023.13239 37459141
    [Google Scholar]
  10. Barakos J. Purcell D. Suhy J. Chalkias S. Burkett P. Grassi C.M. Castrillo-Viguera C. Rubino I. Vijverberg E. Detection and management of amyloid-related imaging abnormalities in patients with Alzheimer’s disease treated with anti-amyloid beta therapy. J. Prev. Alzheimers Dis. 2022 9 2 211 220 10.14283/jpad.2022.21 35542992
    [Google Scholar]
  11. Yadollahikhales G. Rojas J.C. Anti-amyloid immunotherapies for Alzheimer’s disease: A 2023 clinical update. Neurotherapeutics 2023 20 4 914 931 10.1007/s13311‑023‑01405‑0 37490245
    [Google Scholar]
  12. Doran S.J. Sawyer R.P. Risk factors in developing amyloid related imaging abnormalities (ARIA) and clinical implications. Front. Neurosci. 2024 18 1326784 10.3389/fnins.2024.1326784 38312931
    [Google Scholar]
  13. Hampel H. Elhage A. Cho M. Nicoll J.A.R. Atri A. Amyloid-related imaging abnormalities (ARIA) and their radiological, biological and clinical characteristics: A plain language summary. Neurodegener. Dis. Manag. 2024 14 3-4 51 62 10.1080/17582024.2024.2343539 38949171
    [Google Scholar]
  14. Hales C.M. Alzheimer’s disease diagnosis and management in the age of amyloid monoclonal antibodies. Med. Clin. North Am. 2025 109 2 463 483 10.1016/j.mcna.2024.10.003 39893023
    [Google Scholar]
  15. Jeremic D. Navarro-López J.D. Jiménez-Díaz L. Efficacy and safety of anti-amyloid-β monoclonal antibodies in current Alzheimer’s disease phase III clinical trials: A systematic review and interactive web app-based meta-analysis. Ageing Res. Rev. 2023 90 102012 10.1016/j.arr.2023.102012 37423541
    [Google Scholar]
  16. Söderberg L. Johannesson M. Nygren P. Laudon H. Eriksson F. Osswald G. Möller C. Lannfelt L. 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 1 195 206 10.1007/s13311‑022‑01308‑6 36253511
    [Google Scholar]
  17. Selkoe D.J. Amyloid protein and Alzheimer’s disease. Sci. Am. 1991 265 5 68 78 10.1038/scientificamerican1191‑68 1785042
    [Google Scholar]
  18. Rosen J. Jessen F. Patient eligibility for amyloid-targeting immunotherapies in Alzheimer’s disease. J. Prev. Alzheimers Dis. 2025 12 4 100102 10.1016/j.tjpad.2025.100102 40011174
    [Google Scholar]
  19. Jucker M. Walker L.C. Alzheimer’s disease: From immunotherapy to immunoprevention. Cell 2023 186 20 4260 4270 10.1016/j.cell.2023.08.021 37729908
    [Google Scholar]
  20. Ashraf F. Rasool F.K. Uddin M.M.N. Siddiq M.A. Mustafa M.S. Targeting beta-amyloid protein with monoclonal antibodies: A new hope for Alzheimer’s treatment. Ann. Neurosci. 2024 31 4 243 245 10.1177/09727531231190989 39840140
    [Google Scholar]
  21. Tomimoto H. Matsumoto M. Shiina H. Saeki Y. Niidome T. Nakamura Y. Pathophysiology and clinical presentation of amyloid-related imaging abnormality induced by anti-amyloid-β antibody lecanemab. Brain Nerve 2025 77 2 175 187
    [Google Scholar]
  22. Greenberg S.M. Bax F. van Veluw S.J. Amyloid-related imaging abnormalities: Manifestations, metrics and mechanisms. Nat. Rev. Neurol. 2025 21 4 193 203 10.1038/s41582‑024‑01053‑8 39794509
    [Google Scholar]
  23. Qiao Y. Gu J. Yu M. Chi Y. Ma Y. Comparative efficacy and safety of monoclonal antibodies for cognitive decline in patients with Alzheimer’s disease: A systematic review and network meta-analysis. CNS Drugs 2024 38 3 169 192 10.1007/s40263‑024‑01067‑2 38429615
    [Google Scholar]
  24. Wan X. Wang W. Liu J. Tong T. Estimating the sample mean and standard deviation from the sample size, median, range and/or interquartile range. BMC Med. Res. Methodol. 2014 14 1 135 10.1186/1471‑2288‑14‑135 25524443
    [Google Scholar]
  25. Landen J.W. Zhao Q. Cohen S. Borrie M. Woodward M. Billing C.B. Bales K. Alvey C. McCush F. Yang J. Kupiec J.W. Bednar M.M. Safety and pharmacology of a single intravenous dose of ponezumab in subjects with mild-to-moderate Alzheimer disease: A phase I, randomized, placebo-controlled, double-blind, dose-escalation study. Clin. Neuropharmacol. 2013 36 1 14 23 10.1097/WNF.0b013e31827db49b 23334070
    [Google Scholar]
  26. Jadad A.R. Moore R.A. Carroll D. Jenkinson C. Reynolds D.J.M. Gavaghan D.J. McQuay H.J. Assessing the quality of reports of randomized clinical trials: Is blinding necessary? Control. Clin. Trials 1996 17 1 1 12 10.1016/0197‑2456(95)00134‑4 8721797
    [Google Scholar]
  27. Ma L. Wang Y. Huynh A.L.H. Amadoru S. Wrigley S. Yates P. Masters C.L. Goudey B. Jin L. Pan Y. Exploring epidemiological risk factors for cerebral amyloid angiopathy: Considerations for monoclonal antibody therapy in people with Alzheimer’s disease. Alzheimers Dement. 2025 21 3 e14602 10.1002/alz.14602 40042470
    [Google Scholar]
  28. Foley K.E. Wilcock D.M. Three major effects of APOEε4 on Aβ immunotherapy induced ARIA. Front. Aging Neurosci. 2024 16 1412006 10.3389/fnagi.2024.1412006 38756535
    [Google Scholar]
  29. Sato K. Niimi Y. Ihara R. Suzuki K. Iwata A. Iwatsubo T. APOE-ε4 allele[s]-associated adverse events reported from placebo arm in clinical trials for Alzheimer’s disease: Implications for anti-amyloid beta therapy. Front. Dementia 2024 2 1320329 10.3389/frdem.2023.1320329
    [Google Scholar]
  30. Hardy J. Schott J.M. Identifying genetic risk for amyloid-related imaging abnormalities. Neurology 2024 102 3 e208096 10.1212/WNL.0000000000208096 38165303
    [Google Scholar]
  31. Bilodeau P.A. Dickson J.R. Kozberg M.G. The impact of anti-amyloid immunotherapies on stroke care. J. Clin. Med. 2024 13 5 1245 10.3390/jcm13051245 38592119
    [Google Scholar]
  32. Tao Y. Xia W. Zhao Q. Xiang H. Han C. Zhang S. Gu W. Tang W. Li Y. Tan L. Li D. Liu C. Structural mechanism for specific binding of chemical compounds to amyloid fibrils. Nat. Chem. Biol. 2023 19 10 1235 1245 10.1038/s41589‑023‑01370‑x 37400537
    [Google Scholar]
  33. Xu Q. Ma Y. Sun Y. Li D. Zhang X. Liu C. Protein amyloid aggregate: Structure and function. Aggregate 2023 4 4 e333 10.1002/agt2.333
    [Google Scholar]
  34. Agarwal A. Gupta V. Brahmbhatt P. Desai A. Vibhute P. Joseph-Mathurin N. Bathla G. Amyloid-related imaging abnormalities in Alzheimer disease treated with anti-amyloid-β therapy. Radiographics 2023 43 9 e230009 10.1148/rg.230009 37651273
    [Google Scholar]
  35. Söderberg L. Johannesson M. Gkanatsiou E. Nygren P. Fritz N. Zachrisson O. Rachalski A. Svensson A.S. Button E. Dentoni G. Osswald G. Lannfelt L. Möller C. Amyloid-beta antibody binding to cerebral amyloid angiopathy fibrils and risk for amyloid-related imaging abnormalities. Sci. Rep. 2024 14 1 10868 10.1038/s41598‑024‑61691‑2 38740836
    [Google Scholar]
  36. Rabinovici G.D. Selkoe D.J. Schindler S.E. Aisen P. Apostolova L.G. Atri A. Greenberg S.M. Hendrix S.B. Petersen R.C. Weiner M. Salloway S. Cummings J. Donanemab: Appropriate use recommendations. J. Prev. Alzheimers Dis. 2025 12 5 100150 10.1016/j.tjpad.2025.100150 40155270
    [Google Scholar]
  37. Wang H. Serap Monkul Nery E. Ardayfio P. Khanna R. Otero Svaldi D. Gueorguieva I. Shcherbinin S. Andersen S.W. Hauck P.M. Engle S.E. Brooks D.A. Collins E.C. Fox N.C. Greenberg S.M. Salloway S. Mintun M.A. Sims J.R. Modified titration of donanemab reduces ARIA risk and maintains amyloid reduction. Alzheimers Dement. 2025 21 4 e70062 10.1002/alz.70062 40172303
    [Google Scholar]
  38. Bobbins A. Davies M. Lynn E. Roy D. Yeomans A. Shakir S.A.W. Safety and effectiveness of the anti‐amyloid monoclonal antibody (mAb) drug lecanemab for early Alzheimer’s disease: The pharmacovigilance perspective. Br. J. Clin. Pharmacol. 2025 91 5 1352 1360 10.1002/bcp.70021 40051090
    [Google Scholar]
  39. Zavarella M. Cecchetti G. Rugarli G. Ghirelli A. Bottale I. Orlandi F. Spinelli E.G. Santangelo R. Caso F. Calloni S.F. Vezzulli P.Q. Falini A. Magnani G. Agosta F. Filippi M. Favorable long-term cognitive outcomes following recurrent ARIA linked to amyloid-lowering therapies: two cases. J. Neurol. 2025 272 2 168 10.1007/s00415‑025‑12910‑x 39853424
    [Google Scholar]
  40. Li X. Singh S. Rasouli B. Lyons J. Cocoros N.M. Platt R. Abi-Elias I. Gurwitz J.H. Generating real‐world evidence in early Alzheimer’s disease: Considerations for applying the target trial emulation framework to study the safety of anti‐amyloid therapies. Alzheimers Dement. 2025 11 2 e70080 10.1002/trc2.70080 40242567
    [Google Scholar]
  41. Cummings J.L. Maximizing the benefit and managing the risk of anti-amyloid monoclonal antibody therapy for Alzheimer’s disease: Strategies and research directions. Neurotherapeutics 2025 22 3 e00570 10.1016/j.neurot.2025.e00570 40118715
    [Google Scholar]
  42. Weber M. Roth H.L. Abramowitz A. Johnson K.G. Developing treatment models for the delivery of the antiamyloid therapy, lecanemab: Considerations for implementation of lecanemab in healthcare systems. Am. J. Geriatr. Psychiatry 2025 33 6 601 610 10.1016/j.jagp.2025.02.007
    [Google Scholar]
  43. Villain N. Planche V. Lilamand M. Cordonnier C. Soto-Martin M. Mollion H. Bombois S. Delrieu J. Lecanemab for early Alzheimer’s disease: Appropriate use recommendations from the French federation of memory clinics. J. Prev. Alzheimers Dis. 2025 12 4 100094 10.1016/j.tjpad.2025.100094 40011173
    [Google Scholar]
  44. Panza F. Dibello V. Sardone R. Zupo R. Castellana F. Leccisotti I. Moretti M.C. Altamura M. Bellomo A. Daniele A. Solfrizzi V. Resta E. Lozupone M. Successes and failures: The latest advances in the clinical development of amyloid–β–targeting monoclonal antibodies for treating Alzheimer’s disease. Expert Opin. Biol. Ther. 2025 25 3 275 283 10.1080/14712598.2025.2463963 39908579
    [Google Scholar]
  45. Shields L.B.E. Hust H. Cooley S.D. Cooper G.E. Hart R.N. Dennis B.C. Freeman S.W. Cain J.F. Shang W.Y. Wasz K.M. Orr A.T. Shields C.B. Barve S.S. Pugh K.G. Initial experience with lecanemab and lessons learned in 71 patients in a regional medical center. J. Prev. Alzheimers Dis. 2024 11 6 1549 1562 10.14283/jpad.2024.159 39559868
    [Google Scholar]
  46. Fertan E. Lam J.Y.L. Albertini G. Dewilde M. Wu Y. Akingbade O.E.S. Böken D. English E.A. De Strooper B. Klenerman D. Lecanemab preferentially binds to smaller aggregates present at early Alzheimer’s disease. Alzheimers Dement. 2025 21 4 e70086 10.1002/alz.70086 40237235
    [Google Scholar]
  47. Bateman R.J. Li Y. McDade E.M. Llibre-Guerra J.J. Clifford D.B. Atri A. Mills S.L. Santacruz A.M. Wang G. Supnet C. Benzinger T.L.S. Gordon B.A. Ibanez L. Klein G. Baudler M. Doody R.S. Delmar P. Kerchner G.A. Bittner T. Wojtowicz J. Bonni A. Fontoura P. Hofmann C. Kulic L. Hassenstab J. Aschenbrenner A.J. Perrin R.J. Cruchaga C. Renton A.E. Xiong C. Goate A.A. Morris J.C. Holtzman D.M. Snider B.J. Mummery C. Brooks W.S. Wallon D. Berman S.B. Roberson E. Masters C.L. Galasko D.R. Jayadev S. Sanchez-Valle R. Pariente J. Kinsella J. van Dyck C.H. Gauthier S. Hsiung G.Y.R. Masellis M. Dubois B. Honig L.S. Jack C.R. Daniels A. Aguillón D. Allegri R. Chhatwal J. Day G. Fox N.C. Huey E. Ikeuchi T. Jucker M. Lee J.H. Levey A.I. Levin J. Lopera F. Roh J. Rosa-Neto P. Schofield P.R. Safety and efficacy of long-term gantenerumab treatment in dominantly inherited Alzheimer’s disease: An open-label extension of the phase 2/3 multicentre, randomised, double-blind, placebo-controlled platform DIAN-TU trial. Lancet Neurol. 2025 24 4 316 330 10.1016/S1474‑4422(25)00024‑9 40120616
    [Google Scholar]
  48. Karkisaval A.G. Rostagno A. Azimov R. Ban D.K. Ghiso J. Kagan B.L. Lal R. Ion channel formation by N-terminally truncated Aβ (4–42): relevance for the pathogenesis of Alzheimer’s disease. Nanomedicine 2020 29 102235 10.1016/j.nano.2020.102235 32531337
    [Google Scholar]
  49. Taylor X. Clark I.M. Fitzgerald G.J. Oluoch H. Hole J.T. DeMattos R.B. Wang Y. Pan F. Amyloid-β (Aβ) immunotherapy induced microhemorrhages are associated with activated perivascular macrophages and peripheral monocyte recruitment in Alzheimer’s disease mice. Mol. Neurodegener. 2023 18 1 59 10.1186/s13024‑023‑00649‑w 37649100
    [Google Scholar]
  50. Bohrmann B. Baumann K. Benz J. Gerber F. Huber W. Knoflach F. Messer J. Oroszlan K. Rauchenberger R. Richter W.F. Rothe C. Urban M. Bardroff M. Winter M. Nordstedt C. Loetscher H. 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 1 49 69 10.3233/JAD‑2011‑110977 21955818
    [Google Scholar]
  51. Lopez-Noguerola J.S. Giessen N.M.E. Ueberück M. Meißner J.N. Pelgrim C.E. Adams J. Wirths O. Bouter Y. Bayer T.A. Synergistic effect on neurodegeneration by n-truncated aβ4−42 and pyroglutamate aβ3−42 in a mouse model of Alzheimer’s disease. Front. Aging Neurosci. 2018 10 64 10.3389/fnagi.2018.00064 29568268
    [Google Scholar]
  52. Vaillant-Beuchot L. Mary A. Pardossi-Piquard R. Bourgeois A. Lauritzen I. Eysert F. Kinoshita P.F. Cazareth J. Badot C. Fragaki K. Bussiere R. Martin C. Mary R. Bauer C. Pagnotta S. Paquis-Flucklinger V. Buée-Scherrer V. Buée L. Lacas-Gervais S. Checler F. Chami M. Accumulation of amyloid precursor protein C-terminal fragments triggers mitochondrial structure, function, and mitophagy defects in Alzheimer’s disease models and human brains. Acta Neuropathol. 2021 141 1 39 65 10.1007/s00401‑020‑02234‑7 33079262
    [Google Scholar]
  53. Yoshida K. Moein A. Bittner T. Ostrowitzki S. Lin H. Honigberg L. Jin J.Y. Quartino A. Pharmacokinetics and pharmacodynamic effect of crenezumab on plasma and cerebrospinal fluid beta-amyloid in patients with mild-to-moderate Alzheimer’s disease. Alzheimers Res. Ther. 2020 12 1 16 10.1186/s13195‑020‑0580‑2 31969177
    [Google Scholar]
  54. Lowe S.L. Duggan Evans C. Shcherbinin S. Cheng Y.J. Willis B.A. Gueorguieva I. Lo A.C. Fleisher A.S. Dage J.L. Ardayfio P. Aguiar G. Ishibai M. Takaichi G. Chua L. Mullins G. Sims J.R. 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 4 414 424 10.14283/jpad.2021.56 34585215
    [Google Scholar]
  55. Alexander G.C. Emerson S. Kesselheim A.S. Evaluation of aducanumab for Alzheimer disease. JAMA 2021 325 17 1717 1718 10.1001/jama.2021.3854 33783469
    [Google Scholar]
  56. McDade E. Cummings J.L. Dhadda S. Swanson C.J. Reyderman L. Kanekiyo M. Koyama A. Irizarry M. Kramer L.D. Bateman R.J. Lecanemab in patients with early Alzheimer’s disease: detailed results on biomarker, cognitive, and clinical effects from the randomized and open-label extension of the phase 2 proof-of-concept study. Alzheimers Res. Ther. 2022 14 1 191 10.1186/s13195‑022‑01124‑2 36544184
    [Google Scholar]
  57. Salloway S. Sperling R. Fox N.C. Blennow K. Klunk W. Raskind M. Sabbagh M. Honig L.S. Porsteinsson A.P. Ferris S. Reichert M. Ketter N. Nejadnik B. Guenzler V. Miloslavsky M. Wang D. Lu Y. Lull J. Tudor I.C. Liu E. Grundman M. Yuen E. Black R. Brashear H.R. Two phase 3 trials of bapineuzumab in mild-to-moderate Alzheimer’s disease. N. Engl. J. Med. 2014 370 4 322 333 10.1056/NEJMoa1304839 24450891
    [Google Scholar]
  58. Sperling R.A. Donohue M.C. Raman R. Rafii M.S. Johnson K. Masters C.L. van Dyck C.H. Iwatsubo T. Marshall G.A. Yaari R. Mancini M. Holdridge K.C. Case M. Sims J.R. Aisen P.S. Trial of solanezumab in preclinical Alzheimer’s disease. N. Engl. J. Med. 2023 389 12 1096 1107 10.1056/NEJMoa2305032 37458272
    [Google Scholar]
  59. Bateman R.J. Smith J. Donohue M.C. Delmar P. Abbas R. Salloway S. Wojtowicz J. Blennow K. Bittner T. Black S.E. Klein G. Boada M. Grimmer T. Tamaoka A. Perry R.J. Turner R.S. Watson D. Woodward M. Thanasopoulou A. Lane C. Baudler M. Fox N.C. Cummings J.L. Fontoura P. Doody R.S. Two phase 3 trials of gantenerumab in early Alzheimer’s disease. N. Engl. J. Med. 2023 389 20 1862 1876 10.1056/NEJMoa2304430 37966285
    [Google Scholar]
  60. Zabel M. Sheehan K. Alhomsy Y. Gesiotto Q. Ly E. Stephen A. Homayouni A. Fisher J. Venkataraman P. Habib M. Amyloidosis: Systems-based therapies. Amyloid Diseases. Kurouski D. Rijeka IntechOpen 2019 10.5772/intechopen.85201
    [Google Scholar]
  61. Saxena A. Wu D. Advances in therapeutic fc engineering – modulation of igg-associated effector functions and serum half-life. Front. Immunol. 2016 7 580 10.3389/fimmu.2016.00580 28018347
    [Google Scholar]
  62. Brezski R.J. Georgiou G. Immunoglobulin isotype knowledge and application to Fc engineering. Curr. Opin. Immunol. 2016 40 62 69 10.1016/j.coi.2016.03.002 27003675
    [Google Scholar]
  63. Yu J. Song Y. Tian W. How to select IgG subclasses in developing anti-tumor therapeutic antibodies. J. Hematol. Oncol. 2020 13 1 45 10.1186/s13045‑020‑00876‑4 32370812
    [Google Scholar]
  64. Rabinovici G.D. La Joie R. Amyloid-targeting monoclonal antibodies for Alzheimer disease. JAMA 2023 330 6 507 509 10.1001/jama.2023.11703 37459124
    [Google Scholar]
  65. Sengupta U. Nilson A.N. Kayed R. The role of amyloid-β oligomers in toxicity, propagation, and immunotherapy. EBioMedicine 2016 6 42 49 10.1016/j.ebiom.2016.03.035 27211547
    [Google Scholar]
  66. Majid O. Cao Y. Willis B.A. Hayato S. Takenaka O. Lalovic B. Sreerama Reddy S.H. Penner N. Reyderman L. Yasuda S. Hussein Z. Population pharmacokinetics and exposure–response analyses of safety (ARIA-E and isolated ARIA‐H) of lecanemab in subjects with early Alzheimer’s disease. CPT Pharmacometrics Syst. Pharmacol. 2024 13 12 2111 2123 10.1002/psp4.13224 39207112
    [Google Scholar]
  67. Karran E. De Strooper B. The amyloid hypothesis in Alzheimer disease: New insights from new therapeutics. Nat. Rev. Drug Discov. 2022 21 4 306 318 10.1038/s41573‑022‑00391‑w 35177833
    [Google Scholar]
  68. Mintun M.A. Lo A.C. Duggan Evans C. Wessels A.M. Ardayfio P.A. Andersen S.W. Shcherbinin S. Sparks J. Sims J.R. Brys M. Apostolova L.G. Salloway S.P. Skovronsky D.M. Donanemab in early Alzheimer’s disease. N. Engl. J. Med. 2021 384 18 1691 1704 10.1056/NEJMoa2100708 33720637
    [Google Scholar]
  69. Ostrowitzki S. Lasser R.A. Dorflinger E. Scheltens P. Barkhof F. Nikolcheva T. Ashford E. Retout S. Hofmann C. Delmar P. Klein G. Andjelkovic M. Dubois B. Boada M. Blennow K. Santarelli L. Fontoura P. A phase III randomized trial of gantenerumab in prodromal Alzheimer’s disease. Alzheimers Res. Ther. 2017 9 1 95 10.1186/s13195‑017‑0318‑y 29221491
    [Google Scholar]
  70. Sevigny J. Chiao P. Bussière T. Weinreb P.H. Williams L. Maier M. Dunstan R. Salloway S. Chen T. Ling Y. O’Gorman J. Qian F. Arastu M. Li M. Chollate S. Brennan M.S. Quintero-Monzon O. Scannevin R.H. Arnold H.M. Engber T. Rhodes K. Ferrero J. Hang Y. Mikulskis A. Grimm J. Hock C. Nitsch R.M. Sandrock A. The antibody aducanumab reduces Aβ plaques in Alzheimer’s disease. Nature 2016 537 7618 50 56 10.1038/nature19323 27582220
    [Google Scholar]
  71. Klein G. Delmar P. Voyle N. Rehal S. Hofmann C. Abi-Saab D. Andjelkovic M. Ristic S. Wang G. Bateman R. Kerchner G.A. Baudler M. Fontoura P. Doody R. 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 10.1186/s13195‑019‑0559‑z 31831056
    [Google Scholar]
  72. Honig L.S. Vellas B. Woodward M. Boada M. Bullock R. Borrie M. Hager K. Andreasen N. Scarpini E. Liu-Seifert H. Case M. Dean R.A. Hake A. Sundell K. Poole Hoffmann V. Carlson C. Khanna R. Mintun M. DeMattos R. Selzler K.J. Siemers E. Trial of solanezumab for mild dementia due to Alzheimer’s disease. N. Engl. J. Med. 2018 378 4 321 330 10.1056/NEJMoa1705971 29365294
    [Google Scholar]
  73. Linse S. Scheidt T. Bernfur K. Vendruscolo M. Dobson C.M. Cohen S.I.A. Sileikis E. Lundqvist M. Qian F. O’Malley T. Bussiere T. Weinreb P.H. Xu C.K. Meisl G. Devenish S.R.A. Knowles T.P.J. Hansson O. Kinetic fingerprints differentiate the mechanisms of action of anti-Aβ antibodies. Nat. Struct. Mol. Biol. 2020 27 12 1125 1133 10.1038/s41594‑020‑0505‑6 32989305
    [Google Scholar]
  74. Smith E.E. Phillips N.A. Feldman H.H. Borrie M. Ganesh A. Henri-Bhargava A. Desmarais P. Frank A. Badhwar A. Barlow L. Bartha R. Best S. Bethell J. Bhangu J. Black S.E. Bocti C. Bronskill S.E. Burhan A.M. Calon F. Camicioli R. Campbell B. Collins D.L. Dadar M. DeMarco M.L. Ducharme S. Duchesne S. Einstein G. Fisk J.D. Gawryluk J.R. Grossman L. Ismail Z. Itzhak I. Joshi M. Harrison A. Kröger E. Kumar S. Laforce R. Lanctot K.L. Lau M. Lee L. Masellis M. Massoud F. Mitchell S.B. Montero-Odasso M. Myers Barnett K. Nygaard H.B. Pasternak S.H. Peters J. Rajah M.N. Robillard J.M. Rockwood K. Rosa-Neto P. Seitz D.P. Soucy J.P. Trenaman S.C. Wellington C.L. Zadem A. Chertkow H. Use of lecanemab and donanemab in the Canadian healthcare system: Evidence, challenges, and areas for future research. J. Prev. Alzheimers Dis. 2025 12 3 100068 10.1016/j.tjpad.2025.100068 39893139
    [Google Scholar]
  75. VandeVrede L. Gibbs D.M. Koestler M. La Joie R. Ljubenkov P.A. Provost K. Soleimani-Meigooni D. Strom A. Tsoy E. Rabinovici G.D. Boxer A.L. Symptomatic amyloid‐related imaging abnormalities in an APOE ε4/ε4 patient treated with aducanumab. Alzheimers Dement. 2020 12 1 e12101 10.1002/dad2.12101 33072846
    [Google Scholar]
  76. Sheng L. Bhalla R. Biomarkers and target-specific small-molecule drugs in Alzheimer’s diagnostic and therapeutic research: From amyloidosis to tauopathy. Neurochem. Res. 2024 49 9 2273 2302 10.1007/s11064‑024‑04178‑w 38844706
    [Google Scholar]
  77. Ramanan V.K. Day G.S. Anti-amyloid therapies for Alzheimer disease: Finally, good news for patients. Mol. Neurodegener. 2023 18 1 42 10.1186/s13024‑023‑00637‑0 37381015
    [Google Scholar]
  78. Cogswell P.M. Burkett B.J. Johnson D.R. Pillai J.J. Altered clearance and amyloid-related imaging abnormalities. Neuroimaging Clin. N. Am. 2025 35 2 267 275 10.1016/j.nic.2024.12.002 40210382
    [Google Scholar]
/content/journals/cn/10.2174/011570159X391766250806091602
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Structural and Functional Determinants of ARIA-H Risk in Anti-Amyloid Monoclonal Antibodies: A Comparative Mechanistic Framework for 
Alzheimer's Immunotherapy Development
Bentham Science Publishers ; https://doi.org/10.2174/011570159X391766250806091602
/content/journals/cn/10.2174/011570159X391766250806091602
/content/journals/cn/10.2174/011570159X391766250806091602
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  • Article Type:     Research Article
Keywords: ARIA-H ; Amyloid-related imaging abnormalities with hemorrhage ; monoclonal antibodies ; neuropharmacology ; Aβ binding ; Alzheimer’s disease

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