Current state of anti-amyloid therapy and the search for new vectors in combined treatment of Alzheimer's disease
DOI:
https://doi.org/10.48612/pfiet/0031-2991.2026.02.180-186Keywords:
Alzheimer's disease, therapeutic strategies, anti-amyloid monoclonal antibodies, neuroinflammation, amyloid-beta peptide, tau protein, senescence, neuroreparationAbstract
With the global population aging, Alzheimer’s disease (AD) poses a formidable challenge to healthcare systems, as disease-modifying therapies are currently lacking and the effectiveness of symptomatic treatments remains limited. In the early 2000s, a promising disease-modifying strategy emerged, focusing on the clearance of pathological beta-amyloid (Aβ) aggregates using anti-amyloid monoclonal antibodies (anti-Aβ mAbs). Despite adjunctive symptomatic treatment, several anti-Aβ mAbs have demonstrated modest efficacy at best, while others failed to complete Phase III clinical trials. Furthermore, a significant limitation of this strategy is the high incidence of adverse events, most notably amyloid-related imaging abnormalities (ARIA), including vasogenic edema and microhemorrhages. Consequently, multi-target approaches combining Aβ clearance, microglial activation, and modulation of neurotransmitter systems have yet to achieve the expected clinical benefits. These circumstances underscore the urgent need to revise current therapeutic strategies and seek new fundamental approaches to AD treatment. This review provides a critical evaluation of the efficacy of anti-amyloid antibody therapy and proposes conceptual frameworks for the further development of therapeutic strategies aimed at comprehensive pathogenetic treatment of Alzheimer’s disease.
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1. Shaw J.S., Huang P.C., Rosenberg P.B., et al. Motor symptoms in autopsy‐confirmed Alzheimer's disease increase the risk of progression to severe cognitive impairment. Alzheimer's & Dementia. 2025; 21(3). https://doi.org/10.1002/alz.70039.
2. 2025 Alzheimer's disease facts and figures. Alzheimer's & Dementia. 2025; 21(4). https://doi.org/10.1002/alz.70235.
3. Nichols E., Steinmetz J.D., Vollset S.E., et al. Estimation of the global prevalence of dementia in 2019 and forecasted prevalence in 2050: an analysis for the Global Burden of Disease Study 2019. The Lancet Public Health. 2022; 7(2): e105-e125. https://doi.org/10.1016/s2468-2667(21)00249-8.
4. Wu C.-K., Fuh J.-L. A 2025 update on treatment strategies for the Alzheimer’s disease spectrum. Journal of the Chinese Medical Association. 2025; 88(7): 495-502. https://doi.org/10.1097/jcma.0000000000001252.
5. Liu S., Zhao M., Liu Y., et al. Comparative efficacy and safety of symptomatic therapy and disease-modifying therapy for Alzheimer’s disease: a systematic review and network meta-analysis. Frontiers in Neuroscience. 2025; 19. https://doi.org/10.3389/fnins.2025.1656906.
6. Hardy J. Alzheimer's Disease: Treatment Challenges for the Future. Journal of Neurochemistry. 2025; 169(8). https://doi.org/10.1111/jnc.70176.
7. Makin S. The future of Alzheimer’s treatment. Nature. 2025; 640(8059): S4-S6. https://doi.org/10.1038/d41586-025-01102-2.
8. Vissel B. Anti-amyloid antibodies for Alzheimer’s disease are not truly disease modifying. Bmj. 2026; 392. https://doi.org/10.1136/bmj.s28.
9. Kepp K.P., Robakis N.K., Høilund-Carlsen P.F., et al. The amyloid cascade hypothesis: an updated critical review. Brain. 2023; 146(10): 3969-3990. https://doi.org/10.1093/brain/awad159.
10. Schenk D., Barbour R., Dunn W., et al. Immunization with amyloid-β attenuates Alzheimer-disease-like pathology in the PDAPP mouse. Nature. 1999; 400(6740): 173-177. https://doi.org/10.1038/22124.
11. van Dyck C.H., Swanson C.J., Aisen P., et al. Lecanemab in Early Alzheimer’s Disease. New England Journal of Medicine. 2023; 388(1): 9-21. https://doi.org/10.1056/NEJMoa2212948.
12. Zimmer J.A., Sims J.R., Evans C.D., et al. Donanemab in early symptomatic Alzheimer's disease: results from the TRAILBLAZER-ALZ 2 long-term extension. J Prev Alzheimers Dis. 2025: 100446. https://doi.org/10.1016/j.tjpad.2025.100446.
13. Sims J.R., Zimmer J.A., Evans C.D., et al. Donanemab in Early Symptomatic Alzheimer Disease. Jama. 2023; 330(6). https://doi.org/10.1001/jama.2023.13239.
14. Forlenza O.V., Barbosa B.J.A.P. What are the reasons for the repeated failures of clinical trials with anti-amyloid drugs for AD treatment? Dementia & Neuropsychologia. 2025; 19. https://doi.org/10.1590/1980-5764-dn-2025-e001.
15. Bocti C., Bergman H. Anti-Amyloid Therapies for Alzheimer’s Disease: Not the Way Forward. Canadian Geriatrics Journal. 2025; 28(4): 400-402. https://doi.org/10.5770/cgj.28.888.
16. Avgerinos K.I., Manolopoulos A., Ferrucci L., et al. Critical assessment of anti-amyloid-beta monoclonal antibodies effects in Alzheimer's disease: a systematic review and meta-analysis highlighting target engagement and clinical meaningfulness. Sci Rep. 2024; 14(1): 25741. https://doi.org/10.1038/s41598-024-75204-8.
17. Teipel S.J., Tang Y., Khachaturian A. Sex differences in treatment effects of lecanemab and donanemab: A Bayesian reanalysis of CLARITY-AD and TRAILBLAZER-ALZ2. Alzheimers Dement (N Y). 2025; 11(3): e70155. https://doi.org/10.1002/trc2.70155.
18. Andrews D., Ducharme S., Chertkow H., et al. The higher benefit of lecanemab in males compared to females in CLARITY AD is probably due to a real sex effect. Alzheimer's & Dementia. 2025; 21(1). https://doi.org/10.1002/alz.14467.
19. Honig L.S., Sabbagh M.N., van Dyck C.H., et al. Updated safety results from phase 3 lecanemab study in early Alzheimer’s disease. Alzheimer's Research & Therapy. 2024; 16(1). https://doi.org/10.1186/s13195-024-01441-8.
20. De Strooper B., Haass C., Hardy J., et al. The regulatory rollercoaster continues—EMA refuses donanemab. The Lancet. 2025; 405(10492): 1810-1812. https://doi.org/10.1016/s0140-6736(25)00833-5.
21. Li T., Lu L., Pember E., et al. New Insights into Neuroinflammation Involved in Pathogenic Mechanism of Alzheimer's Disease and Its Potential for Therapeutic Intervention. Cells. 2022; 11(12). https://doi.org/10.3390/cells11121925.
22. Andreasson K.I., Bachstetter A.D., Colonna M., et al. Targeting innate immunity for neurodegenerative disorders of the central nervous system. J Neurochem. 2016; 138(5): 653-693. https://doi.org/10.1111/jnc.13667.
23. Bathini P., Schilling S., Lemere C.A. Anti‐Amyloid Immunotherapy for AD: A Potential Link between ARIA and Complement. Alzheimer's & Dementia. 2025; 20(S1). https://doi.org/10.1002/alz.093183.
24. Millet A., Ledo J.H., Tavazoie S.F. An exhausted-like microglial population accumulates in aged and APOE4 genotype Alzheimer’s brains. Immunity. 2024; 57(1): 153-170.e156. https://doi.org/10.1016/j.immuni.2023.12.001.
25. Christova P., James L.M., Georgopoulos A.P. Brain volumes discriminate clinical dementia rating scale categories. Scientific Reports. 2025; 15(1). https://doi.org/10.1038/s41598-025-23418-9.
26. Sideris D.I., Danial J.S.H., Emin D., et al. Soluble amyloid beta-containing aggregates are present throughout the brain at early stages of Alzheimer’s disease. Brain Communications. 2021; 3(3). https://doi.org/10.1093/braincomms/fcab147.
27. Cai L., Fan Q., Pang R., et al. Microglia programmed cell death in neurodegenerative diseases and CNS injury. Apoptosis. 2024; 30(1-2): 446-465. https://doi.org/10.1007/s10495-024-02041-5.
28. Zheng Q., Wang X. Alzheimer’s disease: insights into pathology, molecular mechanisms, and therapy. Protein & Cell. 2025; 16(2): 83-120. https://doi.org/10.1093/procel/pwae026.
29. Hoenig M.C., Dzialas V., Doering E., et al. Modifiable Factors Associated with the Longitudinal Increase and Spatial Extent of Tau Pathology in Alzheimer Disease. J Nucl Med. 2025. https://doi.org/10.2967/jnumed.125.270593.
30. Do A.N., Song S., Ali M., et al. CSF proteomic profiling with amyloid and tau pathology identifies distinctive sex‐specific alteration of multiple proteins involved in Alzheimer's disease. Alzheimer's & Dementia. 2026; 22(1). https://doi.org/10.1002/alz.71063.
31. Moreira I.P., Vieira‐Coelho M.A., Guimarães J. Dopamine System Dysfunction in Alzheimer's Disease. Psychogeriatrics. 2025; 25(5). https://doi.org/10.1111/psyg.70097.
32. Kuźniar J., Kozubek P., Czaja M., et al. Connections Between Cellular Senescence and Alzheimer’s Disease—A Narrative Review. International Journal of Molecular Sciences. 2025; 26(17). https://doi.org/10.3390/ijms26178638.
33. Akyuz E., Arulsamy A., Aslan F.S., et al. An Expanded Narrative Review of Neurotransmitters on Alzheimer’s Disease: The Role of Therapeutic Interventions on Neurotransmission. Molecular Neurobiology. 2024; 62(2): 1631-1674. https://doi.org/10.1007/s12035-024-04333-y.
34. Wei X., Campagna J.J., Jagodzinska B., et al. A therapeutic small molecule enhances γ-oscillations and improves cognition/memory in Alzheimer’s disease model mice. Proceedings of the National Academy of Sciences. 2024; 121(33). https://doi.org/10.1073/pnas.2400420121.
35. Filippatou A.G., Calabresi P.A., Saidha S., et al. Spotlight on Trans-Synaptic Degeneration in the Visual Pathway in Multiple Sclerosis. Eye and Brain. 2023; Volume 15: 153-160. https://doi.org/10.2147/eb.S389632.
36. Manippa V., Palmisano A., Filardi M., et al. An update on the use of gamma (multi)sensory stimulation for Alzheimer’s disease treatment. Frontiers in Aging Neuroscience. 2022; 14. https://doi.org/10.3389/fnagi.2022.1095081.
37. Roemer-Cassiano S.N., Wagner F., Evangelista L., et al. Amyloid-associated hyperconnectivity drives tau spread across connected brain regions in Alzheimer’s disease. Science Translational Medicine. 2025; 17(782). https://doi.org/10.1126/scitranslmed.adp2564.
38. Yin H., Wang Y., Ren Z., et al. TDP43 is a newly identified substrate for PS1, enhancing the expression of APP following cleavage. Cell Death Discovery. 2025; 11(1). https://doi.org/10.1038/s41420-025-02340-z.
39. Suda M., Shimizu I., Katsuumi G., et al. Senolytic vaccination improves normal and pathological age-related phenotypes and increases lifespan in progeroid mice. Nature Aging. 2021; 1(12): 1117-1126. https://doi.org/10.1038/s43587-021-00151-2.
40. Shekari A., Fahnestock M., 2022. Retrograde Axonal Transport of Neurotrophins in Basal Forebrain Cholinergic Neurons, Axonal Transport, pp. 249-270.
41. Torok J., Maia P.D., Anand C., et al. Searching for the cellular underpinnings of the selective vulnerability to tauopathic insults in Alzheimer’s disease. Communications Biology. 2025; 8(1). https://doi.org/10.1038/s42003-025-07575-1.
42. Dwamena A., Beragama-Arachchi R., Wang H. Boosting Neurogenesis as a Strategy in Treating Alzheimer’s Disease. International Journal of Molecular Sciences. 2025; 26(18). https://doi.org/10.3390/ijms26188926.
43. Zota I., Chanoumidou K., Gravanis A., et al. Stimulating myelin restoration with BDNF: a promising therapeutic approach for Alzheimer's disease. Frontiers in Cellular Neuroscience. 2024; 18. https://doi.org/10.3389/fncel.2024.1422130.
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Copyright (c) 2026 Валерия Владимировна Голоборщева, Виктор Сергеевич Кохан
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