Beta-Amyloid Monoclonal Antibodies for Alzheimer's Disease: Development and Challenges

Yiyang Li

doi:10.62051/tqpmmr64

Authors

Yiyang Li

DOI:

https://doi.org/10.62051/tqpmmr64

Keywords:

Dementia, Alzheimer’s disease, monoclonal antibodies, neurodegenerative disease.

Abstract

As one of the most common diseases of the elderly, the detection and diagnosis of Alzheimer's disease (AD) remain a challenge at the early stage. As the disease progresses, patients will suffer from memory and cognitive loss, which will impair their ability to live independently. The care required for these patients will be costly and time-consuming, placing a significant burden on both the family and society. At the same time, Alzheimer's disease has a complex pathogenesis and there is still and there is an unmet need for drugs that can reverse the disease. The beta-amyloid (Aβ) proteins produced by improper cleavage of amyloid precursor proteins tend to aggregate into insoluble plaques in the brain. This study reviews the latest progress in the treatment of AD with Aβ monoclonal antibodies (mAbs). In recent years, aducanumab, lecanemab, donenamab have been successively approved. Besides, small molecule drugs also play an important role in AD treatment. Despite the inability to impede the progression of the disease, they are still irreplaceable and effective in relieving symptoms at this stage. In addition, as Aβ deposition begins decades before clinical symptoms appear, advances in diagnostic technology are essential for early intervention. Future research needs to pay more attention to the side effects of this therapy and their solutions.

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References

[1] Ren, R., Qi, J., Lin, S., Liu, X., Yin, P., Wang, Z., Tang, R., Wang, J., Huang, Q., Li, J., Xie, X., Hu, Y., Cui, S., Zhu, Y., Yu, X., Wang, P., Zhu, Y., Wang, Y., Huang, Y., Hu, Y., … Wang, G. (2022). The China Alzheimer Report 2022. General psychiatry, 35(1), e100751.

[2] Haass, C., & Selkoe, D. J. (2007). Soluble protein oligomers in neurodegeneration: lessons from the Alzheimer's amyloid beta-peptide. Nature reviews. Molecular cell biology, 8(2), 101–112.

[3] Chen, Y. R., & Glabe, C. G. (2006). Distinct early folding and aggregation properties of Alzheimer amyloid-beta peptides Abeta40 and Abeta42: stable trimer or tetramer formation by Abeta42. The Journal of biological chemistry, 281(34), 24414–24422.

[4] Bai, R., Guo, J., Ye, X. Y., Xie, Y., & Xie, T. (2022). Oxidative stress: The core pathogenesis and mechanism of Alzheimer's disease. Ageing research reviews, 77, 101619.

[5] Selkoe, D. J., & Hardy, J. (2016). The amyloid hypothesis of Alzheimer's disease at 25 years. EMBO molecular medicine, 8(6), 595–608.

[6] Wegmann, S., Biernat, J., & Mandelkow, E. (2021). A current view on Tau protein phosphorylation in Alzheimer's disease. Current opinion in neurobiology, 69, 131–138.

[7] Tolar, M., Abushakra, S., & Sabbagh, M. (2020). The path forward in Alzheimer's disease therapeutics: Reevaluating the amyloid cascade hypothesis. Alzheimer's & dementia: the journal of the Alzheimer's Association, 16(11), 1553–1560.

[8] Gustavsson, A., Norton, N., Fast, T., Frölich, L., Georges, J., Holzapfel, D., Kirabali, T., Krolak-Salmon, P., Rossini, P. M., Ferretti, M. T., Lanman, L., Chadha, A. S., & van der Flier, W. M. (2023). Global estimates on the number of persons across the Alzheimer's disease continuum. Alzheimer's & dementia: the journal of the Alzheimer's Association, 19(2), 658–670.

[9] Wegmann, S., Biernat, J., & Mandelkow, E. (2021). A current view on Tau protein phosphorylation in Alzheimer's disease. Current opinion in neurobiology, 69, 131–138.

[10] Ferrari, C., & Sorbi, S. (2021). The complexity of Alzheimer's disease: an evolving puzzle. Physiological reviews, 101(3), 1047–1081.

[11] Bloom G. S. (2014). Amyloid-β and tau: the trigger and bullet in Alzheimer disease pathogenesis. JAMA neurology, 71(4), 505–508.

[12] Drummond, E., Pires, G., MacMurray, C., Askenazi, M., Nayak, S., Bourdon, M., Safar, J., Ueberheide, B., & Wisniewski, T. (2020). Phosphorylated tau interactome in the human Alzheimer's disease brain. Brain: a journal of neurology, 143(9), 2803–2817.

[13] Liang, S. H., Chen, J. M., Normandin, M. D., Chang, J. S., Chang, G. C., Taylor, C. K., Trapa, P., Plummer, M. S., Para, K. S., Conn, E. L., Lopresti-Morrow, L., Lanyon, L. F., Cook, J. M., Richter, K. E., Nolan, C. E., Schachter, J. B., Janat, F., Che, Y., Shanmugasundaram, V., Lefker, B. A., … Vasdev, N. (2016). Discovery of a Highly Selective Glycogen Synthase Kinase-3 Inhibitor (PF-04802367) That Modulates Tau Phosphorylation in the Brain: Translation for PET Neuroimaging. Angewandte Chemie (International ed. in English), 55(33), 9601–9605.

[14] DaRocha-Souto, B., Coma, M., Pérez-Nievas, B. G., Scotton, T. C., Siao, M., Sánchez-Ferrer, P., Hashimoto, T., Fan, Z., Hudry, E., Barroeta, I., Serenó, L., Rodríguez, M., Sánchez, M. B., Hyman, B. T., & Gómez-Isla, T. (2012). Activation of glycogen synthase kinase-3 beta mediates β-amyloid induced neuritic damage in Alzheimer's disease. Neurobiology of disease, 45(1), 425–437.

[15] Dutta, D., Jana, M., Paidi, R. K., Majumder, M., Raha, S., Dasarathy, S., & Pahan, K. (2023). Tau fibrils induce glial inflammation and neuropathology via TLR2 in Alzheimer's disease-related mouse models. The Journal of clinical investigation, 133(18), e161987.

[16] 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., … Bapineuzumab 301 and 302 Clinical Trial Investigators (2014). Two phase 3 trials of bapineuzumab in mild-to-moderate Alzheimer's disease. The New England journal of medicine, 370(4), 322–333.

[17] Tolar, M., Abushakra, S., & Sabbagh, M. (2020). The path forward in Alzheimer's disease therapeutics: Reevaluating the amyloid cascade hypothesis. Alzheimer's & dementia : the journal of the Alzheimer's Association, 16(11), 1553–1560.

[18] 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. (2023). Lecanemab in Early Alzheimer's Disease. The New England journal of medicine, 388(1), 9–21.

[19] Sehlin, D., Fang, X. T., Cato, L., Antoni, G., Lannfelt, L., & Syvänen, S. (2016). Antibody-based PET imaging of amyloid beta in mouse models of Alzheimer's disease. Nature communications, 7, 10759.

[20] Tolar, M., Abushakra, S., Hey, J. A., Porsteinsson, A., & Sabbagh, M. (2020). Aducanumab, gantenerumab, BAN2401, and ALZ-801-the first wave of amyloid-targeting drugs for Alzheimer's disease with potential for near term approval. Alzheimer's research & therapy, 12(1), 95.

[21] Bateman, R. J., Cummings, J., Schobel, S., Salloway, S., Vellas, B., Boada, M., Black, S. E., Blennow, K., Fontoura, P., Klein, G., Assunção, S. S., Smith, J., & Doody, R. S. (2022). Gantenerumab: an anti-amyloid monoclonal antibody with potential disease-modifying effects in early Alzheimer's disease. Alzheimer's research & therapy, 14(1), 178.

[22] 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., … Bapineuzumab 301 and 302 Clinical Trial Investigators (2014). Two phase 3 trials of bapineuzumab in mild-to-moderate Alzheimer's disease. The New England journal of medicine, 370(4), 322–333.

[23] Jeremic, D., Jiménez-Díaz, L., & Navarro-López, J. D. (2021). Past, present and future of therapeutic strategies against amyloid-β peptides in Alzheimer's disease: a systematic review. Ageing research reviews, 72, 101496.

[24] Hampel, H., Elhage, A., Cho, M., Apostolova, L. G., Nicoll, J. A. R., & Atri, A. (2023). Amyloid-related imaging abnormalities (ARIA): radiological, biological and clinical characteristics. Brain: a journal of neurology, 146(11), 4414–4424.

[25] Bayer T. A. (2022). Pyroglutamate Aβ cascade as drug target in Alzheimer's disease. Molecular psychiatry, 27(4), 1880–1885.

[26] Rashad, A., Rasool, A., Shaheryar, M., Sarfraz, A., Sarfraz, Z., Robles-Velasco, K., & Cherrez-Ojeda, I. (2022). Donanemab for Alzheimer's Disease: A Systematic Review of Clinical Trials. Healthcare (Basel, Switzerland), 11(1), 32.

[27] Hansen, R. A., Gartlehner, G., Webb, A. P., Morgan, L. C., Moore, C. G., & Jonas, D. E. (2008). Efficacy and safety of donepezil, galantamine, and rivastigmine for the treatment of Alzheimer's disease: a systematic review and meta-analysis. Clinical interventions in aging, 3(2), 211–225.

[28] Birks, J. S., & Harvey, R. J. (2018). Donepezil for dementia due to Alzheimer's disease. The Cochrane database of systematic reviews, 6(6), CD001190.

[29] "Donepezil Hydrochloride Monograph for Professionals". Drugs.com. American Society of Health-System Pharmacists. Retrieved 4 February 2019.

[30] Folch, J., Busquets, O., Ettcheto, M., Sánchez-López, E., Castro-Torres, R. D., Verdaguer, E., Garcia, M. L., Olloquequi, J., Casadesús, G., Beas-Zarate, C., Pelegri, C., Vilaplana, J., Auladell, C., & Camins, A. (2018). Memantine for the Treatment of Dementia: A Review on its Current and Future Applications. Journal of Alzheimer's disease: JAD, 62(3), 1223–1240.

[31] van de Haar, H. J., Burgmans, S., Jansen, J. F., van Osch, M. J., van Buchem, M. A., Muller, M., Hofman, P. A., Verhey, F. R., & Backes, W. H. (2017). Blood-Brain Barrier Leakage in Patients with Early Alzheimer Disease. Radiology, 282(2), 615.

[32] Sweeney, M. D., Sagare, A. P., & Zlokovic, B. V. (2018). Blood-brain barrier breakdown in Alzheimer disease and other neurodegenerative disorders. Nature reviews.

[33] Montagne, A., Nikolakopoulou, A. M., Huuskonen, M. T., Sagare, A. P., Lawson, E. J., Lazic, D., Rege, S. V., Grond, A., Zuniga, E., Barnes, S. R., Prince, J., Sagare, M., Hsu, C. J., LaDu, M. J., Jacobs, R. E., & Zlokovic, B. V. (2021). APOE4 accelerates advanced-stage vascular and neurodegenerative disorder in old Alzheimer's mice via cyclophilin A independently of amyloid-β. Nature aging, 1(6), 506–520.

[34] Moir, R. D., Lathe, R., & Tanzi, R. E. (2018). The antimicrobial protection hypothesis of Alzheimer's disease. Alzheimer's & dementia: the journal of the Alzheimer's Association, 14(12), 1602–1614.

[35] Barthélemy, N. R., Salvadó, G., Schindler, S. E., He, Y., Janelidze, S., Collij, L. E., Saef, B., Henson, R. L., Chen, C. D., Gordon, B. A., Li, Y., La Joie, R., Benzinger, T. L. S., Morris, J. C., Mattsson-Carlgren, N., Palmqvist, S., Ossenkoppele, R., Rabinovici, G. D., Stomrud, E., Bateman, R. J., … Hansson, O. (2024). Highly accurate blood test for Alzheimer's disease is similar or superior to clinical cerebrospinal fluid tests. Nature medicine, 30(4), 1085–1095.