Alzheimer's Disease: A New Paradigm, New Treatments, New Challenges, New Approaches

Year 2025, Volume: 7 Issue: 1, 59 - 76, 07.08.2025

Lütfü Hanoğlu , Deniz Eruçar Tehran Aliyeva Beyza Tağraf

https://doi.org/10.52675/jhesp.1680912

Abstract

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and the leading cause of dementia worldwide. Recent advances in biomarker-based diagnostics and disease-modifying therapies have shifted the landscape of AD from symptom management to early intervention. This review examines current therapeutic innovations, with a particular focus on monoclonal antibodies such as lecanemab, aducanumab, and donanemab. While these agents show potential in slowing disease progression by targeting amyloid-beta accumulation, concerns remain regarding their clinical efficacy, safety profiles, and cost-effectiveness—especially in aging populations with high healthcare burdens. Additionally, developments in biological diagnosis through fluid and imaging biomarkers have introduced new ethical and policy-related challenges. The paper also highlights the role of non-pharmacological interventions, such as multidomain lifestyle programs, in enhancing cognitive reserve and delaying disease onset. Finally, the article calls for a comprehensive public health approach that includes precision medicine, national screening strategies, and policy reforms to address the growing societal impact of Alzheimer’s disease.

Keywords

Alzheimer’s disease, monoclonal antibodies, biomarkers, cognitive reserve, public health

References

• Almeida, Z. L., Vaz, D. C., & Brito, R. M. M. (2024). Morphological and molecular profiling of amyloid-β species in Alzheimer’s pathogenesis. Molecular Neurobiology, 62(4), 4391–4419. https://doi.org/10.1007/s12035-024-04543-4
• Angevaare, M. J., Vonk, J. M. J., Bertola, L., Zahodne, L., Watson, C. W.-M., Boehme, A., Schupf, N., Mayeux, R., Geerlings, J. J., & Manly, J. J. (2022). Predictors of incident mild cognitive impairment and its course in a diverse community-based population. Neurology, 98(1), e15–e26. https://doi.org/10.1212/WNL.0000000000013017
• Atri, A. (2019). The Alzheimer’s disease clinical spectrum: Diagnosis and management. Medical Clinics of North America, 103(2), 263–293. https://doi.org/10.1016/j.mcna.2018.10.009
• Brookmeyer, R., & Abdalla, N. (2018). Estimation of lifetime risks of Alzheimer’s disease dementia using biomarkers for preclinical disease. Alzheimer’s & Dementia, 14(8), 981–988. https://doi.org/10.1016/j.jalz.2018.03.005
• Chandler, J., Done, N., Desai, U., Georgieva, M., Gomez-Lievano, A., Ye, W., Zhao, A., Eid, D., Hilts, A., Kirson, N., Schilling, T., & Alzheimer’s Disease Neuroimaging Initiative. Potential implications of slowing disease progression in amyloid-positive early Alzheimer’s disease: Estimates from realworld data. Journal of Prevention of Alzheimer’s Disease, 11(2), 310–319. https://doi.org/10.14283/jpad.2024.27
• Chen, Y.-H., Lin, R.-R., Huang, H.-F., Xue, Y.-Y., & Tao, Q.-Q. (2022). Microglial activation, tau pathology, and neurodegeneration biomarkers predict longitudinal cognitive decline in Alzheimer’s disease continuum. Frontiers in Aging Neuroscience, 14, 848180. https://doi.org/10.3389/fnagi.2022.848180
• Crowell, V., Reyes, A., Zhou, S. Q., Vassilaki, M., Gsteiger, S., & Gustavsson, A. (2023). Diseaseseverity and mortality in Alzheimer’s disease: An analysis using the U.S. National Alzheimer’s Coordinating Center Uniform Data Set. BMC Neurology, 23(1), 302. https://doi.org/10.1186/s12883-023-03353-w
• Cummings, J., Zhou, Y., Lee, G., Zhong, K., Fonseca, J., & Cheng, F. (2024). Alzheimer’s disease drug development pipeline: 2024. Alzheimer’s & Dementia: Translational Research & Clinical Interventions, 10(2), e12465. https://doi.org/10.1002/trc2.12465
• Desai, U., Gomes, D. A., Chandler, J., Ye, W., Daly, M., Kirson, N., & Dennehy, E. B. (2024). Understanding the impact of slowing disease progression for individuals with biomarker-confirmed early symptomatic Alzheimer’s disease. Current Medical Research and Opinion, 40(10), 1719–1725. https://doi.org/10.1080/03007995.2024.2394602
• Dubois, B., Feldman, H. H., Jacova, C., Hampel, H., Molinuevo, J. L., Blennow, K., DeKosky, S. T., Gauthier, S., Selkoe, D., Bateman, R., Cappa, S., Crutch, S., Engelborghs, S., Frisoni, G. B., Fox, N.C., Galasko, D., Habert, M.-O., Jicha, G. A., Nordberg, A., Pasquier, F., & Cummings, J. L. (2014). Advancing research diagnostic criteria for Alzheimer’s disease: The IWG-2 criteria. The Lancet Neurology, 13(6), 614–629. https://doi.org/10.1016/S1474-4422(14)70090-0
• Gustavsson, E., Raaschou, P., Lärfars, G., Sandman, L., & Juth, N. (2021). Novel drug candidates targeting Alzheimer’s disease: Ethical challenges with identifying the relevant patient population. Journal of Medical Ethics, 47(9), 608–614. https://doi.org/10.1136/medethics-2021-107304
• Jack, C. R., Bennett, D. A., Blennow, K., Carrillo, M. C., Dunn, B., Haeberlein, S. B., Holtzman, D. M., Jagust, W., Jessen, F., Karlawish, J., Liu, E., Molinuevo, J. L., Montine, T., Phelps, C., Rankin, K. P.,Rowe, C. C., Scheltens, P., Siemers, E., Snyder, H. M., Sperling, R., Elliott, C., Masliah, E., Ryan, L., & Silverberg, N. (2018). NIA-AA research framework: Toward a biological definition of Alzheimer’s disease. Alzheimer’s & Dementia, 14(4), 535–562. https://doi.org/10.1016/j.jalz.2018.02.018
• Jack, C. R. Jr., Andrews, J. S., Beach, T. G., Buracchio, T., Dunn, B., Graf, A., Hansson, O., Ho, C., Jagust, W., McDade, E., Molinuevo, J. L., Okonkwo, O. C., Pani, L., Rafii, M. S., Scheltens, P., Siemers, E., Snyder, H. M., Sperling, R., Teunissen, C. E., & Carrillo, M. C. (2024). Revised criteria for diagnosis and staging of Alzheimer’s disease: Alzheimer’s Association Workgroup. Alzheimer’s & Dementia, 20(8), 5143–51 69. https://doi.org/10.1002/alz.13859
• Japan Health Policy NOW. (2025, April 9). The New Orange Plan (2015). https://japanhpn.org/en/1-2/
• Jönsson, L., Wimo, A., Handels, R., Johansson, G., Boada, M., Engelborghs, S., Frölich, L., Jessen, F., Kehoe, P. G., Kramberger, M., de Mendonça, A., Ousset, P. J., Scarmeas, N., Visser, P. J., Waldemar, G., & Winblad, B. (2023). The affordability of lecanemab, an amyloid-targeting therapy for Alzheimer’s disease: An EADC-EC viewpoint. The Lancet Regional Health - Europe, 29, 100657. https://doi.org/10.1016/j.lanepe.2023.100657
• Kurkinen, M. (2023). Lecanemab (Leqembi) is not the right drug for patients with Alzheimer’s disease. Advances in Clinical and Experimental Medicine, 32(9), 943–947. https://doi.org/10.17219/acem/171379
• Kwon, D. (2024, March 1). Debate rages over Alzheimer’s drug lecanemab as UK limits approval. Nature. https://doi.org/10.1038/d41586-024-02720-y
• Livingston, G., Huntley, J., Liu, K. Y., Costafreda, S. G., Selbæk, G., Alladi, S., Ames, D., Banerjee, S., Burns, A., Brayne, C., Fox, N. C., Ferri, C. P., Gitlin, L. N., Howard, R., Kales, H. C., Kivimäki, M., Larson, E. B., Nakasujja, N., Rockwood, K., Samus, Q., Shirai, K., Singh-Manoux, A., Schneider, L. S., Walsh, S., Yao, Y., Sommerlad, A., & Mukadam, N. (2024). Dementia prevention, intervention, and care: 2024 report of the Lancet standing Commission. The Lancet, 404(10452), 572–628. https://doi.org/10.1016/S0140-6736(24)01296-0
• Maki, Y., Ubuka, T., & Yamane, Y. (2025). The importance of non-pharmacological interventions to improve cognitive reserve prior to the administration of a drug against the causative agent of Alzheimer’s disease. Journal of Alzheimer’s Disease, 103(2), 358–360. https://doi.org/10.1177/13872877241301806
• Martorana, A., Bonomi, C. G., Di Donna, M. G., & Motta, C. (2025). Lecanemab’s path forward: Navigating the future of Alzheimer’s treatment in Europe amidst the EMA’s rejection. Neurology and Therapy, 14(1), 1–5. https://doi.org/10.1007/s40120-024-00675-w
• McKhann, G., Drachman, D., Folstein, M., Katzman, R., Price, D., & Stadlan, E. M. (1984). Clinical diagnosis of Alzheimer’s disease: Report of the NINCDS-ADRDA Work Group* under the auspices of Department of Health and Human Services Task Force on Alzheimer’s Disease. Neurology, 34(7), 939–939. https://doi.org/10.1212/WNL.34.7.939
• Pais, M. V., Kuo, C.-L., Ances, B. M., Wetherell, J. L., Lenze, E. J., & Diniz, B. S. (2023). Relationship between baseline plasma p-tau181 and longitudinal changes in cognition and structural brain measures in a cohort of cognitively unimpaired older adults. Alzheimer’s & dementia (Amsterdam, Netherlands), 15(4), e12487. https://doi.org/10.1002/dad2.12487
• Rafii, M. S., & Aisen, P. S. (2023). Detection and treatment of Alzheimer’s disease in its preclinical stage. Nature Aging, 3(5), 520–531. https://doi.org/10.1038/s43587-023-00410-4
• 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. (2016). The antibody aducanumab reduces Aβ plaques in Alzheimer’s disease. Nature, 537(7618), 50–56. https://doi.org/10.1038/nature19323
• Souchet, B., Michaïl, A., Billoir, B., & Braudeau, J. (2023). Biological diagnosis of Alzheimer’s disease based on amyloid status: An illustration of confirmation bias in medical research? International Journal of Molecular Sciences, 24(24), 17544. https://doi.org/10.3390/ijms242417544
• Tan, C.-C., Yu, J.-T., & Tan, L. (2014). Biomarkers for preclinical Alzheimer’s disease. Journal of Alzheimer’s Disease, 42(4), 1051–1069. https://doi.org/10.3233/JAD-140843
• Turkish Statistical Institute (TURKSTAT). (2025, May 12). İ statistiklerle yaşlılar, 2024. https://data.tuik.gov.tr/Bulten/Index?p=Istatistiklerle-Yaslilar-2024-54079
• U.S. Food and Drug Administration (FDA). (2023, July 6). FDA converts novel Alzheimer’s disease treatment to traditional approval. FDA News Release. https://www.fda.gov/news-events/pressannouncements/fda-converts-novel-alzheimers-disease-treatment-traditional-approval
• 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, 9–21. https://doi.org/10.1056/NEJMoa2212948
• Yaffe, K., Vittinghoff, E., Dublin, S., Peltz, C. B., Fleckenstein, L. E., Rosenberg, D. E., Barnes, D. E., Balderson, B. H., & Larson, E. B. (2024). Effect of personalized risk-reduction strategies on cognition and dementia risk profile among older adults: The SMARRT randomized clinical trial. JAMA Internal Medicine, 184(1), 54–62. https://doi.org/10.1001/jamainternmed.2023.6279
• Yiğit, T., Ata, N., Dinçer, M., Ülgü, M. M., Birinci, Ş., & Ayvalı, M. O. (2024). Insights from Turkey’s big data: Unraveling the preventability, pathogenesis, and risk management of Alzheimer’s disease (AD). Scientific Reports, 14(1), 6005. https://doi.org/10.1038/s41598-024-56702-1