Advancements in Alzheimer’s Disease Biomarkers: Emerging Protein Targets for Early Diagnosis and Therapeutic Intervention

Mst Muslima Khatun; Most. Israt Jahan  Oni; Md. Shadin; B S M Bodiuzzaman

doi:10.71193/jmct.20250001

Authors

Mst Muslima Khatun Gopalganj Science and Technology University, Gopalganj 8100, Bangladesh Author https://orcid.org/0009-0004-1801-1928
Most. Israt Jahan Oni Gopalganj Science and Technology University, Gopalganj 8100, Bangladesh Author https://orcid.org/0009-0002-1236-5501
Md. Shadin Gopalganj Science and Technology University, Gopalganj 8100, Bangladesh Author https://orcid.org/0009-0000-1587-2838
B S M Bodiuzzaman Daffodil International University, Dhaka 1216, Bangladesh Author https://orcid.org/0009-0009-8941-1554

DOI:

https://doi.org/10.71193/jmct.20250001

Keywords:

Alzheimer’s disease, Biomarker, Astrocyte, Neurodegeneration, Pathophysiology

Abstract

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and neuronal loss. The identification of reliable biomarkers is crucial for early diagnosis and therapeutic intervention. This study explores an insight into current strategies and future approaches for improvement of the treatment, diagnosis, or prevention of AD. AD relevant data were collected from databases like PubMed, Google Scholar, and ScienceDirect. Our study findings reveal that traditional biomarkers such as amyloid-beta (Aβ) and tau proteins remain central to AD pathology, but emerging targets, including neurofilament light chain (NfL), triggering receptor expressed on myeloid cells 2 (TREM2), and synaptic proteins, are gaining attention for their diagnostic and prognostic value. Additionally, lipid peroxidation markers (4-HNE, MDA) and Cytokines (IL-6, TNF-α, and IL-1β) analyses have provided an invasive alternatives for disease monitoring. These advancements facilitate the development of precision medicine approaches, including targeted therapies aimed at modulating key pathological proteins.

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References

Agostinho, P., Cunha, R. A., & Oliveira, C. (2010). Neuroinflammation, oxidative stress and the pathogenesis of Alzheimer's disease. Current pharmaceutical design, 16(25), 2766–2778. https://doi.org/10.2174/138161210793176572 DOI: https://doi.org/10.2174/138161210793176572

Antonucci, F., Corradini, I., Fossati, G., Tomasoni, R., Menna, E., & Matteoli, M. (2016). SNAP-25, a Known Presynaptic Protein with Emerging Postsynaptic Functions. Frontiers in synaptic neuroscience, 8, 7. https://doi.org/10.3389/fnsyn.2016.00007 DOI: https://doi.org/10.3389/fnsyn.2016.00007

Bateman, R. J., Barthélemy, N. R., & Horie, K. (2020). Another step forward in blood-based diagnostics for Alzheimer's disease. Nature medicine, 26(3), 314–316. https://doi.org/10.1038/s41591-020-0797-4 DOI: https://doi.org/10.1038/s41591-020-0797-4

Botella Lucena, P., & Heneka, M. T. (2024). Inflammatory aspects of Alzheimer's disease. Acta neuropathologica, 148(1), 31. https://doi.org/10.1007/s00401-024-02790-2 DOI: https://doi.org/10.1007/s00401-024-02790-2

Breitzig, M., Bhimineni, C., Lockey, R., & Kolliputi, N. (2016). 4-Hydroxy-2-nonenal: a critical target in oxidative stress?. American journal of physiology. Cell physiology, 311(4), C537–C543. https://doi.org/10.1152/ajpcell.00101.2016 DOI: https://doi.org/10.1152/ajpcell.00101.2016

Budson, A. E., & Solomon, P. R. (2012). New criteria for Alzheimer disease and mild cognitive impairment: implications for the practicing clinician. The neurologist, 18(6), 356–363. https://doi.org/10.1097/NRL.0b013e31826a998d DOI: https://doi.org/10.1097/NRL.0b013e31826a998d

Bukke, V. N., Archana, M., Villani, R., Romano, A. D., Wawrzyniak, A., Balawender, K., Orkisz, S., Beggiato, S., Serviddio, G., & Cassano, T. (2020). The Dual Role of Glutamatergic Neurotransmission in Alzheimer's Disease: From Pathophysiology to Pharmacotherapy. International journal of molecular sciences, 21(20), 7452. https://doi.org/10.3390/ijms21207452 DOI: https://doi.org/10.3390/ijms21207452

Cacquevel, M., Lebeurrier, N., Chéenne, S., & Vivien, D. (2004). Cytokines in neuroinflammation and Alzheimer's disease. Current drug targets, 5(6), 529–534. https://doi.org/10.2174/1389450043345308 DOI: https://doi.org/10.2174/1389450043345308

Carmona, S., Zahs, K., Wu, E., Dakin, K., Bras, J., & Guerreiro, R. (2018). The role of TREM2 in Alzheimer's disease and other neurodegenerative disorders. The Lancet. Neurology, 17(8), 721–730. https://doi.org/10.1016/S1474-4422(18)30232-1 DOI: https://doi.org/10.1016/S1474-4422(18)30232-1

Chen, G. F., Xu, T. H., Yan, Y., Zhou, Y. R., Jiang, Y., Melcher, K., & Xu, H. E. (2017). Amyloid beta: structure, biology and structure-based therapeutic development. Acta pharmacologica Sinica, 38(9), 1205–1235. https://doi.org/10.1038/aps.2017.28 DOI: https://doi.org/10.1038/aps.2017.28

Chen, Z. R., Huang, J. B., Yang, S. L., & Hong, F. F. (2022). Role of Cholinergic Signaling in Alzheimer's Disease. Molecules (Basel, Switzerland), 27(6), 1816. https://doi.org/10.3390/molecules27061816 DOI: https://doi.org/10.3390/molecules27061816

Cummings, J., Zhou, Y., Lee, G., Zhong, K., Fonseca, J., & Cheng, F. (2024). Alzheimer's disease drug development pipeline: 2024. Alzheimer's & dementia (New York, N. Y.), 10(2), e12465. https://doi.org/10.1002/trc2.12465 DOI: https://doi.org/10.1002/trc2.12465

Gratuze, M., Leyns, C. E. G., & Holtzman, D. M. (2018). New insights into the role of TREM2 in Alzheimer's disease. Molecular neurodegeneration, 13(1), 66. https://doi.org/10.1186/s13024-018-0298-9 DOI: https://doi.org/10.1186/s13024-018-0298-9

Hardy, J. A., & Higgins, G. A. (1992). Alzheimer's disease: the amyloid cascade hypothesis. Science (New York, N.Y.), 256(5054), 184–185. https://doi.org/10.1126/science.1566067 DOI: https://doi.org/10.1126/science.1566067

Heneka, M. T., Carson, M. J., El Khoury, J., Landreth, G. E., Brosseron, F., Feinstein, D. L., Jacobs, A. H., Wyss-Coray, T., Vitorica, J., Ransohoff, R. M., Herrup, K., Frautschy, S. A., Finsen, B., Brown, G. C., Verkhratsky, A., Yamanaka, K., Koistinaho, J., Latz, E., Halle, A., Petzold, G. C., … Kummer, M. P. (2015). Neuroinflammation in Alzheimer's disease. The Lancet. Neurology, 14(4), 388–405. https://doi.org/10.1016/S1474-4422(15)70016-5 DOI: https://doi.org/10.1016/S1474-4422(15)70016-5

Jacobsen, H., Ozmen, L., Caruso, A., Narquizian, R., Hilpert, H., Jacobsen, B., Terwel, D., Tanghe, A., & Bohrmann, B. (2014). Combined treatment with a BACE inhibitor and anti-Aβ antibody gantenerumab enhances amyloid reduction in APPLondon mice. The Journal of neuroscience : the official journal of the Society for Neuroscience, 34(35), 11621–11630. https://doi.org/10.1523/JNEUROSCI.1405-14.2014 DOI: https://doi.org/10.1523/JNEUROSCI.1405-14.2014

Janelidze, S., Mattsson, N., Palmqvist, S., Smith, R., Beach, T. G., Serrano, G. E., Chai, X., Proctor, N. K., Eichenlaub, U., Zetterberg, H., Blennow, K., Reiman, E. M., Stomrud, E., Dage, J. L., & Hansson, O. (2020). Plasma P-tau181 in Alzheimer's disease: relationship to other biomarkers, differential diagnosis, neuropathology and longitudinal progression to Alzheimer's dementia. Nature medicine, 26(3), 379–386. https://doi.org/10.1038/s41591-020-0755-1 DOI: https://doi.org/10.1038/s41591-020-0755-1

Jay, T. R., von Saucken, V. E., & Landreth, G. E. (2017). TREM2 in Neurodegenerative Diseases. Molecular neurodegeneration, 12(1), 56. https://doi.org/10.1186/s13024-017-0197-5 DOI: https://doi.org/10.1186/s13024-017-0197-5

Khan, S., Barve, K. H., & Kumar, M. S. (2020). Recent Advancements in Pathogenesis, Diagnostics and Treatment of Alzheimer's Disease. Current neuropharmacology, 18(11), 1106–1125. https://doi.org/10.2174/1570159X18666200528142429 DOI: https://doi.org/10.2174/1570159X18666200528142429

Kim, K. Y., Shin, K. Y., & Chang, K. A. (2023). GFAP as a Potential Biomarker for Alzheimer's Disease: A Systematic Review and Meta-Analysis. Cells, 12(9), 1309. https://doi.org/10.3390/cells12091309 DOI: https://doi.org/10.3390/cells12091309

Knopman, D. S., Amieva, H., Petersen, R. C., Chételat, G., Holtzman, D. M., Hyman, B. T., Nixon, R. A., & Jones, D. T. (2021). Alzheimer disease. Nature reviews. Disease primers, 7(1), 33. https://doi.org/10.1038/s41572-021-00269-y DOI: https://doi.org/10.1038/s41572-021-00269-y

Kumar, A., Singh, A., & Ekavali (2015). A review on Alzheimer's disease pathophysiology and its management: an update. Pharmacological reports : PR, 67(2), 195–203. https://doi.org/10.1016/j.pharep.2014.09.004 DOI: https://doi.org/10.1016/j.pharep.2014.09.004

Li, J., Huang, X., An, Y., Chen, X., Chen, Y., Xu, M., Shan, H., & Zhang, M. (2024). The role of snapin in regulation of brain homeostasis. Neural regeneration research, 19(8), 1696–1701. https://doi.org/10.4103/1673-5374.389364 DOI: https://doi.org/10.4103/1673-5374.389364

Long, J. M., & Holtzman, D. M. (2019). Alzheimer Disease: An Update on Pathobiology and Treatment Strategies. Cell, 179(2), 312–339. https://doi.org/10.1016/j.cell.2019.09.001 DOI: https://doi.org/10.1016/j.cell.2019.09.001

Masters, C. L., Bateman, R., Blennow, K., Rowe, C. C., Sperling, R. A., & Cummings, J. L. (2015). Alzheimer's disease. Nature reviews. Disease primers, 1, 15056. https://doi.org/10.1038/nrdp.2015.56 DOI: https://doi.org/10.1038/nrdp.2015.56

Mazzucchi, S., Palermo, G., Campese, N., Galgani, A., Della Vecchia, A., Vergallo, A., Siciliano, G., Ceravolo, R., Hampel, H., & Baldacci, F. (2020). The role of synaptic biomarkers in the spectrum of neurodegenerative diseases. Expert review of proteomics, 17(7-8), 543–559. https://doi.org/10.1080/14789450.2020.1831388 DOI: https://doi.org/10.1080/14789450.2020.1831388

Medina, M., & Avila, J. (2014). New perspectives on the role of tau in Alzheimer's disease. Implications for therapy. Biochemical pharmacology, 88(4), 540–547. https://doi.org/10.1016/j.bcp.2014.01.013 DOI: https://doi.org/10.1016/j.bcp.2014.01.013

Meftah, S., & Gan, J. (2023). Alzheimer's disease as a synaptopathy: Evidence for dysfunction of synapses during disease progression. Frontiers in synaptic neuroscience, 15, 1129036. https://doi.org/10.3389/fnsyn.2023.1129036 DOI: https://doi.org/10.3389/fnsyn.2023.1129036

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. (2021). Donanemab in Early Alzheimer's Disease. The New England journal of medicine, 384(18), 1691–1704. https://doi.org/10.1056/NEJMoa2100708 DOI: https://doi.org/10.1056/NEJMoa2100708

Monteiro, A. R., Barbosa, D. J., Remião, F., & Silva, R. (2023). Alzheimer's disease: Insights and new prospects in disease pathophysiology, biomarkers and disease-modifying drugs. Biochemical pharmacology, 211, 115522. https://doi.org/10.1016/j.bcp.2023.115522 DOI: https://doi.org/10.1016/j.bcp.2023.115522

Ng, A., Tam, W. W., Zhang, M. W., Ho, C. S., Husain, S. F., McIntyre, R. S., & Ho, R. C. (2018). IL-1β, IL-6, TNF- α and CRP in Elderly Patients with Depression or Alzheimer's disease: Systematic Review and Meta-Analysis. Scientific reports, 8(1), 12050. https://doi.org/10.1038/s41598-018-30487-6 DOI: https://doi.org/10.1038/s41598-018-30487-6

Novak, P., Schmidt, R., Kontsekova, E., Zilka, N., Kovacech, B., Skrabana, R., Vince-Kazmerova, Z., Katina, S., Fialova, L., Prcina, M., Parrak, V., Dal-Bianco, P., Brunner, M., Staffen, W., Rainer, M., Ondrus, M., Ropele, S., Smisek, M., Sivak, R., Winblad, B., … Novak, M. (2017). Safety and immunogenicity of the tau vaccine AADvac1 in patients with Alzheimer's disease: a randomised, double-blind, placebo-controlled, phase 1 trial. The Lancet. Neurology, 16(2), 123–134. https://doi.org/10.1016/S1474-4422(16)30331-3 DOI: https://doi.org/10.1016/S1474-4422(16)30331-3

Panza, F., Solfrizzi, V., Seripa, D., Imbimbo, B. P., Lozupone, M., Santamato, A., Tortelli, R., Galizia, I., Prete, C., Daniele, A., Pilotto, A., Greco, A., & Logroscino, G. (2016). Tau-based therapeutics for Alzheimer's disease: active and passive immunotherapy. Immunotherapy, 8(9), 1119–1134. https://doi.org/10.2217/imt-2016-0019 DOI: https://doi.org/10.2217/imt-2016-0019

Pekny, M., & Nilsson, M. (2005). Astrocyte activation and reactive gliosis. Glia, 50(4), 427–434. https://doi.org/10.1002/glia.20207 DOI: https://doi.org/10.1002/glia.20207

Perry, D., Sperling, R., Katz, R., Berry, D., Dilts, D., Hanna, D., Salloway, S., Trojanowski, J. Q., Bountra, C., Krams, M., Luthman, J., Potkin, S., Gribkoff, V., Temple, R., Wang, Y., Carrillo, M. C., Stephenson, D., Snyder, H., Liu, E., Ware, T., … Bens, C. (2015). Building a roadmap for developing combination therapies for Alzheimer's disease. Expert review of neurotherapeutics, 15(3), 327–333. https://doi.org/10.1586/14737175.2015.996551 DOI: https://doi.org/10.1586/14737175.2015.996551

Pooler, A. M., Polydoro, M., Wegmann, S., Nicholls, S. B., Spires-Jones, T. L., & Hyman, B. T. (2013). Propagation of tau pathology in Alzheimer's disease: identification of novel therapeutic targets. Alzheimer's research & therapy, 5(5), 49. https://doi.org/10.1186/alzrt214 DOI: https://doi.org/10.1186/alzrt214

Rauf, A., Badoni, H., Abu-Izneid, T., Olatunde, A., Rahman, M. M., Painuli, S., Semwal, P., Wilairatana, P., & Mubarak, M. S. (2022). Neuroinflammatory Markers: Key Indicators in the Pathology of Neurodegenerative Diseases. Molecules (Basel, Switzerland), 27(10), 3194. https://doi.org/10.3390/molecules27103194 DOI: https://doi.org/10.3390/molecules27103194

Rosenmann H. (2013). Immunotherapy for targeting tau pathology in Alzheimer's disease and tauopathies. Current Alzheimer research, 10(3), 217–228. https://doi.org/10.2174/1567205011310030001 DOI: https://doi.org/10.2174/1567205011310030001

Selkoe, D. J., & Hardy, J. (2016). The amyloid hypothesis of Alzheimer's disease at 25 years. EMBO molecular medicine, 8(6), 595–608. https://doi.org/10.15252/emmm.201606210 DOI: https://doi.org/10.15252/emmm.201606210

Shareena, G., & Kumar, D. (2023). Exploring the Role of Tau Proteins in Alzheimer’s Disease from Typical Functioning MAPs to Aberrant Fibrillary Deposits in the Brain. In Deciphering Drug Targets for Alzheimer’s Disease (pp. 321-349). Singapore: Springer Nature Singapore. DOI: https://doi.org/10.1007/978-981-99-2657-2_14

Shi, H., & Zhao, Y. (2024). Modulation of Tau Pathology in Alzheimer's Disease by Dietary Bioactive Compounds. International journal of molecular sciences, 25(2), 831. https://doi.org/10.3390/ijms25020831 DOI: https://doi.org/10.3390/ijms25020831

Thakur, A. K., Kamboj, P., Goswami, K., & Ahuja, K. J. J. A. P. R. (2018). Pathophysiology and management of Alzheimer’s disease: An overview. J anal pharm Res, 9(2), 226-35. DOI: https://doi.org/10.15406/japlr.2018.07.00230

Thijssen, E. H., La Joie, R., Wolf, A., Strom, A., Wang, P., Iaccarino, L., Bourakova, V., Cobigo, Y., Heuer, H., Spina, S., VandeVrede, L., Chai, X., Proctor, N. K., Airey, D. C., Shcherbinin, S., Duggan Evans, C., Sims, J. R., Zetterberg, H., Blennow, K., Karydas, A. M., … Advancing Research and Treatment for Frontotemporal Lobar Degeneration (ARTFL) investigators (2020). Diagnostic value of plasma phosphorylated tau181 in Alzheimer's disease and frontotemporal lobar degeneration. Nature medicine, 26(3), 387–397. https://doi.org/10.1038/s41591-020-0762-2 DOI: https://doi.org/10.1038/s41591-020-0762-2

Weller, J., & Budson, A. (2018). Current understanding of Alzheimer's disease diagnosis and treatment. F1000Research, 7, F1000 Faculty Rev-1161. https://doi.org/10.12688/f1000research.14506.1 DOI: https://doi.org/10.12688/f1000research.14506.1

Yiannopoulou, K. G., & Papageorgiou, S. G. (2020). Current and Future Treatments in Alzheimer Disease: An Update. Journal of central nervous system disease, 12, 1179573520907397. https://doi.org/10.1177/1179573520907397 DOI: https://doi.org/10.1177/1179573520907397

Žarković, N., Gęgotek, A., Łuczaj, W., Jaganjac, M., Šunjić, S. B., Žarković, K., & Skrzydlewska, E. (2024). Overview of the Lipid Peroxidation Measurements in Patients by the Enzyme-Linked Immunosorbent Assay Specific for the 4-Hydroxynonenal-Protein Adducts (4-HNE-ELISA). Frontiers in bioscience (Landmark edition), 29(4), 153. https://doi.org/10.31083/j.fbl2904153 DOI: https://doi.org/10.31083/j.fbl2904153

Zheng, C., Zhou, X. W., & Wang, J. Z. (2016). The dual roles of cytokines in Alzheimer's disease: update on interleukins, TNF-α, TGF-β and IFN-γ. Translational neurodegeneration, 5, 7. https://doi.org/10.1186/s40035-016-0054-4 DOI: https://doi.org/10.1186/s40035-016-0054-4