SELECTED BLOOD-BASED BIOMARKERS IN ALZHEIMER'S DISEASE: CLINICAL APPLICATIONS, DIAGNOSTIC UTILITY, AND IMPLEMENTATION CHALLENGES

Małgorzata Witaszczyk; Alicja Sołtan; Natalia Wiktorzak; Julia Lipska; Jagoda  Prządka; Dominika Kochan-Olszewska; Longin  Rudnicki; Jakub Pawlicki; Gracjan  Koźma; Justyna Laskus; Paweł  Klimas; Bartosz  Gawior; Olga  Stasiak

doi:10.31435/ijitss.3(51).2026.6433

Authors

Małgorzata Witaszczyk University Clinical Center of the Medical University of Silesia in Katowice, ul. Medyków 18, 40-752 Katowice, Poland https://orcid.org/0009-0004-0197-5480
Alicja Sołtan Central Clinical Hospital of the Medical University of Warsaw, ul. Banacha 1A, 02-097 Warsaw, Poland https://orcid.org/0009-0006-8750-0797
Natalia Wiktorzak Cardinal Stefan Wyszyński Voivodeship Hospital in Łomża, Marszałka Józefa Piłsudskiego 11, 18-400 Łomża, Poland https://orcid.org/0009-0004-8601-3087
Julia Lipska Medical University of Lublin, al. Racławickie 1, 20-059 Lublin, Poland https://orcid.org/0009-0009-4093-2543
Jagoda Prządka Nicolaus Copernicus University in Toruń Ludwik Rydygier Collegium Medicum in Bydgoszcz, ul. Jagiellońska 15, 85-067 Bydgoszcz https://orcid.org/0009-0001-7921-919X
Dominika Kochan-Olszewska Holycross Cancer Center, 25-734 Kielce, ul. Artwińskiego 3, 25-734 Kielce, Poland https://orcid.org/0009-0002-0001-7809
Longin Rudnicki Gdańsk Medical University: Gdansk, Poland https://orcid.org/0009-0003-8980-8718
Jakub Pawlicki Specialist Hospital. St. Wojciech based in Gdansk, Aleja Jana Pawła II 50, 80-462 Gdańsk, Polska https://orcid.org/0009-0007-3888-4672
Gracjan Koźma Military Institute of Aviation Medicine in Warsaw, 54/56 Krasińskiego Street, 01-755 Warsaw, Poland https://orcid.org/0009-0002-8812-6427
Justyna Laskus Bielański Hospital, ul. Cegłowska 80, 01-809 Warsaw, Poland https://orcid.org/0009-0004-8065-0464
Paweł Klimas Św. Wincentego a Paulo Hospital, 1 Wójta Radtkego St., 81-348 Gdynia, Poland https://orcid.org/0009-0002-8803-0476
Bartosz Gawior Mazovian Bródno Hospital, ul. Ludwika Kondratowicza 8, 03-242 Warsaw, Poland https://orcid.org/0009-0003-0935-5414
Olga Stasiak Międzylesie Specialist Hospital in Warsaw, ul. Bursztynowa 2, 04-749 Warsaw, Poland https://orcid.org/0009-0008-3013-8015

DOI:

https://doi.org/10.31435/ijitss.3(51).2026.6433

Keywords:

Alzheimer’s Disease, Blood-Based Biomarkers, Mild Cognitive Impairment, Immunoprecipitation-Mass Spectrometry (IP-MS)

Abstract

Background: Alzheimer’s disease (AD) poses major public health challenges. Traditional CSF and PET diagnostics are invasive, expensive, and limited in routine practice, driving the need for accessible plasma biomarkers.

Objectives: To evaluate the diagnostic and prognostic utility of key plasma biomarkers (plasma Aβ42/Aβ40 ratio, p-tau species, NfL, t-tau, GFAP, sTREM2) and identify limitations to their clinical implementation.

Methods: A structured literature search was conducted in the PubMed database for English-language clinical studies and review articles published between October 2007 and June 2026. Keywords and MeSH terms included "Alzheimer’s disease", "blood-based biomarkers", "immunoprecipitation-mass spectrometry (IP-MS)", and "mild cognitive impairment". Studies focusing on adult clinical biomarkers underwent a narrative synthesis.

Results: Plasma Aβ42/Aβ40 and p-tau species (p-tau181, p-tau231, p-tau217) reliably detect early amyloid pathology and differentiate AD from other dementias. NfL, GFAP, and sTREM2 track axonal damage, astrogliosis, and microglial activity, facilitating disease monitoring and therapeutic response assessment. However, clinical translation is constrained by demographic variations, somatic comorbidities, and a lack of standardized multi-marker reference ranges.

Conclusions: Plasma biomarkers offer a transformative, non-invasive approach to early AD diagnosis and primary care triage, reducing reliance on CSF and PET scans. Overcoming demographic and methodological limitations is essential for their widespread clinical adoption.

References

Tahami Monfared, A. A., Byrnes, M. J., White, L. A., & Zhang, Q. (2022). Alzheimer’s disease: Epidemiology and clinical progression. Neurology and Therapy, 11(2), 553–569. https://doi.org/10.1007/s40120-022-00338-8

Xu, L., Wang, Z., Li, M., & Li, Q. (2025). Global incidence trends and projections of Alzheimer disease and other dementias: An age-period-cohort analysis 2021. Journal of Global Health, 15, 04156. https://doi.org/10.7189/jogh.15.04156

Safiri, S., Ghaffari Jolfayi, A., Fazlollahi, A., Morsali, S., Sarkesh, A., Daei Sorkhabi, A., et al. (2024). Alzheimer’s disease: A comprehensive review of epidemiology, risk factors, symptoms diagnosis, management, caregiving, advanced treatments and associated challenges. Frontiers in Medicine, 11, 1474043. https://doi.org/10.3389/fmed.2024.1474043

Rahman, M., Tabassum, A., Sultana, S., Saha, T., Nayeem, M. A. J., Jahan, I., et al. (2025). Epidemiology and risk factors of Alzheimer’s disease and related dementias in South and Southeast Asia: A systematic review and meta-analysis protocol. BMJ Open, 15(8), e105955. https://doi.org/10.1136/bmjopen-2025-105955

Vanya, Kumari, S., Bagri, K., & Deshmukh, R. (2025). Tangles and plaques: A deep dive into the pathological hallmarks of Alzheimer’s disease. Neuroscience, 590, 170–185. https://doi.org/10.1016/j.neuroscience.2025.10.050

Murakami, K., Masuda, Y., Shirasawa, T., Shimizu, T., & Irie, K. (2010). The turn formation at positions 22 and 23 in the 42-mer amyloid β peptide: The emerging role in the pathogenesis of Alzheimer’s disease. Geriatrics & Gerontology International, 10(S1). https://doi.org/10.1111/j.1447-0594.2010.00598.x

Jan, A., Gokce, O., Luthi-Carter, R., & Lashuel, H. A. (2008). The ratio of monomeric to aggregated forms of Aβ40 and Aβ42 is an important determinant of amyloid-β aggregation, fibrillogenesis, and toxicity. Journal of Biological Chemistry, 283(42), 28176–28189. https://doi.org/10.1074/jbc.M803159200

Schulz, B., Liebisch, G., Grandl, M., Werner, T., Barlage, S., & Schmitz, G. (2007). β-Amyloid (Aβ40, Aβ42) binding to modified LDL accelerates macrophage foam cell formation. Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids, 1771(10), 1335–1344. https://doi.org/10.1016/j.bbalip.2007.08.002

Fandos, N., Pérez-Grijalba, V., Pesini, P., Olmos, S., Bossa, M., Villemagne, V. L., et al. (2017). Plasma amyloid β 42/40 ratios as biomarkers for amyloid β cerebral deposition in cognitively normal individuals. Alzheimer’s & Dementia: Diagnosis, Assessment & Disease Monitoring, 8(1), 179–187. https://doi.org/10.1016/j.dadm.2017.07.004

Seppala, T. T., Herukka, S. K., Hanninen, T., Tervo, S., Hallikainen, M., Soininen, H., et al. (2010). Plasma Aβ42 and Aβ40 as markers of cognitive change in follow-up: A prospective, longitudinal, population-based cohort study. Journal of Neurology, Neurosurgery & Psychiatry, 81(10), 1123–1127. https://doi.org/10.1136/jnnp.2010.205757

Pérez-Grijalba, V., Romero, J., Pesini, P., Sarasa, L., Monleón, I., San-José, I., et al. (2019). Plasma Aβ42/40 ratio detects early stages of Alzheimer’s disease and correlates with CSF and neuroimaging biomarkers in the AB255 study. The Journal of Prevention of Alzheimer’s Disease, 6(1), 34–41. https://doi.org/10.14283/jpad.2018.41

West, T., Kirmess, K. M., Meyer, M. R., Holubasch, M. S., Knapik, S. S., Hu, Y., et al. (2021). A blood-based diagnostic test incorporating plasma Aβ42/40 ratio, ApoE proteotype, and age accurately identifies brain amyloid status: Findings from a multi cohort validity analysis. Molecular Neurodegeneration, 16(1), 30. https://doi.org/10.1186/s13024-021-00451-6

Milà-Alomà, M., Ashton, N. J., Shekari, M., Salvadó, G., Ortiz-Romero, P., Montoliu-Gaya, L., et al. (2022). Plasma p-tau231 and p-tau217 as state markers of amyloid-β pathology in preclinical Alzheimer’s disease. Nature Medicine. https://doi.org/10.1038/s41591-022-01925-w

Li, Z., Fan, Z., & Zhang, Q. (2024). The associations of phosphorylated tau 181 and tau 231 levels in plasma and cerebrospinal fluid with cognitive function in Alzheimer’s disease: A systematic review and meta-analysis. Journal of Alzheimer’s Disease, 98(1), 13–32. https://doi.org/10.3233/JAD-230799

Ferreira, P. C. L., Bellaver, B., Povala, G., Bauer-Negrini, G., Aguzzoli, C. S., Ferrari-Souza, J. P., et al. (2026). Evaluating plasma p-tau217 as an endpoint for Alzheimer disease clinical trials. Neurology, 106(1), e214441. https://doi.org/10.1212/WNL.0000000000214441

Mohammed, H. E., Haseeb, M. E., Nasser, M., Hanen, G., Abdelkader, M. S., Yaser, H., et al. (2026). Diagnostic accuracy of CSF and plasma pTau-181, pTau-217, and pTau-231 for Alzheimer’s disease: A diagnostic meta-analysis. Acta Neurologica Belgica. https://doi.org/10.1007/s13760-026-03107-8

Thijssen, E. H., La Joie, R., Strom, A., Fonseca, C., Iaccarino, L., Wolf, A., et al. (2021). Plasma phosphorylated tau 217 and phosphorylated tau 181 as biomarkers in Alzheimer’s disease and frontotemporal lobar degeneration: A retrospective diagnostic performance study. The Lancet Neurology, 20(9), 739–752. https://doi.org/10.1016/S1474-4422(21)00214-3

Chong, J. R., Hilal, S., Tan, B. Y., Venketasubramanian, N., Schöll, M., Zetterberg, H., et al. (2025). Clinical utility of plasma p-tau217 in identifying abnormal brain amyloid burden in an Asian cohort with high prevalence of concomitant cerebrovascular disease. Alzheimer’s & Dementia, 21(2), e14502. https://doi.org/10.1002/alz.14502

Monane, M., Maraganore, D. M., Carlile, R. M., Johnson, K. G., Merrill, D. A., Gitelman, D. R., et al. (2025). Clinical utility of an Alzheimer’s disease blood test among cognitively impaired patients: Results from the Quality Improvement PrecivityAD2 (QUIP II) clinician survey study. Diagnostics, 15(2), 167. https://doi.org/10.3390/diagnostics15020167

Brodini, G., Roveta, F., Chiarandon, A. M., Boschi, S., Bonino, L., Piella, E. M., et al. (2026). Plasma p-tau217 for Alzheimer’s disease diagnosis: A memory clinic implementation approach. Alzheimer’s & Dementia: Diagnosis, Assessment & Disease Monitoring, 18(1), e70286. https://doi.org/10.1002/dad2.70286

Howe, M. D., Britton, K. J., Joyce, H. E., Menard, W., Emrani, S., Kunicki, Z. J., et al. (2024). Clinical application of plasma P-tau217 to assess eligibility for amyloid-lowering immunotherapy in memory clinic patients with early Alzheimer’s disease. Alzheimer’s Research & Therapy, 16(1), 154. https://doi.org/10.1186/s13195-024-01521-9

Varela-Vidales, C. A., Martínez-Hernández, A., Hernández-Castellanos, E., & Delgado-Lara, D. L. C. (2025). P-tau217 as a biomarker in Alzheimer’s disease: Applications in Latin American populations. International Journal of Molecular Sciences, 26(14), 6633. https://doi.org/10.3390/ijms26146633

Abukuri, D. N. (2024). Novel biomarkers for Alzheimer’s disease: Plasma neurofilament light and cerebrospinal fluid. International Journal of Alzheimer’s Disease, 2024, 1–15. https://doi.org/10.1155/2024/6668159

Dong, Y., Hou, T., Li, Y., Liu, R., Cong, L., Liu, K., et al. (2023). Plasma amyloid-β, total tau, and neurofilament light chain across the Alzheimer’s disease clinical spectrum: A population-based study. Journal of Alzheimer’s Disease, 96(2), 845–858. https://doi.org/10.3233/JAD-230932

Giacomucci, G., Mazzeo, S., Bagnoli, S., Ingannato, A., Leccese, D., Berti, V., et al. (2022). Plasma neurofilament light chain as a biomarker of Alzheimer’s disease in subjective cognitive decline and mild cognitive impairment. Journal of Neurology, 269(8), 4270–4280. https://doi.org/10.1007/s00415-022-11055-5

Abed, S. S., Hamdan, F. B., Hussein, M. M., et al. (2023). Plasma tau and neurofilament light chain as biomarkers of Alzheimer’s disease and their relation to cognitive functions. Journal of Medicine and Life, 16(2), 284–289. https://doi.org/10.25122/jml-2022-0251

Sugarman, M. A., Zetterberg, H., Blennow, K., Tripodis, Y., McKee, A. C., Stein, T. D., et al. (2020). A longitudinal examination of plasma neurofilament light and total tau for the clinical detection and monitoring of Alzheimer’s disease. Neurobiology of Aging, 94, 60–70. https://doi.org/10.1016/j.neurobiolaging.2020.05.011

Kawarabayashi, T., Nakamura, T., Miyashita, K., Segawa, T., Fukamachi, I., Sugawara, T., et al. (2023). Clinical evaluation of cerebrospinal fluid p217tau and neurofilament light chain levels in patients with Alzheimer’s disease or other neurological diseases. Journal of Alzheimer’s Disease, 96(4), 1623–1638. https://doi.org/10.3233/JAD-230419

Kurihara, M., Ihara, R., Yoshii, G., Shimasaki, R., Hatano, K., Bannai, T., et al. (2026). ATNIVS biomarker heterogeneity in real-world patients receiving lecanemab. The Journal of Prevention of Alzheimer’s Disease, 13(6), 100567. https://doi.org/10.1016/j.tjpad.2026.100567

Raket, L. L., Kühnel, L., Schmidt, E., Blennow, K., Zetterberg, H., & Mattsson-Carlgren, N. (2020). Utility of plasma neurofilament light and total tau for clinical trials in Alzheimer’s disease. Alzheimer’s & Dementia: Diagnosis, Assessment & Disease Monitoring, 12(1). https://doi.org/10.1002/dad2.12099

Yang, J., Zhao, X., Liu, Y., Cai, Y., & Fan, Y. (2026). Associations of plasma biomarkers with longitudinal co-pathologies in Alzheimer’s disease and cerebral small vessel disease comorbidity. The Journal of Prevention of Alzheimer’s Disease, 13(2), 100449. https://doi.org/10.1016/j.tjpad.2025.100449

Bandara, E. M. S., Asih, P. R., Pedrini, S., Hone, E., Fernando, W. M. A. D. B., & Martins, R. N. (2025). The role of glial fibrillary acidic protein in the neuropathology of Alzheimer’s disease and its potential as a blood biomarker for early diagnosis and progression. Molecular Neurobiology, 62(12), 15576–15608. https://doi.org/10.1007/s12035-025-05219-3

Fernández-Matarrubia, M., Valera-Barrero, A., Renuncio-García, M., Aguilella, M., Lage, C., López-García, S., et al. (2025). Early microglial and astrocyte reactivity in preclinical Alzheimer’s disease. Alzheimer’s & Dementia, 21(8), e70502. https://doi.org/10.1002/alz.70502

Warmenhoven, N., Sánchez-Benavides, G., González-Escalante, A., Milà-Alomà, M., Shekari, M., López-Martos, D., et al. (2024). CSF glial biomarkers are associated with cognition in individuals at risk of Alzheimer’s disease. Alzheimer’s & Dementia, 20(9), 5819–5832. https://doi.org/10.1002/alz.13862

Roveta, F., Bonino, L., Piella, E. M., Rainero, I., & Rubino, E. (2024). Neuroinflammatory biomarkers in Alzheimer’s disease: From pathophysiology to clinical implications. International Journal of Molecular Sciences, 25(22), 11941. https://doi.org/10.3390/ijms252211941

Hampel, H., Hu, Y., Cummings, J., Mattke, S., Iwatsubo, T., Nakamura, A., et al. (2023). Blood-based biomarkers for Alzheimer’s disease: Current state and future use in a transformed global healthcare landscape. Neuron, 111(18), 2781–2799. https://doi.org/10.1016/j.neuron.2023.05.017

Gopalakrishna, P. K., Che Mohd Nassir, C. M. N., Anandan, S., Hussan, F., Dandala, K. C. R., Sura, S., et al. (2026). The immuno-glial connectome in Alzheimer’s disease: Integrating central and peripheral inflammatory networks. Cellular and Molecular Neurobiology, 46(1), 31. https://doi.org/10.1007/s10571-026-01671-4

Hansson, O., Blennow, K., Zetterberg, H., & Dage, J. (2023). Blood biomarkers for Alzheimer’s disease in clinical practice and trials. Nature Aging, 3(5), 506–519. https://doi.org/10.1038/s43587-023-00403-3

Pais, M. V., Forlenza, O. V., & Diniz, B. S. (2023). Plasma biomarkers of Alzheimer’s disease: A review of available assays, recent developments, and implications for clinical practice. Journal of Alzheimer’s Disease Reports, 7(1), 355–380. https://doi.org/10.3233/ADR-230029

DuBois, K. N., Pal, S., Reader, J. M., Jackman, B., Perkins, M. D., Khobeir, N., et al. (2026). Evaluation of a panel of plasma biomarkers for Alzheimer’s disease in a diverse research cohort. Journal of Alzheimer’s Disease, 109(1), 247–265. https://doi.org/10.1177/13872877251393405

Chemas, N., Anjum, R., Marshall, C. R., Cooper, C., & Keshavan, A. (2026). Evaluating blood-based biomarkers for Alzheimer’s disease diagnosis across ethnic groups: A systematic review. Alzheimer’s & Dementia, 21(S2), e097986. https://doi.org/10.1002/alz70856_097986

Simson, R. L., Ong, M. L., Lei, M. K., Beach, S. R. H., Zhang, Y., Philibert, R., & Mielke, M. M. (2024). Racial discrimination during middle age predicts higher serum phosphorylated tau and neurofilament light chain levels a decade later: A study of aging Black Americans. Alzheimer’s & Dementia, 20(5), 3485–3494. https://doi.org/10.1002/alz.13751

Petersen, M. E., Zhou, Z., Hall, J. R., Philips, N., Meeker, K. L., Borzage, M. T., Braskie, M. N., Clark, A. L., Shi, Y., Rissman, R. A., Zhang, F., Vintimilla, R., Casas, A., Rhodes, J., Barber, R. C., Johnson, L., Yaffe, K., Toga, A. W., & O’Bryant, S. E. (2025). Health and Aging Brain Study–Health Disparities (HABS-HD) methods and partner characteristics. Alzheimer’s & Dementia: Translational Research & Clinical Interventions, 11(3), e70140. https://doi.org/10.1002/trc2.70140