Current status and prospects of clinical application of blood biomarkers in Alzheimer’s disease_West China Medical Journal

Authors：

LI Hongqi ,  DONG Qiang ,  YU Jintai

Department of Neurology and Institute of Neurology, Huashan Hospital, Fudan University, Shanghai 200040, P. R. China;

Corresponding author：

DONG Qiang, Email: dong_qiang@fudan.edu.cn; YU Jintai, Email: jintai_yu@fudan.edu.cn

Keywords：

Alzheimer’s disease; blood biomarker; phosphorylated Tau protein

DOI：

10.7507/1002-0179.202305069

Video：

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Biological markers play a pivotal role in the early and accurate diagnosis of Alzheimer’s disease, enabling precise identification and monitoring of therapeutic interventions. The detection of central β-amyloid and Tau proteins has become an indispensable tool in clinical trials. Recent years have witnessed substantial progress in the development of readily accessible and cost-effective blood biomarkers. This comprehensive article provides a comprehensive overview of the clinical applications of blood biomarkers, encompassing β-amyloid, phosphorylated Tau protein, neurofilament light chain protein, and glial fibrillary acidic protein, all of which have demonstrated clinical relevance in Alzheimer’s disease diagnosis. Notably, phosphorylated Tau protein exhibits superior diagnostic efficacy. The incorporation of blood biomarkers facilitates early screening, accurate diagnosis, and efficacious treatment of Alzheimer’s disease.

Citation： LI Hongqi, DONG Qiang, YU Jintai. Current status and prospects of clinical application of blood biomarkers in Alzheimer’s disease. West China Medical Journal, 2023, 38(5): 641-644. doi: 10.7507/1002-0179.202305069 Copy

1.	Stephan BCM, Siervo M, Brayne C. How can population-based studies best be utilized to reduce the global impact of dementia? Recommendations for researchers, funders, and policymakers. Alzheimers Dement, 2020, 16(10): 1448-1456.
2.	Prince MJ, Wimo A, Guerchet MM, et al. World Alzheimer report 2015. The global impact of dementia: an analysis of prevalence, incidence, cost and trends. London: Alzheimer’s Disease International, 2015.
3.	Jack CR, Bennett DA, Blennow K, et al. NIA-AA Research Framework: toward a biological definition of Alzheimer’s disease. Alzheimers Dement, 2018, 14(4): 535-562.
4.	Molinuevo JL, Ayton S, Batrla R, et al. Current state of Alzheimer’s fluid biomarkers. Acta Neuropathol, 2018, 136(6): 821-853.
5.	Scheltens P, De Strooper B, Kivipelto M, et al. Alzheimer’s disease. Lancet, 2021, 397(10284): 1577-1590.
6.	Hansson O. Biomarkers for neurodegenerative diseases. Nat Med, 2021, 27(6): 954-963.
7.	Hansson O, Zetterberg H, Vanmechelen E, et al. Evaluation of plasma Aβ₄₀ and Aβ₄₂ as predictors of conversion to Alzheimer’s disease in patients with mild cognitive impairment. Neurobiol Aging, 2010, 31(3): 357-367.
8.	Palmqvist S, Janelidze S, Stomrud E, et al. Performance of fully automated plasma assays as screening tests for Alzheimer disease-related β-amyloid status. JAMA Neurol, 2019, 76(9): 1060-1069.
9.	Palmqvist S, Insel PS, Zetterberg H, et al. Accurate risk estimation of β-amyloid positivity to identify prodromal Alzheimer’s disease: cross-validation study of practical algorithms. Alzheimers Dement, 2019, 15(2): 194-204.
10.	Schindler SE, Bollinger JG, Ovod V, et al. High-precision plasma β-amyloid 42/40 predicts current and future brain amyloidosis. Neurology, 2019, 93(17): e1647-e1659.
11.	Olsson B, Lautner R, Andreasson U, et al. CSF and blood biomarkers for the diagnosis of Alzheimer’s disease: a systematic review and meta-analysis. Lancet Neurol, 2016, 15(7): 673-684.
12.	Janelidze S, Stomrud E, Palmqvist S, et al. Plasma β-amyloid in Alzheimer’s disease and vascular disease. Sci Rep, 2016, 6: 26801.
13.	Verberk IMW, Slot RE, Verfaillie SCJ, et al. Plasma amyloid as prescreener for the earliest Alzheimer pathological changes. Ann Neurol, 2018, 84(5): 648-658.
14.	Nakamura A, Kaneko N, Villemagne VL, et al. High performance plasma amyloid-β biomarkers for Alzheimer’s disease. Nature, 2018, 554(7691): 249-254.
15.	Li Y, Schindler SE, Bollinger JG, et al. Validation of plasma amyloid-β 42/40 for detecting Alzheimer disease amyloid plaques. Neurology, 2022, 98(7): e688-e699.
16.	Janelidze S, Teunissen CE, Zetterberg H, et al. Head-to-head comparison of 8 plasma amyloid-β 42/40 assays in Alzheimer disease. JAMA Neurol, 2021, 78(11): 1375-1382.
17.	Mattsson-Carlgren N, Palmqvist S, Blennow K, et al. Increasing the reproducibility of fluid biomarker studies in neurodegenerative studies. Nat Commun, 2020, 11(1): 6252.
18.	Brickman AM, Manly JJ, Honig LS, et al. Plasma p-tau181, p-tau217, and other blood-based Alzheimer’s disease biomarkers in a multi-ethnic, community study. Alzheimers Dement, 2021, 17(8): 1353-1364.
19.	Palmqvist S, Janelidze S, Quiroz YT, et al. Discriminative accuracy of plasma phospho-tau217 for Alzheimer disease vs. other neurodegenerative disorders. JAMA, 2020, 324(8): 772-781.
20.	Ashton NJ, Pascoal TA, Karikari TK, et al. Plasma p-tau231: a new biomarker for incipient Alzheimer’s disease pathology. Acta Neuropathol, 2021, 141(5): 709-724.
21.	Thijssen EH, La Joie R, Wolf A, et al. Diagnostic value of plasma phosphorylated tau181 in Alzheimer’s disease and frontotemporal lobar degeneration. Nat Med, 2020, 26(3): 387-397.
22.	Janelidze S, Mattsson N, Palmqvist S, et al. Plasma P-tau181 in Alzheimer’s disease: relationship to other biomarkers, differential diagnosis, neuropathology and longitudinal progression to Alzheimer’s dementia. Nat Med, 2020, 26(3): 379-386.
23.	Thijssen EH, La Joie R, Strom A, et al. Plasma phosphorylated tau 217 and phosphorylated tau 181 as biomarkers in Alzheimer’s disease and frontotemporal lobar degeneration: a retrospective diagnostic performance study. Lancet Neurol, 2021, 20(9): 739-752.
24.	Tissot C, Therriault J, Kunach P, et al. Comparing tau status determined via plasma pTau181, pTau231 and [18F]MK6240 tau-PET. EBioMedicine, 2022, 76: 103837.
25.	Van Egroo M, Riphagen JM, Ashton NJ, et al. Ultra-high field imaging, plasma markers and autopsy data uncover a specific rostral locus coeruleus vulnerability to hyperphosphorylated tau. Mol Psychiatry, 2023: 1-11.
26.	Bridel C, van Wieringen WN, Zetterberg H, et al. Diagnostic value of cerebrospinal fluid neurofilament light protein in neurology: a systematic review and meta-analysis. JAMA Neurol, 2019, 76(9): 1035-1048.
27.	Preische O, Schultz SA, Apel A, et al. Serum neurofilament dynamics predicts neurodegeneration and clinical progression in presymptomatic Alzheimer’s disease. Nat Med, 2019, 25(2): 277-283.
28.	Hol EM, Pekny M. Glial fibrillary acidic protein (GFAP) and the astrocyte intermediate filament system in diseases of the central nervous system. Curr Opin Cell Biol, 2015, 32: 121-130.
29.	Elahi FM, Casaletto KB, La Joie R, et al. Plasma biomarkers of astrocytic and neuronal dysfunction in early- and late-onset Alzheimer’s disease. Alzheimers Dement, 2020, 16(4): 681-695.
30.	Chatterjee P, Pedrini S, Ashton NJ, et al. Diagnostic and prognostic plasma biomarkers for preclinical Alzheimer’s disease. Alzheimers Dement, 2022, 18(6): 1141-1154.
31.	Stevenson-Hoare J, Heslegrave A, Leonenko G, et al. Plasma biomarkers and genetics in the diagnosis and prediction of Alzheimer’s disease. Brain, 2023, 146(2): 690-699.
32.	Shen XN, Huang SY, Cui M, et al. Plasma glial fibrillary acidic protein in the Alzheimer disease continuum: relationship to other biomarkers, differential diagnosis, and prediction of clinical progression. Clin Chem, 2023, 69(4): 411-421.

1. Stephan BCM, Siervo M, Brayne C. How can population-based studies best be utilized to reduce the global impact of dementia? Recommendations for researchers, funders, and policymakers. Alzheimers Dement, 2020, 16(10): 1448-1456.
2. Prince MJ, Wimo A, Guerchet MM, et al. World Alzheimer report 2015. The global impact of dementia: an analysis of prevalence, incidence, cost and trends. London: Alzheimer’s Disease International, 2015.
3. Jack CR, Bennett DA, Blennow K, et al. NIA-AA Research Framework: toward a biological definition of Alzheimer’s disease. Alzheimers Dement, 2018, 14(4): 535-562.
4. Molinuevo JL, Ayton S, Batrla R, et al. Current state of Alzheimer’s fluid biomarkers. Acta Neuropathol, 2018, 136(6): 821-853.
5. Scheltens P, De Strooper B, Kivipelto M, et al. Alzheimer’s disease. Lancet, 2021, 397(10284): 1577-1590.
6. Hansson O. Biomarkers for neurodegenerative diseases. Nat Med, 2021, 27(6): 954-963.
7. Hansson O, Zetterberg H, Vanmechelen E, et al. Evaluation of plasma Aβ₄₀ and Aβ₄₂ as predictors of conversion to Alzheimer’s disease in patients with mild cognitive impairment. Neurobiol Aging, 2010, 31(3): 357-367.
8. Palmqvist S, Janelidze S, Stomrud E, et al. Performance of fully automated plasma assays as screening tests for Alzheimer disease-related β-amyloid status. JAMA Neurol, 2019, 76(9): 1060-1069.
9. Palmqvist S, Insel PS, Zetterberg H, et al. Accurate risk estimation of β-amyloid positivity to identify prodromal Alzheimer’s disease: cross-validation study of practical algorithms. Alzheimers Dement, 2019, 15(2): 194-204.
10. Schindler SE, Bollinger JG, Ovod V, et al. High-precision plasma β-amyloid 42/40 predicts current and future brain amyloidosis. Neurology, 2019, 93(17): e1647-e1659.
11. Olsson B, Lautner R, Andreasson U, et al. CSF and blood biomarkers for the diagnosis of Alzheimer’s disease: a systematic review and meta-analysis. Lancet Neurol, 2016, 15(7): 673-684.
12. Janelidze S, Stomrud E, Palmqvist S, et al. Plasma β-amyloid in Alzheimer’s disease and vascular disease. Sci Rep, 2016, 6: 26801.
13. Verberk IMW, Slot RE, Verfaillie SCJ, et al. Plasma amyloid as prescreener for the earliest Alzheimer pathological changes. Ann Neurol, 2018, 84(5): 648-658.
14. Nakamura A, Kaneko N, Villemagne VL, et al. High performance plasma amyloid-β biomarkers for Alzheimer’s disease. Nature, 2018, 554(7691): 249-254.
15. Li Y, Schindler SE, Bollinger JG, et al. Validation of plasma amyloid-β 42/40 for detecting Alzheimer disease amyloid plaques. Neurology, 2022, 98(7): e688-e699.
16. Janelidze S, Teunissen CE, Zetterberg H, et al. Head-to-head comparison of 8 plasma amyloid-β 42/40 assays in Alzheimer disease. JAMA Neurol, 2021, 78(11): 1375-1382.
17. Mattsson-Carlgren N, Palmqvist S, Blennow K, et al. Increasing the reproducibility of fluid biomarker studies in neurodegenerative studies. Nat Commun, 2020, 11(1): 6252.
18. Brickman AM, Manly JJ, Honig LS, et al. Plasma p-tau181, p-tau217, and other blood-based Alzheimer’s disease biomarkers in a multi-ethnic, community study. Alzheimers Dement, 2021, 17(8): 1353-1364.
19. Palmqvist S, Janelidze S, Quiroz YT, et al. Discriminative accuracy of plasma phospho-tau217 for Alzheimer disease vs. other neurodegenerative disorders. JAMA, 2020, 324(8): 772-781.
20. Ashton NJ, Pascoal TA, Karikari TK, et al. Plasma p-tau231: a new biomarker for incipient Alzheimer’s disease pathology. Acta Neuropathol, 2021, 141(5): 709-724.
21. Thijssen EH, La Joie R, Wolf A, et al. Diagnostic value of plasma phosphorylated tau181 in Alzheimer’s disease and frontotemporal lobar degeneration. Nat Med, 2020, 26(3): 387-397.
22. Janelidze S, Mattsson N, Palmqvist S, et al. Plasma P-tau181 in Alzheimer’s disease: relationship to other biomarkers, differential diagnosis, neuropathology and longitudinal progression to Alzheimer’s dementia. Nat Med, 2020, 26(3): 379-386.
23. Thijssen EH, La Joie R, Strom A, et al. Plasma phosphorylated tau 217 and phosphorylated tau 181 as biomarkers in Alzheimer’s disease and frontotemporal lobar degeneration: a retrospective diagnostic performance study. Lancet Neurol, 2021, 20(9): 739-752.
24. Tissot C, Therriault J, Kunach P, et al. Comparing tau status determined via plasma pTau181, pTau231 and [18F]MK6240 tau-PET. EBioMedicine, 2022, 76: 103837.
25. Van Egroo M, Riphagen JM, Ashton NJ, et al. Ultra-high field imaging, plasma markers and autopsy data uncover a specific rostral locus coeruleus vulnerability to hyperphosphorylated tau. Mol Psychiatry, 2023: 1-11.
26. Bridel C, van Wieringen WN, Zetterberg H, et al. Diagnostic value of cerebrospinal fluid neurofilament light protein in neurology: a systematic review and meta-analysis. JAMA Neurol, 2019, 76(9): 1035-1048.
27. Preische O, Schultz SA, Apel A, et al. Serum neurofilament dynamics predicts neurodegeneration and clinical progression in presymptomatic Alzheimer’s disease. Nat Med, 2019, 25(2): 277-283.
28. Hol EM, Pekny M. Glial fibrillary acidic protein (GFAP) and the astrocyte intermediate filament system in diseases of the central nervous system. Curr Opin Cell Biol, 2015, 32: 121-130.
29. Elahi FM, Casaletto KB, La Joie R, et al. Plasma biomarkers of astrocytic and neuronal dysfunction in early- and late-onset Alzheimer’s disease. Alzheimers Dement, 2020, 16(4): 681-695.
30. Chatterjee P, Pedrini S, Ashton NJ, et al. Diagnostic and prognostic plasma biomarkers for preclinical Alzheimer’s disease. Alzheimers Dement, 2022, 18(6): 1141-1154.
31. Stevenson-Hoare J, Heslegrave A, Leonenko G, et al. Plasma biomarkers and genetics in the diagnosis and prediction of Alzheimer’s disease. Brain, 2023, 146(2): 690-699.
32. Shen XN, Huang SY, Cui M, et al. Plasma glial fibrillary acidic protein in the Alzheimer disease continuum: relationship to other biomarkers, differential diagnosis, and prediction of clinical progression. Clin Chem, 2023, 69(4): 411-421.

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