Skip to main content Accessibility help

We use cookies to distinguish you from other users and to provide you with a better experience on our websites. Close this message to accept cookies or find out how to manage your cookie settings.

Close cookie message
×
Hostname: page-component-586b7cd67f-vdxz6 Total loading time: 0 Render date: 2024-11-22T13:06:10.233Z Has data issue: false hasContentIssue false

32 - Development of Fluid Biomarkers for Alzheimer’s Disease

from Section 4 - Imaging and Biomarker Development in Alzheimer’s Disease Drug Discovery

Published online by Cambridge University Press:  03 March 2022

By
Kaj Blennow
Edited by
Jeffrey Cummings ,
Jefferson Kinney  and
Howard Fillit
Jeffrey Cummings
Affiliation:
University of Nevada, Las Vegas
Jefferson Kinney
Affiliation:
University of Nevada, Las Vegas
Howard Fillit
Affiliation:
Alzheimer’s Drug Discovery Foundation
Get access

Summary

There has been a rapid development of cerebrospinal fluid (CSF) and also blood biomarkers in the field of Alzheimer’s disease (AD) clinical research and drug development. Clinical research studies support that the core AD CSF biomarkers amyloid beta (Aβ42 and Aβ42/40 ratio), total-tau (t-tau), and hyperphosphorylated tau (p-tau) reflect key elements of AD pathophysiology. The “Alzheimer CSF profile”, decreased Aβ42/40 ratio together with increased t-tau and p-tau, has high diagnostic value, and high concordance with amyloid PET. These biomarkers have undergone thorough standardization and are today available on fully automated laboratory analyzers. Recent technical developments in the field of ultrasensitive immunoassays and mass spectrometry methods also allow for measurement of these AD biomarkers in blood samples. Blood neurofilament light may also be a biomarker to grade axonal degeneration in AD and other neurodegenerative disorders. These biomarkers are important in AD drug development, for screening tools and diagnostic markers, and the verification of target engagement of candidate molecules in early trials and identification of downstream drug effects in late-stage trials.

Keywords

Biomarkerscerebrospinal fluidamyloidtauneurofilament lightscreening toolsdiagnostic markers
Type
Chapter
Information
Alzheimer's Disease Drug Development
Research and Development Ecosystem
 , pp. 361 - 374
Publisher: Cambridge University Press
Print publication year: 2022

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

Jack, CR Jr., Bennett, DA, Blennow, K, et al. A/T/N: an unbiased descriptive classification scheme for Alzheimer disease biomarkers. Neurology 2016; 87: 539–47.CrossRefGoogle ScholarPubMed
Blennow, K. Biomarkers in Alzheimer’s disease drug development. Nat Med 2010; 16: 1218–22.Google Scholar
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: 673–84.Google Scholar
Portelius, E, Tran, AJ, Andreasson, U, et al. Characterization of amyloid beta peptides in cerebrospinal fluid by an automated immunoprecipitation procedure followed by mass spectrometry. J Proteome Res 2007; 6: 4433–9.CrossRefGoogle ScholarPubMed
Andreasen, N, Minthon, L, Vanmechelen, E, et al. Cerebrospinal fluid tau and Abeta42 as predictors of development of Alzheimer’s disease in patients with mild cognitive impairment. Neurosci Lett 1999; 273: 5–8.CrossRefGoogle ScholarPubMed
Blennow, K, Mattsson, N, Scholl, M, Hansson, O, Zetterberg, H. Amyloid biomarkers in Alzheimer’s disease. Trends Pharmacol Sci 2015; 36: 297–309.Google Scholar
Lewczuk, P, Lelental, N, Spitzer, P, Maler, JM, Kornhuber, J. Amyloid-beta 42/40 cerebrospinal fluid concentration ratio in the diagnostics of Alzheimer’s disease: validation of two novel assays. J Alzheimers Dis 2015; 43: 183–91.Google ScholarPubMed
Janelidze, S, Zetterberg, H, Mattsson, N, et al. CSF Abeta42/Abeta40 and Abeta 42/Abeta 38 ratios: better diagnostic markers of Alzheimer disease. Ann Clin Transl Neurol 2016; 3: 154–65.Google Scholar
Sato, C, Barthelemy, NR, Mawuenyega, KG, et al. Tau kinetics in neurons and the human central nervous system. Neuron 2018; 98: 861–4.Google Scholar
Mudher, A, Colin, M, Dujardin, S, et al. What is the evidence that tau pathology spreads through prion-like propagation? Acta Neuropathol Commun 2017; 5: 99.Google Scholar
Skillback, T, Rosen, C, Asztely, F, et al. Diagnostic performance of cerebrospinal fluid total tau and phosphorylated tau in Creutzfeldt–Jakob disease: results from the Swedish Mortality Registry. JAMA Neurol 2014; 71: 476–83.CrossRefGoogle ScholarPubMed
Blennow, K, Hampel, H. CSF markers for incipient Alzheimer’s disease. Lancet Neurol 2003; 2: 605–13.Google Scholar
Hampel, H, Buerger, K, Zinkowski, R, et al. Measurement of phosphorylated tau epitopes in the differential diagnosis of Alzheimer disease: a comparative cerebrospinal fluid study. Arch Gen Psychiatry 2004; 61: 95–102.CrossRefGoogle ScholarPubMed
Hanes, J, Kovac, A, Kvartsberg, H, et al. Evaluation of a novel immunoassay to detect p-tau Thr127 in the CSF to distinguish Alzheimer disease from other dementias. Neurology 2020; 95: e3026–35.Google Scholar
Hesse, C, Rosengren, L, Andreasen, N, et al. Transient increase in total tau but not phospho-tau in human cerebrospinal fluid after acute stroke. Neurosci Lett 2001; 297: 187–90.CrossRefGoogle Scholar
Suarez-Calvet, M, Karikari, TK, Ashton, NJ, et al. Novel tau biomarkers phosphorylated at T181, T217 or T231 rise in the initial stages of the preclinical Alzheimer’s continuum when only subtle changes in Abeta pathology are detected. EMBO Mol Med 2020; 12: e12921.CrossRefGoogle ScholarPubMed
Mattsson-Carlgren, N, Andersson, E, Janelidze, S, et al. Abeta deposition is associated with increases in soluble and phosphorylated tau that precede a positive tau PET in Alzheimer’s disease. Sci Adv 2020; 6: eaaz2387.CrossRefGoogle ScholarPubMed
Meredith, JE Jr., Sankaranarayanan, S, Guss, V, et al. Characterization of novel CSF tau and p-tau biomarkers for Alzheimer’s disease. PloS One 2013; 8: e76523.Google Scholar
Zhang, Z, Song, M, Liu, X, et al. Cleavage of tau by asparagine endopeptidase mediates the neurofibrillary pathology in Alzheimer’s disease. Nat Med 2014; 20: 1254–62.CrossRefGoogle ScholarPubMed
Blennow, K, Chen, C, Cicognola, C, et al. Cerebrospinal fluid tau fragment correlates with tau PET: a candidate biomarker for tangle pathology. Brain 2020; 143: 650–60.CrossRefGoogle ScholarPubMed
Hansson, O, Zetterberg, H, Buchhave, P, et al. Association between CSF biomarkers and incipient Alzheimer’s disease in patients with mild cognitive impairment: a follow-up study. Lancet Neurol 2006; 5: 228–34.Google Scholar
Shaw, LM, Vanderstichele, H, Knapik-Czajka, M, et al. Cerebrospinal fluid biomarker signature in Alzheimer’s Disease Neuroimaging Initiative subjects. Ann Neurol 2009; 65: 403–13.Google Scholar
Kuhlmann, J, Andreasson, U, Pannee, J, et al. CSF Abeta 1–42: an excellent but complicated Alzheimer’s biomarker – a route to standardisation. Clin Chim Acta 2017; 467: 27–33.Google Scholar
Hansson, O, Seibyl, J, Stomrud, E, et al. CSF biomarkers of Alzheimer’s disease concord with amyloid-beta PET and predict clinical progression: a study of fully automated immunoassays in BioFINDER and ADNI cohorts. Alzheimers Dement 2018; 14: 1470–81.Google Scholar
Kaplow, J, Vandijck, M, Gray, J, et al. Concordance of Lumipulse cerebrospinal fluid t-tau/Abeta 42 ratio with amyloid PET status. Alzheimers Dement 2020; 16: 144–52.Google Scholar
Boulo, S, Kuhlmann, J, Andreasson, U, et al. First amyloid beta 1–42 certified reference material for re-calibrating commercial immunoassays. Alzheimers Dement 2020; 16 :1493–503.CrossRefGoogle Scholar
Shaw, LM, Arias, J, Blennow, K, et al. Appropriate use criteria for lumbar puncture and cerebrospinal fluid testing in the diagnosis of Alzheimer’s disease. Alzheimers Dement 2018; 14: 1505–21.Google Scholar
Janelidze, S, Stomrud, E, Palmqvist, S, et al. Plasma beta-amyloid in Alzheimer’s disease and vascular disease. Sci Rep 2016; 6: 26801.Google Scholar
Kaneko, N, Yamamoto, R, Sato, TA, Tanaka, K. Identification and quantification of amyloid beta-related peptides in human plasma using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Proc Jpn Acad Ser B Phys Biol Sci 2014; 90: 104–17.Google Scholar
Pannee, J, Tornqvist, U, Westerlund, A, et al. The amyloid-beta degradation pattern in plasma: a possible tool for clinical trials in Alzheimer’s disease. Neurosci Lett 2014; 573: 7–12.CrossRefGoogle ScholarPubMed
Ovod, V, Ramsey, KN, Mawuenyega, KG, et al. Amyloid beta concentrations and stable isotope labeling kinetics of human plasma specific to central nervous system amyloidosis. Alzheimers Dement 2017; 13: 841–9.Google Scholar
Nakamura, A, Kaneko, N, Villemagne, VL, et al. High performance plasma amyloid-beta biomarkers for Alzheimer’s disease. Nature 2018; 554: 249–54.CrossRefGoogle ScholarPubMed
Schindler, SE, Bollinger, JG, Ovod, V, et al. High-precision plasma beta-amyloid 42/40 predicts current and future brain amyloidosis. Neurology 2019; 93: e1647–59.CrossRefGoogle ScholarPubMed
Palmqvist, S, Mattsson, N, Hansson, O, Alzheimer’s Disease Neuroimaging Initiative. Cerebrospinal fluid analysis detects cerebral amyloid-beta accumulation earlier than positron emission tomography. Brain 2016; 139: 1226–36.Google Scholar
Tatebe, H, Kasai, T, Ohmichi, T, et al. Quantification of plasma phosphorylated tau to use as a biomarker for brain Alzheimer pathology: pilot case–control studies including patients with Alzheimer’s disease and Down syndrome. Mol Neurodegener 2017; 12: 63.Google Scholar
Mielke, MM, Hagen, CE, Xu, J, et al. Plasma phospho-tau 181 increases with Alzheimer’s disease clinical severity and is associated with tau- and amyloid-positron emission tomography. Alzheimers Dement 2018; 14: 989–97.Google Scholar
Thijssen, EH, La Joie, R, Wolf, A, et al. Diagnostic value of plasma phosphorylated tau 181 in Alzheimer’s disease and frontotemporal lobar degeneration. Nat Med 2020; 26: 387–97.CrossRefGoogle ScholarPubMed
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: 379–86.CrossRefGoogle ScholarPubMed
Karikari, TK, Pascoal, TA, Ashton, NJ, et al. Blood phosphorylated tau 181 as a biomarker for Alzheimer’s disease: a diagnostic performance and prediction modelling study using data from four prospective cohorts. Lancet Neurol 2020; 19: 422–33.Google Scholar
Ashton, NJ, Pascoal, TA, Karikari, TK, et al. Plasma p-tau231: a new biomarker for incipient Alzheimer’s disease pathology. Acta Neuropathol 2021; 141: 709–24.Google Scholar
Barthelemy, NR, Horie, K, Sato, C, Bateman, RJ. Blood plasma phosphorylated-tau isoforms track CNS change in Alzheimer’s disease. J Exp Med 2020; 217;DOI: http://doi.org/10.1084/jem.20200861.Google Scholar
Barthelemy, NR, Bateman, RJ, Hirtz, C, et al. Cerebrospinal fluid phospho-tau T217 outperforms T181 as a biomarker for the differential diagnosis of Alzheimer’s disease and PET amyloid-positive patient identification. Alzheimers Res Ther 2020; 12: 26.Google Scholar
Palmqvist, S, Janelidze, S, Quiroz, YT, et al. Discriminative accuracy of plasma phospho-tau 217 for Alzheimer disease vs other neurodegenerative disorders. JAMA 2020; 24: 772–81.Google Scholar
O’Connor, A, Karikari, TK, Poole, T, et al. Plasma phospho-tau 181 in presymptomatic and symptomatic familial Alzheimer’s disease: a longitudinal cohort study. Mol Psychiatry 2020;DOI: https://doi.org/10.1038/s41380-020-0838-x.Google Scholar
Lantero Rodriguez, J, Karikari, TK, Suarez-Calvet, M, et al. Plasma p-tau181 accurately predicts Alzheimer’s disease pathology at least 8 years prior to post-mortem and improves the clinical characterisation of cognitive decline. Acta Neuropathol 2020; 140: 267–78.Google Scholar
Kovacs, GG. Invited review: neuropathology of tauopathies: principles and practice. Neuropathol Appl Neurobiol 2015; 41: 3–23.Google Scholar
Rubenstein, R, Chang, B, Yue, JK, et al. Comparing plasma phospho tau, total tau, and phospho tau–total tau ratio as acute and chronic traumatic brain injury biomarkers. JAMA Neurol 2017; 74: 1063–72.Google Scholar
Palmqvist, S, Insel, PS, Stomrud, E, et al. Cerebrospinal fluid and plasma biomarker trajectories with increasing amyloid deposition in Alzheimer’s disease. EMBO Mol Med 2019; 11: e11170.Google Scholar
Randall, J, Mortberg, E, Provuncher, GK, et al. Tau proteins in serum predict neurological outcome after hypoxic brain injury from cardiac arrest: results of a pilot study. Resuscitation 2013; 84: 351–6.Google Scholar
Zetterberg, H, Wilson, D, Andreasson, U, et al. Plasma tau levels in Alzheimer’s disease. Alzheimers Res Ther 2013; 5: 9.Google Scholar
Mattsson, N, Zetterberg, H, Janelidze, S, et al. Plasma tau in Alzheimer disease. Neurology 2016; 87: 1827–35.Google Scholar
Mattsson, N, Zetterberg, H, Nielsen, N, et al. Serum tau and neurological outcome in cardiac arrest. Ann Neurol 2017; 82: 665–75.Google Scholar
Shahim, P, Tegner, Y, Wilson, DH, et al. Blood biomarkers for brain injury in concussed professional ice hockey players. JAMA Neurol 2014; 71: 684–92.Google Scholar
Vacchi, E, Kaelin-Lang, A, Melli, G. Tau and alpha synuclein synergistic effect in neurodegenerative diseases: when the periphery is the core. Int J Mol Sci 2020; 21: 5030.Google Scholar
Gisslen, M, Price, RW, Andreasson, U, et al. plasma concentration of the neurofilament light protein (NfL) is a biomarker of CNS injury in HIV infection: a cross-sectional study. EBioMedicine 2016; 3: 135–40.CrossRefGoogle ScholarPubMed
Mattsson, N, Andreasson, U, Zetterberg, H, Blennow, K. Association between longitudinal plasma neurofilament light and neurodegeneration in patients with Alzheimer disease. JAMA Neurol 2019; 76: 791–9.Google Scholar
Weston, PSJ, Poole, T, Ryan, NS, et al. Serum neurofilament light in familial Alzheimer disease: a marker of early neurodegeneration. Neurology 2017; 89: 2167–75.Google Scholar
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: 277–83.Google Scholar
Khalil, M, Teunissen, CE, Otto, M, et al. Neurofilaments as biomarkers in neurological disorders. Nat Rev Neurol 2018; 14: 577–89.CrossRefGoogle ScholarPubMed
Schindler, SE, Bollinger, JG, Ovod, V, et al. High-precision plasma beta-amyloid 42/40 predicts current and future brain amyloidosis. Neurology 2019; 93: e1647–59.CrossRefGoogle ScholarPubMed
Hansson, O, Janelidze, S, Hall, S, et al. Blood-based NfL: a biomarker for differential diagnosis of parkinsonian disorder. Neurology 2017; 88: 930–7.Google Scholar
Illan-Gala, I, Lleo, A, Karydas, A, et al. Plasma tau and neurofilament light in frontotemporal lobar degeneration and Alzheimer’s disease. Neurology 2021; 96: e671–83.Google Scholar
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: 1060–9.CrossRefGoogle ScholarPubMed
Hampel, H, O’Bryant, SE, Molinuevo, JL, et al. Blood-based biomarkers for Alzheimer disease: mapping the road to the clinic. Nat Rev Neurol 2018; 14: 639–52.Google Scholar
Karikari, TK, Benedet, AL, Ashton, NJ, et al. Diagnostic performance and prediction of clinical progression of plasma phospho-tau 181 in the Alzheimer’s disease neuroimaging initiative. Mol Psychiatry 2020; 26: 429–42.Google Scholar
Mattke, S, Cho, SK, Bittner, T, Hlavka, J, Hanson, M. Blood-based biomarkers for Alzheimer’s pathology and the diagnostic process for a disease-modifying treatment: projecting the impact on the cost and wait times. Alzheimers Dement (Amst) 2020; 12: e12081.Google Scholar
Beach, TG, Monsell, SE, Phillips, LE, Kukull, W. Accuracy of the clinical diagnosis of Alzheimer disease at National Institute on Aging Alzheimer Disease Centers, 2005–2010. J Neuropathol Exp Neurol 2012; 71: 266–73.Google Scholar
Knopman, DS, DeKosky, ST, Cummings, JL, et al. Practice parameter: diagnosis of dementia (an evidence-based review). Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2001; 56: 1143–53.CrossRefGoogle ScholarPubMed
Portelius, E, Olsson, B, Hoglund, K, et al. Cerebrospinal fluid neurogranin concentration in neurodegeneration: relation to clinical phenotypes and neuropathology. Acta Neuropathol 2018; 136: 363–76.CrossRefGoogle ScholarPubMed
Blennow, K, de Leon, MJ, Zetterberg, H. Alzheimer’s disease. Lancet 2006; 368: 387–403.Google Scholar
Kennedy, ME, Stamford, AW, Chen, X, et al. The BACE1 inhibitor verubecestat (MK-8931) reduces CNS beta-amyloid in animal models and in Alzheimer’s disease patients. Sci Transl Med 2016; 8: 363ra150.Google Scholar
Wessels, AM, Lines, C, Stern, RA, et al. Cognitive outcomes in trials of two BACE inhibitors in Alzheimer’s disease. Alzheimers Dement 2020; 16: 1483–92.CrossRefGoogle ScholarPubMed
Masters, CL, Bateman, R, Blennow, K, et al. Alzheimer’s disease. Nat Rev Dis Primers 2015; 1: 15056.CrossRefGoogle ScholarPubMed
Olsson, B, Alberg, L, Cullen, NC, et al. NfL is a marker of treatment response in children with SMA treated with nusinersen. J Neurol 2019; 266: 2129–36.Google Scholar
Piehl, F, Kockum, I, Khademi, M, et al. Plasma neurofilament light chain levels in patients with MS switching from injectable therapies to fingolimod. Mult Scler 2018; 24: 1046–54.Google Scholar
Blennow, K, Zetterberg, H, Rinne, JO, et al. Effect of immunotherapy with bapineuzumab on cerebrospinal fluid biomarker levels in patients with mild to moderate Alzheimer disease. Arch Neurol 2012; 69: 1002–10.Google Scholar
Ostrowitzki, S, Lasser, RA, Dorflinger, E, et al. A Phase III randomized trial of gantenerumab in prodromal Alzheimer’s disease. Alzheimers Res Ther 2017; 9: 95.Google Scholar
Salloway, S, Sperling, R, Fox, NC, et al. Two Phase 3 trials of bapineuzumab in mild-to-moderate Alzheimer’s disease. N Engl J Med 2014; 370: 322–33.Google Scholar
Tolar, M, Abushakra, S, Hey, JA, Porsteinsson, A, Sabbagh, M. Aducanumab, gantenerumab, BAN2401, and ALZ-801-the first wave of amyloid-targeting drugs for Alzheimer’s disease with potential for near term approval. Alzheimers Res Ther 2020; 12: 95.Google Scholar
Blennow, K, Zetterberg, H, Minthon, L, et al. Longitudinal stability of CSF biomarkers in Alzheimer’s disease. Neurosci Lett 2007; 419: 18–22.CrossRefGoogle ScholarPubMed
Zetterberg, H, Pedersen, M, Lind, K, et al. Intra-individual stability of CSF biomarkers for Alzheimer’s disease over two years. J Alzheimers Dis 2007; 12: 255–60.Google Scholar
Sevigny, J, Chiao, P, Bussiere, T, et al. The antibody aducanumab reduces Abeta plaques in Alzheimer’s disease. Nature 2016; 537: 50–6.CrossRefGoogle ScholarPubMed
Sperling, RA, Jack, CR Jr., Black, SE, et al. Amyloid-related imaging abnormalities in amyloid-modifying therapeutic trials: recommendations from the Alzheimer’s Association Research Roundtable Workgroup. Alzheimers Dement 2011; 7: 367–85.Google Scholar

Save book to Kindle

To save this book to your Kindle, first ensure [email protected] is added to your Approved Personal Document E-mail List under your Personal Document Settings on the Manage Your Content and Devices page of your Amazon account. Then enter the ‘name’ part of your Kindle email address below. Find out more about saving to your Kindle.

Note you can select to save to either the @free.kindle.com or @kindle.com variations. ‘@free.kindle.com’ emails are free but can only be saved to your device when it is connected to wi-fi. ‘@kindle.com’ emails can be delivered even when you are not connected to wi-fi, but note that service fees apply.

Find out more about the Kindle Personal Document Service.

Available formats
×

Save book to Dropbox

To save content items to your account, please confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your account. Find out more about saving content to Dropbox.

Available formats
×

Save book to Google Drive

To save content items to your account, please confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your account. Find out more about saving content to Google Drive.

Available formats
×