Well-authenticated biomarkers can provide critical insights into the biological basis of Alzheimer disease (AD) to enable timely and accurate diagnosis, estimate future burden and support therapeutic trials. Current cerebrospinal fluid and molecular neuroimaging biomarkers fulfil these criteria but lack the scalability and simplicity necessary for widespread application. Blood biomarkers of adequate effectiveness have the potential to act as first-line diagnostic and prognostic tools, and offer the possibility of extensive population screening and use that is not limited to specialized centres. Accelerated progress in our understanding of the biochemistry of brain-derived tau protein and advances in ultrasensitive technologies have enabled the development of AD-specific phosphorylated tau (p-tau) biomarkers in blood. In this Review we discuss how new information on the molecular processing of brain p-tau and secretion of specific fragments into biofluids is informing blood biomarker development, enabling the evaluation of preanalytical factors that affect quantification, and informing harmonized protocols for blood handling. We also review the performance of blood p-tau biomarkers in the context of AD and discuss their potential contexts of use for clinical and research purposes. Finally, we highlight outstanding ethical, clinical and analytical challenges, and outline the steps that need to be taken to standardize inter-laboratory and inter-assay measurements.
Blood p-tau181, p-tau217 and p-tau231 biomarkers that reflect brain tau and amyloid-β (Aβ) pathophysiology have been developed and validated.
The levels of p-tau species in blood increase with increasing Aβ accumulation and clinical severity in individuals with AD; these changes are absent in individuals with cognitive impairment not due to AD.
Blood concentration of p-tau is associated with, and predicts changes in, cerebrospinal fluid (CSF) and PET measures of Aβ, tau and neurodegeneration; ante-mortem blood p-tau concentration predicts definite neuropathological diagnosis several years later, outperforming clinical diagnosis during life.
Blood p-tau has potential uses for definitive and differential diagnosis in specialized care, for prescreening in primary care and therapeutic trials, and for population-based and epidemiological studies.
Future studies in real-world settings (for example, heterogeneous and diverse memory clinic cohorts) will show whether blood p-tau can serve as a stand-alone confirmatory biomarker or replace CSF or PET biomarkers in specific scenarios.
Outstanding challenges such as the need for analytical guidelines, inter-laboratory method comparison and standardization, cut-off value generation and validation, appropriate use criteria for clinical implementation, and consideration of the ethics of direct-to-consumer tests should be addressed to enable accelerated progress.
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The data used to generate the figures in Box 4 are available from the corresponding author on reasonable request. The data can also be directly requested from the Alzheimer’s Disease Neuroimaging Initiative (ADNI, http://adni.loni.usc.edu) and the Translational Biomarkers in Aging and Dementia (TRIAD) cohort, McGill University (https://triad.tnl-mcgill.com/).
Hippius, H. & Neundörfer, G. The discovery of Alzheimer’s disease. Dialogues Clin. Neurosci. 5, 101–108 (2003).
Alzheimer’s Association. 2020 Alzheimer’s disease facts and figures. Alzheimers Dement. 16, 391–460 (2020).
Prince, M. et al. The global prevalence of dementia: a systematic review and metaanalysis. Alzheimers Dement. 9, 63–75 (2013).
Nichols, E. et al. Global, regional, and national burden of Alzheimer’s disease and other dementias, 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol. 18, 88–106 (2019).
GBD 2019 Dementia Forecasting Collaborators Estimation of the global prevalence of dementia in 2019 and forecasted prevalence in 2050: an analysis for the Global Burden of Disease Study 2019. Lancet Public Health 7, e105–e125 (2022).
McKhann, G., Drachman, G., Katzman, R., Price, D. & Stadian, E. M. 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, 939–944 (1984).
Beach, T. G., Monsell, S. E., Phillips, L. E. & Kukull, W. Accuracy of the clinical diagnosis of Alzheimer disease at National Institute on Aging Alzheimer Disease Centers, 2005-2010. J. Neuropathol. Exp. Neurol. 71, 266–273 (2012).
Selvackadunco, S. et al. Comparison of clinical and neuropathological diagnoses of neurodegenerative diseases in two centres from the Brains for Dementia Research (BDR) cohort. J. Neural Transm. 126, 327–337 (2019).
Jack, C. R. et al. NIA-AA Research Framework: Toward a biological definition of Alzheimer’s disease. Alzheimers Dement. 14, 535–562 (2018).
Zetterberg, H. & Blennow, K. Moving fluid biomarkers for Alzheimer’s disease from research tools to routine clinical diagnostics. Mol. Neurodegeneration 16, 10 (2021).
Zetterberg, H. & Blennow, K. Blood biomarkers: democratizing Alzheimer’s diagnostics. Neuron 106, 881–883 (2020).
Ashton, N. J. et al. An update on blood-based biomarkers for non-Alzheimer neurodegenerative disorders. Nat. Rev. Neurol. 16, 265–284 (2020).
DeTure, M. A. & Dickson, D. W. The neuropathological diagnosis of Alzheimer’s disease. Mol. Neurodegeneration 14, 32 (2019).
Nordberg, A., Rinne, J. O., Kadir, A. & Långström, B. The use of PET in Alzheimer disease. Nat. Rev. Neurol. 6, 78–87 (2010).
Blennow, K., Hampel, H., Weiner, M. & Zetterberg, H. Cerebrospinal fluid and plasma biomarkers in Alzheimer disease. Nat. Rev. Neurol. 6, 131–144 (2010).
Strozyk, D., Blennow, K., White, L. R. & Launer, L. J. CSF Aβ 42 levels correlate with amyloid-neuropathology in a population-based autopsy study. Neurology 60, 652–656 (2003).
Hansson, O. et al. Association between CSF biomarkers and incipient Alzheimer’s disease in patients with mild cognitive impairment: a follow-up study. Lancet Neurol. 5, 228–234 (2006).
Fleisher, A. S. et al. Positron emission tomography imaging with [18F]flortaucipir and postmortem assessment of Alzheimer disease neuropathologic changes. JAMA Neurol. 77, 829–839 (2020).
Leuzy, A. et al. 2020 update on the clinical validity of cerebrospinal fluid amyloid, tau, and phospho-tau as biomarkers for Alzheimer’s disease in the context of a structured 5-phase development framework. Eur. J. Nucl. Med. Mol. Imaging 48, 2121–2139 (2021).
Engelborghs, S. et al. Diagnostic performance of a CSF-biomarker panel in autopsy-confirmed dementia. Neurobiol. Aging 29, 1143–1159 (2008).
Seeburger, J. L. et al. Cerebrospinal fluid biomarkers distinguish postmortem-confirmed Alzheimer’s disease from other dementias and healthy controls in the OPTIMA cohort. J. Alzheimers Dis. 44, 525–539 (2015).
Dubois, B. et al. Advancing research diagnostic criteria for Alzheimer’s disease: the IWG-2 criteria. Lancet Neurol. 13, 614–629 (2014).
Dubois, B. et al. Clinical diagnosis of Alzheimer’s disease: recommendations of the International Working Group. Lancet Neurol. 20, 484–496 (2021).
Hampel, H. et al. Blood-based biomarkers for Alzheimer disease: mapping the road to the clinic. Nat. Rev. Neurol. 14, 639–652 (2018).
Day, G. S., Rappai, T., Sathyan, S. & Morris, J. C. Deciphering the factors that influence participation in studies requiring serial lumbar punctures. Alzheimers Dement. 12, e12003 (2020).
Chaudhry, A. & Rizig, M. Comparing fluid biomarkers of Alzheimer’s disease between African American or Black African and white groups: a systematic review and meta-analysis. J. Neurol. Sci. 421, 117270 (2020).
Karikari, T. K., Charway-Felli, A., Höglund, K., Blennow, K. & Zetterberg, H. Commentary: Global, regional, and national burden of neurological disorders during 1990–2015: a systematic analysis for the Global Burden of Disease Study 2015. Front. Neurol. 9, 201 (2018).
Liu, K. Y. & Howard, R. Can we learn lessons from the FDA’s approval of aducanumab? Nat. Rev. Neurol. 17, 715–722 (2021).
Ashton, N. J. et al. The validation status of blood biomarkers of amyloid and phospho-tau assessed with the 5-phase development framework for AD biomarkers. Eur. J. Nucl. Med. Mol. Imaging 48, 2140–2156 (2021). This study reviewed the maturation status of blood p-tau and amyloid biomarkers using a validated five-phase framework.
Skillbäck, T. et al. Cerebrospinal fluid tau and amyloid-β1-42 in patients with dementia. Brain 138, 2716–2731 (2015). This large-scale clinical study demonstrated that CSF p-tau181 is specifically increased in AD, whereas total tau becomes abnormal in several neurodegenerative disorders.
Goedert, M., Wischik, C. M., Crowther, R. A., Walker, J. E. & Klug, A. Cloning and sequencing of the cDNA encoding a core protein of the paired helical filament of Alzheimer disease: identification as the microtubule-associated protein tau. Proc. Natl Acad. Sci. USA 85, 4051–4055 (1988).
Goedert, M. & Jakes, R. Mutations causing neurodegenerative tauopathies. Biochim. Biophys. Acta Mol. Basis Dis. 1739, 240–250 (2005).
Hill, E., Wall, M. J., Moffat, K. G. & Karikari, T. K. Understanding the pathophysiological actions of tau oligomers: a critical review of current electrophysiological approaches. Front. Mol. Neurosci. 13, 155 (2020).
Hanger, D. P., Anderton, B. H. & Noble, W. Tau phosphorylation: the therapeutic challenge for neurodegenerative disease. Trends Mol. Med. 15, 112–119 (2009).
Augustinack, J. C., Schneider, A., Mandelkow, E.-M. & Hyman, B. T. Specific tau phosphorylation sites correlate with severity of neuronal cytopathology in Alzheimer’s disease. Acta Neuropathol. 103, 26–35 (2002).
Braak, H. & Braak, E. Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol. 82, 239–259 (1991).
Barthélemy, N. R. et al. A soluble phosphorylated tau signature links tau, amyloid and the evolution of stages of dominantly inherited Alzheimer’s disease. Nat. Med. 26, 398–407 (2020). This CSF study found that tau phosphorylation in familial AD might be a time-regulated process, with abnormalities becoming evident at different stages of the disease continuum.
Mattsson-Carlgren, N. et al. Aβ deposition is associated with increases in soluble and phosphorylated tau that precede a positive tau PET in Alzheimer’s disease. Sci. Adv. 6, eaaz2387 (2020).
Hanger, D. P. et al. Novel phosphorylation sites in tau from Alzheimer brain support a role for casein kinase 1 in disease pathogenesis. J. Biol. Chem. 282, 23645–23654 (2007).
Hanger, D. P., Betts, J. C., Loviny, T. L. F., Blackstock, W. P. & Anderton, B. H. New phosphorylation sites identified in hyperphosphorylated tau (paired helical filament-tau) from Alzheimer’s disease brain using nanoelectrospray mass spectrometry. J. Neurochem. 71, 2465–2476 (1998).
Lantero-Rodriguez, J. et al. P-tau235: a novel biomarker for staging preclinical Alzheimer’s disease. EMBO Mol. Med. 13, e15098 (2021).
Karikari, T. K. et al. Head-to-head comparison of clinical performance of CSF phospho-tau T181 and T217 biomarkers for Alzheimer’s disease diagnosis. Alzheimers Dement. 17, 755–767 (2021). This study showed that, using new methods of CSF p-tau217 and p-tau181 measurement (measured on N-terminal fragments), levels become abnormal earlier in the AD continuum (in prodromal AD) than if standard CSF p-tau methods (targeting mid-region epitopes) are used.
Suárez-Calvet, M. et al. Novel tau biomarkers phosphorylated at T181, T217 or T231 rise with subtle changes in Aβ pathology. EMBO Mol. Med. 12, e12921 (2020). This was the first study to demonstrate that p-tau181, p-tau217 and p-tau231 biomarkers measured on N-terminal-directed fragments become abnormal very early in individuals with preclinical AD and sub-threshold levels of Aβ pathology.
Hanes, J. et al. Evaluation of a novel immunoassay to detect p-tau Thr217 in the CSF to distinguish Alzheimer disease from other dementias. Neurology 95, e3026–e3035 (2020).
Ashton, N. J. et al. Cerebrospinal fluid p-tau231 as an early indicator of emerging pathology in Alzheimer’s disease. eBiomedicine 76, 103836 (2022). This study showed that CSF p-tau231 becomes abnormal very early in AD, and associates with Aβ pathological changes in early-accumulating regions.
Buerger, K. et al. CSF tau protein phosphorylated at threonine 231 correlates with cognitive decline in MCI subjects. Neurology 59, 627–629 (2002).
Ashton, N. J. et al. Plasma p-tau231: a new biomarker for incipient Alzheimer’s disease pathology. Acta Neuropathol. 141, 709–724 (2021). This article reports the development of a plasma p-tau231 biomarker that detects AD with high accuracy, especially in the preclinical stages.
Karikari, T. K. 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. 19, 422–433 (2020). This article describes the analytical development of a novel blood p-tau181 biomarker on the Simoa platform and its validation in four independent clinical cohorts.
Palmqvist, S. et al. Discriminative accuracy of plasma phospho-tau217 for Alzheimer disease vs other neurodegenerative disorders. JAMA 324, 772–781 (2020). This study showed high diagnostic accuracy of plasma p-tau217 in three independent cohorts.
Mattsson, N. et al. Plasma tau in Alzheimer disease. Neurology 87, 1827–1835 (2016).
Dage, J. L. et al. Levels of tau protein in plasma are associated with neurodegeneration and cognitive function in a population based elderly cohort. Alzheimers Dement. 12, 1226–1234 (2016).
Mielke, M. M. et al. Association of plasma total tau level with cognitive decline and risk of mild cognitive impairment or dementia in the Mayo Clinic Study on Aging. JAMA Neurol. 74, 1073–1080 (2017).
Zetterberg, H. et al. Plasma tau levels in Alzheimer’s disease. Alzheimers Res. Ther. 5, 9 (2013).
Simrén, J. et al. The diagnostic and prognostic capabilities of plasma biomarkers in Alzheimer’s disease. Alzheimers Dement. 17, 1145–1156 (2021). This paper reports the capacity of different blood biomarkers, including plasma p-tau181, for AD diagnosis, prognosis and longitudinal monitoring in the multicentre European AddNeuroMed cohort classified by clinical diagnosis without the use of CSF or PET biomarkers.
Deters, K. D. et al. Plasma tau association with brain atrophy in mild cognitive impairment and Alzheimer’s disease. J. Alzheimers Dis. 58, 1245–1254 (2017).
Pase, M. P. et al. Assessment of plasma total tau level as a predictive biomarker for dementia and related endophenotypes. JAMA Neurol. 76, 598–606 (2019).
Rajan, K. B. et al. Remote blood biomarkers of longitudinal cognitive outcomes in a population study. Ann. Neurol. 88, 1065–1076 (2020).
Barthélemy, N. R., Horie, K., Sato, C. & Bateman, R. J. Blood plasma phosphorylated-tau isoforms track CNS change in Alzheimer’s disease. J. Exp. Med. 217, e20200861 (2020). This study using IP-MS showed that plasma p-tau217 might be a superior AD biomarker to p-tau181; this finding in one cohort was not replicated in another.
Müller, S. et al. Tau plasma levels in subjective cognitive decline: results from the DELCODE study. Sci. Rep. 7, 9529 (2017).
Olivera, A. et al. Peripheral total tau in military personnel who sustain traumatic brain injuries during deployment. JAMA Neurol. 72, 1109–1116 (2015).
Shahim, P. et al. Blood biomarkers for brain injury in concussed professional ice hockey players. JAMA Neurol. 71, 684–692 (2014).
Neselius, S. et al. Olympic boxing is associated with elevated levels of the neuronal protein tau in plasma. Brain Inj. 27, 425–433 (2013).
Rubenstein, R. et al. Comparing plasma phospho tau, total tau, and phospho tau–total tau ratio as acute and chronic traumatic brain injury biomarkers. JAMA Neurol. 74, 1063–1072 (2017). The is the first study to show that plasma p-tau231 is increased in traumatic brain injury.
Thompson, A. G. B. et al. Evaluation of plasma tau and neurofilament light chain biomarkers in a 12-year clinical cohort of human prion diseases. Mol. Psychiatry 26, 5955–5966 (2021).
Chen, Z. et al. Learnings about the complexity of extracellular tau aid development of a blood-based screen for Alzheimer’s disease. Alzheimers Dement. 15, 487–496 (2018). This article discusses the development of immunoassays targeting different regions of tau in CSF and plasma, and describes the NT1 total-tau method.
Chhatwal, J. P. et al. Plasma N-terminal tau fragment levels predict future cognitive decline and neurodegeneration in healthy elderly individuals. Nat. Commun. 11, 6024 (2020).
Mengel, D. et al. Plasma NT1 tau is a specific and early marker of Alzheimer’s disease. Ann. Neurol. 88, 878–892 (2020).
Snellman, A. et al. N-terminal and mid-region tau fragments as fluid biomarkers in neurological diseases. Brain https://doi.org/10.1093/brain/awab481 (2022).
Guillozet-Bongaarts, A. L. et al. Tau truncation during neurofibrillary tangle evolution in Alzheimer’s disease. Neurobiol. Aging 26, 1015–1022 (2005).
Zhang, Q., Zhang, X. & Sun, A. Truncated tau at D421 is associated with neurodegeneration and tangle formation in the brain of Alzheimer transgenic models. Acta Neuropathol. 117, 687–697 (2009).
Zhang, Z. et al. Cleavage of tau by asparagine endopeptidase mediates the neurofibrillary pathology in Alzheimer’s disease. Nat. Med. 20, 1254–1262 (2014).
Gu, J. et al. Truncation of tau selectively facilitates its pathological activities. J. Biol. Chem. 295, 13812–13828 (2020).
Koss, D. J. et al. Soluble pre-fibrillar tau and β-amyloid species emerge in early human Alzheimer’s disease and track disease progression and cognitive decline. Acta Neuropathol. 132, 875–895 (2016).
Han, P. et al. A quantitative analysis of brain soluble tau and the tau secretion factor. J. Neuropathol. Exp. Neurol. 76, 44–51 (2017).
Sato, C. et al. Tau kinetics in neurons and the human central nervous system. Neuron 97, 1284–1298 (2018). This article describes the production and turnover of tau in living humans and induced pluripotent stem cell-derived neuronal cells.
Mattsson, N. et al. 18F-AV-1451 and CSF T-tau and P-tau as biomarkers in Alzheimer’s disease. EMBO Mol. Med. 9, 1212–1223 (2017).
Blennow, K. et al. Tau protein in cerebrospinal fluid: a biochemical marker for axonal degeneration in Alzheimer disease? Mol. Chem. Neuropathol. 26, 231–245 (1995). This was the first study to develop and validate the clinical performance of p-tau and total tau immunoassays for use in CSF (targeting the middle portion of the protein).
Vanderstichele, H. et al. Analytical performance and clinical utility of the INNOTEST PHOSPHO-TAU181P assay for discrimination between Alzheimer’s disease and dementia with Lewy bodies. Clin. Chem. Lab. Med. 44, 1472–1480 (2006).
Leitão, M. J. et al. Clinical validation of the Lumipulse G cerebrospinal fluid assays for routine diagnosis of Alzheimer’s disease. Alzheimers Res. Ther. 11, 91 (2019).
Lifke, V. et al. Elecsys® total-tau and phospho-tau (181P) CSF assays: analytical performance of the novel, fully automated immunoassays for quantification of tau proteins in human cerebrospinal fluid. Clin. Biochem. 72, 30–38 (2019).
Meredith, J. E. Jr et al. Characterization of novel CSF tau and ptau biomarkers for Alzheimer’s disease. PLoS ONE 8, e76523 (2013).
Cicognola, C. et al. Novel tau fragments in cerebrospinal fluid: relation to tangle pathology and cognitive decline in Alzheimer’s disease. Acta Neuropathol. 137, 279–296 (2018).
Basurto-Islas, G. et al. Accumulation of aspartic acid421- and glutamic acid391-cleaved tau in neurofibrillary tangles correlates with progression in Alzheimer disease. J. Neuropathol. Exp. Neurol. 67, 470–483 (2008).
Fitzpatrick, A. W. P. et al. Cryo-EM structures of tau filaments from Alzheimer’s disease. Nature 547, 185–190 (2017).
Li, W. & Lee, V. M.-Y. Characterization of two VQIXXK motifs for tau fibrillization in vitro. Biochemistry 45, 15692–15701 (2006).
Karikari, T. K., Thomas, R. & Moffat, K. G. The C291R tau variant forms different types of protofibrils. Front. Mol. Neurosci. 13, 39 (2020).
Karikari, T. K. et al. Distinct conformations, aggregation and cellular internalization of different tau strains. Front. Cell. Neurosci. 13, 296 (2019).
Bergen, Mvon et al. Assembly of τ protein into Alzheimer paired helical filaments depends on a local sequence motif (306VQIVYK311) forming β structure. Proc. Natl Acad. Sci. USA 97, 5129–5134 (2000).
Lathuilière, A. et al. Motifs in the tau protein that control binding to microtubules and aggregation determine pathological effects. Sci. Rep. 7, 13556 (2017).
Horie, K., Barthélemy, N. R., Sato, C. & Bateman, R. J. CSF tau microtubule binding region identifies tau tangle and clinical stages of Alzheimer’s disease. Brain 144, 515–527 (2020).
Blennow, K. et al. Cerebrospinal fluid tau fragment correlates with tau PET: a candidate biomarker for tangle pathology. Brain 143, 650–660 (2020). This is the first study to demonstrate that tau truncation at amino acid 368 is a potential biomarker of AD in CSF.
Dujardin, S. et al. Tau molecular diversity contributes to clinical heterogeneity in Alzheimer’s disease. Nat. Med. 26, 1256–1263 (2020).
Rubenstein, R. et al. A novel, ultrasensitive assay for tau: potential for assessing traumatic brain injury in tissues and biofluids. J. Neurotrauma 32, 342–352 (2014).
Shekhar, S. et al. Estimation of tau and phosphorylated tau181 in serum of Alzheimer’s disease and mild cognitive impairment patients. PLoS ONE 11, e0159099 (2016).
Yang, C.-C. et al. Assay of plasma phosphorylated tau protein (threonine 181) and total tau protein in early-stage Alzheimer’s disease. J. Alzheimers Dis. 61, 1323–1332 (2018). This paper presents the analytical development and clinical validation of the IMR p-tau181 method.
Tatebe, H. 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. 12, 63 (2017). This article describes a Simoa plasma p-tau181 method developed by changing one of the antibodies in the commercial total-tau kit to a p-tau181-specific antibody.
Mielke, M. M. et al. Plasma phospho-tau181 increases with Alzheimer’s disease clinical severity and is associated with tau- and amyloid-positron emission tomography. Alzheimers Dement. 14, 989–997 (2018). This is the first report on the Eli Lilly plasma p-tau181 method, showing disease-associated increases that correlate with in vivo tau and Aβ deposition.
Janelidze, 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. 26, 379–386 (2020). This study validated the diagnostic value of plasma p-tau181 as an AD biomarker in the BioFINDER cohort and a neuropathology cohort, using the Eli Lilly plasma p-tau181 assay.
Thijssen, E. H. et al. Diagnostic value of plasma phosphorylated tau181 in Alzheimer’s disease and frontotemporal lobar degeneration. Nat. Med. 26, 387–397 (2020). This study showed the potential of plasma p-tau181 for differential diagnosis of AD versus frontotemporal dementia, another tauopathy.
O’Connor, A. et al. Plasma phospho-tau181 in presymptomatic and symptomatic familial Alzheimer’s disease: a longitudinal cohort study. Mol. Psychiatry 26, 5967–5976 (2020). This study showed that plasma p-tau181 is increased in presymptomatic and asymptomatic individuals with familial AD compared with non-carrier control individuals.
Karikari, T. K. et al. Diagnostic performance and prediction of clinical progression of plasma phospho-tau181 in the Alzheimer’s Disease Neuroimaging Initiative. Mol. Psychiatry 26, 429–442 (2021). This multicentre study in the ADNI cohort showed that plasma p-tau181 (using the Gothenburg assay) is increased in prodromal AD and AD dementia according to Aβ accumulation, and predicts longitudinal disease-related changes.
Lantero Rodriguez, J. 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. 140, 267–278 (2020). This study showed that plasma p-tau181 is increased at least 8 years before death in AD and mixed AD, associates better with pathological diagnosis than clinical diagnosis during life, and separates individuals with AD from control individuals and individuals with non-AD neurodegenerative diseases.
Benussi, A. et al. Diagnostic and prognostic value of serum NfL and p-Tau181 in frontotemporal lobar degeneration. J. Neurol. Neurosurg. Psychiatry 91, 960–967 (2020). This study showed that serum p-tau181 has limited diagnostic value in FTLD compared with the global neurodegeneration marker NfL.
Moscoso, A. et al. Time course of phosphorylated-tau181 in blood across the Alzheimer’s disease spectrum. Brain 144, 325–339 (2020). This article describes the natural evolution of plasma p-tau181 across the AD continuum and how the dynamic changes in this biomarker compare with established CSF and PET biomarkers.
Moscoso, A. et al. Longitudinal associations of blood phosphorylated Tau181 and neurofilament light chain with neurodegeneration in Alzheimer disease. JAMA Neurol. 78, 396–406 (2021). This study showed that longitudinal changes in plasma p-tau181 are associated specifically with AD-related brain changes, whereas plasma NfL is associated with general degenerative features.
Brickman, A. M. et al. Plasma p-tau181, p-tau217, and other blood-based Alzheimer’s disease biomarkers in a multi-ethnic, community study. Alzheimers Dement. 17, 1353–1364 (2021). This article describes and compares plasma biomarker profiles in different ethnicities in the USA.
Zettergren, A. et al. Association between polygenic risk score of Alzheimer’s disease and plasma phosphorylated tau in individuals from the Alzheimer’s Disease Neuroimaging Initiative. Alzheimers Res. Ther. 13, 17 (2021). This article reports associations between AD polygenic risk scores and plasma p-tau concentrations.
Clark, C. et al. Plasma neurofilament light and phosphorylated tau 181 as biomarkers of Alzheimer’s disease pathology and clinical disease progression. Alzheimers Res. Ther. 13, 65 (2021).
Tissot, C. et al. Plasma pTau181 predicts cortical brain atrophy in aging and Alzheimer’s disease. Alzheimers Res. Ther. 13, 69 (2021). This study showed that longitudinal changes in plasma p-tau181 are associated with cortical atrophy.
Chong, J. R. et al. Plasma P-tau181 to Aβ42 ratio is associated with brain amyloid burden and hippocampal atrophy in an Asian cohort of Alzheimer’s disease patients with concomitant cerebrovascular disease. Alzheimers Dement. 17, 1649–1662 (2021). In this study in a Singaporean cohort with high incidence of vascular disease, plasma p-tau181 concentration and the p-tau181 to Aβ42 ratio were associated with amyloidosis and atrophy.
Lussier, F. Z. et al. Plasma levels of phosphorylated tau 181 are associated with cerebral metabolic dysfunction in cognitively impaired and amyloid-positive individuals. Brain Commun. 3, fcab073 (2021).
Mielke, M. M. et al. Comparison of plasma phosphorylated tau species with amyloid and tau positron emission tomography, neurodegeneration, vascular pathology, and cognitive outcomes. JAMA Neurol. 78, 1108–1117 (2021). This head-to-head comparison study showed that p-tau181, p-tau217 and p-tau231 biomarkers from different laboratories and companies have the same ability to identify elevated brain Aβ and tau levels.
Chatterjee, P., Pedrini, S. & Ashton, N. J. Diagnostic and prognostic plasma biomarkers for preclinical Alzheimer’s disease. Alzheimers Dement. https://doi.org/10.1002/alz.12447 (2021).
Alcolea, D. et al. Use of plasma biomarkers for AT(N) classification of neurodegenerative dementias. J. Neurol. Neurosurg. Psychiatry 92, 1206–1214 (2021).
Bejanin, A. et al. Association of apolipoprotein E ɛ4 allele with clinical and multimodal biomarker changes of Alzheimer disease in adults with Down syndrome. JAMA Neurol. 78, 937–947 (2021).
Lleó, A. et al. Phosphorylated tau181 in plasma as a potential biomarker for Alzheimer’s disease in adults with Down syndrome. Nat. Commun. 12, 4304 (2021). This study demonstrated the diagnostic and prognostic utility of plasma p-tau181 in a large cohort of participants with Down syndrome.
Smirnov, D. S. et al. Plasma biomarkers for Alzheimer’s disease in relation to neuropathology and cognitive change. Acta Neuropathol. 143, 487–503 (2022). This article describes the time course of plasma biomarkers in a cohort with post-mortem-verified diagnosis.
Meyer, P.-F. et al. Plasma p-tau231, p-tau181, PET biomarkers, and cognitive change in older adults. Ann. Neurol. 91, 548–560 (2022).
Moscoso, A. et al. CSF biomarkers and plasma p-tau181 as predictors of longitudinal tau accumulation: implications for clinical trial design. Alzheimers Dement. https://doi.org/10.1002/alz.12570 (2022).
Tissot, C. et al. Comparing tau status determined via plasma pTau181, pTau231 and [18F]MK6240 tau-PET. eBioMedicine 76, 103837 (2022).
Janelidze, S. et al. Cerebrospinal fluid p-tau217 performs better than p-tau181 as a biomarker of Alzheimer’s disease. Nat. Commun. 11, 1683 (2020).
Triana-Baltzer, G. et al. Development and validation of a high-sensitivity assay for measuring p217 + tau in plasma. Alzheimers Dement. 13, e12204 (2021).
Triana-Baltzer, G. et al. Development and validation of a high sensitivity assay for measuring p217 + tau in cerebrospinal fluid. J. Alzheimers Dis. 77, 1417–1430 (2020).
Bayoumy, S. et al. Clinical and analytical comparison of six Simoa assays for plasma P-tau isoforms P-tau181, P-tau217, and P-tau231. Alzheimers Res. Ther. 13, 198 (2021).
Montoliu-Gaya, L. et al. Simultaneous measurement of site-specific tau phosphorylations in blood for early and accurate diagnosis of Alzheimer´s disease [abstract P404/#423]. Presented at the 15th International Conference on Alzheimer’s and Parkinson’s Diseases and Related Neurological Disorders. https://adpd.kenes.com/wp-content/uploads/sites/102/2021/03/ADPD21-posters-7th-march-edited.pdf (2021).
Ashton, N. J. et al. Effects of pre-analytical procedures on blood biomarkers for Alzheimer pathophysiology, glial activation and neurodegeneration. Alzheimers Dement. 13, e12168 (2021). This article presents pre-analytical factors that affect blood p-tau measurement and quantification in different matrices and conditions.
Verberk, I. M. W. et al. Characterization of pre-analytical sample handling effects on a panel of Alzheimer’s disease-related blood-based biomarkers: results from the Standardization of Alzheimer’s Blood Biomarkers (SABB) working group. Alzheimers Dement. https://doi.org/10.1002/alz.12510 (2021). This study investigated pre-analytical factors for blood sample handling in biomarker assessments, and presents recommended guidelines for other investigators.
Jonaitis, E. M. et al. Crosswalk study on blood collection-tube types for Alzheimer’s disease biomarkers. Alzheimers Dement. 14, e12266 (2022).
Sperling, R. A. et al. Toward defining the preclinical stages of Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement. 7, 280–292 (2011).
Keshavan, A. et al. Population-based blood screening for preclinical Alzheimer’s disease in a British birth cohort at age 70. Brain 144, 434–449 (2021). This article describes the utility of plasma p-tau181 and IP-MS Aβ for preclinical population screening in a British birth cohort, and presents a simulation of the financial, time and logistic benefits of pre-screening with plasma biomarkers to identify Aβ-positive individuals.
Grothe, M. J. et al. Associations of fully automated CSF and novel plasma biomarkers with Alzheimer disease neuropathology at autopsy. Neurology 97, e1229–e1242 (2021). This study demonstrated that CSF and plasma p-tau181 levels reflect AD neuropathological changes in autopsied brain tissues.
Thijssen, E. H. 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. 20, 739–752 (2021). This study showed that plasma p-tau217 and p-tau181 are interchangeable for the differential diagnosis of autopsy-verified AD versus other tauopathies.
Mattsson-Carlgren, N. et al. Longitudinal plasma p-tau217 is increased in early stages of Alzheimer’s disease. Brain 143, 3234–3241 (2020). This study investigated the longitudinal profiles of plasma p-tau217 and their association with brain amyloid, tau and neurodegeneration in the BioFINDER study.
Shen, X.-N. et al. Plasma amyloid, tau, and neurodegeneration biomarker profiles predict Alzheimer’s disease pathology and clinical progression in older adults without dementia. Alzheimers Dement 12, e12104 (2020).
Simrén, J., Ashton, N. J., Blennow, K. & Zetterberg, H. Blood neurofilament light in remote settings: alternative protocols to support sample collection in challenging pre-analytical conditions. Alzheimers Dement 13, e12145 (2021). This study showed that NfL levels in blood samples processed with alternative protocols similar to those in settings without immediate access to basic haematology facilities (for example, delayed centrifugation, dry blood spots, etc.) concord almost perfectly with those in samples processed as normal (standard of truth).
Cullen, N. C. et al. Individualized prognosis of cognitive decline and dementia in mild cognitive impairment based on plasma biomarker combinations. Nat. Aging 1, 114–123 (2021). This study showed that integrating plasma p-tau and neurodegeneration abnormality data can provide individualized longitudinal prognostic trajectories.
Chételat, G. et al. Amyloid imaging in cognitively normal individuals, at-risk populations and preclinical Alzheimer’s disease. NeuroImage Clin. 2, 356–365 (2013).
Janelidze, S. et al. Associations of plasma phospho-Tau217 levels with tau positron emission tomography in early Alzheimer disease. JAMA Neurol. 78, 149–156 (2021). This study pointed to the likelihood that plasma p-tau levels become abnormal ahead of tau PET in AD.
Nakamura, A. et al. High performance plasma amyloid-β biomarkers for Alzheimer’s disease. Nature 554, 249–254 (2018).
Schindler, S. E. et al. High-precision plasma β-amyloid 42/40 predicts current and future brain amyloidosis. Neurology 93, e1647–e1659 (2019).
Benedet, A. L. et al. The accuracy and robustness of plasma biomarker models for amyloid PET positivity. Alzheimers Res. Ther. 14, 26 (2022).
Janelidze, S. et al. Head-to-head comparison of 8 plasma amyloid-β 42/40 assays in Alzheimer disease. JAMA Neurol. 78, 1375–1382 (2021).
Mattsson-Carlgren, N. et al. Soluble P-tau217 reflects amyloid and tau pathology and mediates the association of amyloid with tau. EMBO Mol. Med. 13, e14022 (2021). This study showed that plasma p-tau217 is associated with amyloid pathology in early AD and tau pathology in advanced stages, and modulates the relationship between amyloid and tau in vivo.
Barthélemy, N. R. 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. 12, 26 (2020).
Emeršič, A. et al. CSF phosphorylated tau-217 is increased in Alzheimer’s and Creutzfeldt-Jakob diseases and correlates with amyloid pathology. Alzheimers Dement. 16, e045296 (2020).
Palmqvist, S. et al. Prediction of future Alzheimer’s disease dementia using plasma phospho-tau combined with other accessible measures. Nat. Med. 27, 1034–1042 (2021). This study showed that plasma p-tau217 or p-tau181 in combination with brief cognitive testing and APOE ε4 genotyping has high capacity for the prediction of future AD dementia.
Liu, F., Iqbal, K., Grundke-Iqbal, I. & Gong, C.-X. Involvement of aberrant glycosylation in phosphorylation of tau by cdk5 and GSK-3β. FEBS Lett. 530, 209–214 (2002).
Liu, F. et al. PKA modulates GSK-3β- and cdk5-catalyzed phosphorylation of tau in site- and kinase-specific manners. FEBS Lett. 580, 6269–6274 (2006).
Doré, V. et al. Plasma p217+tau vs NAV4694 amyloid and MK6240 tau PET across the Alzheimer continuum. Alzheimers Dement 14, e12307 (2022). This study validated the Janssen plasma p-tau217 assay in individuals characterized by amyloid and tau PET.
Shcherbinin, S. & Andersen, S. W. TRAILBLAZER-ALZ study: dynamics of amyloid reduction after donanemab treatment. Alzheimers Dement. 17, e057492 (2021).
Leuzy, A. et al. Biomarker-based prediction of longitudinal tau positron emission tomography in Alzheimer disease. JAMA Neurol. 79, 149–158 (2022).
Ryan, J., Fransquet, P., Wrigglesworth, J. & Lacaze, P. Phenotypic heterogeneity in dementia: a challenge for epidemiology and biomarker studies. Front. Public Health 6, 181 (2018).
Andreasson, U. et al. A practical guide to immunoassay method validation. Front. Neurol. 6, 179 (2015).
Paskett, E. D. et al. Recruitment of minority and underserved populations in the United States: the Centers for Population Health and Health Disparities experience. Contemp. Clin. Trials 29, 847–861 (2008).
Wilkins, C. H., Schindler, S. E. & Morris, J. C. Addressing health disparities among minority populations: why clinical trial recruitment is not enough. JAMA Neurol. 77, 1063–1064 (2020).
Morris, J. C. et al. Assessment of racial disparities in biomarkers for Alzheimer disease. JAMA Neurol. 76, 264–273 (2019).
Schindler, S. E. et al. Effect of race on prediction of brain amyloidosis by plasma Aβ42/Aβ40, phosphorylated tau, and neurofilament light. Neurology https://doi.org/10.1212/WNL.0000000000200358 (2022).
Kaeser, S. A. et al. CSF p-tau increase in response to Aβ-type and Danish-type cerebral amyloidosis and in the absence of neurofibrillary tangles. Acta Neuropathol. 143, 287–290 (2022). This study showed that p-tau217 and p-tau181 are increased in the CSF of mouse models overexpressing different forms of amyloid in the absence of tangle formation.
Kitaguchi, N. et al. Influx of tau and amyloid-β proteins into the blood during hemodialysis as a therapeutic extracorporeal blood amyloid-β removal system for Alzheimer’s disease. J. Alzheimers Dis. 69, 687–707 (2019).
Nho, K. et al. Association of altered liver enzymes with Alzheimer disease diagnosis, cognition, neuroimaging measures, and cerebrospinal fluid biomarkers. JAMA Netw. Open 2, e197978 (2019).
Portelius, E. et al. Ex vivo 18O-labeling mass spectrometry identifies a peripheral amyloid β clearance pathway. Mol. Neurodegeneration 12, 18 (2017).
Mably, A. J. et al. Anti-Aβ antibodies incapable of reducing cerebral Aβ oligomers fail to attenuate spatial reference memory deficits in J20 mice. Neurobiol. Dis. 82, 372–384 (2015).
Sato, C. et al. MAPT R406W increases tau T217 phosphorylation in absence of amyloid pathology. Ann. Clin. Transl. Neurol. 8, 1817–1830 (2021).
Feinstein, I. et al. Plasma biomarkers of tau and neurodegeneration during major cardiac and noncardiac surgery. JAMA Neurol. 78, 1407–1409 (2021).
Largent, E. A., Wexler, A. & Karlawish, J. The future is p-tau–anticipating direct-to-consumer Alzheimer’s disease blood tests. JAMA Neurol. 78, 379–380 (2021).
Tillerås, K. H., Kjoelaas, S. H., Dramstad, E., Feragen, K. B. & von der Lippe, C. Psychological reactions to predictive genetic testing for Huntington’s disease: a qualitative study. J. Genet. Couns. 29, 1093–1105 (2020).
Goldman, J. et al. Predictive testing for neurodegenerative diseases in the age of next-generation sequencing. J. Genet. Couns. 30, 553–562 (2021).
Hampel, H. et al. Developing the ATX(N) classification for use across the Alzheimer disease continuum. Nat. Rev. Neurol. 17, 580–589 (2021).
Pascoal, T. A. et al. 18F-MK-6240 PET for early and late detection of neurofibrillary tangles. Brain 143, 2818–2830 (2020).
Leuzy, A. et al. Diagnostic performance of RO948 F 18 tau positron emission tomography in the differentiation of Alzheimer disease from other neurodegenerative disorders. JAMA Neurol. 77, 955–965 (2020).
Hansson, O., Lehmann, S., Otto, M., Zetterberg, H. & Lewczuk, P. Advantages and disadvantages of the use of the CSF amyloid β (Aβ) 42/40 ratio in the diagnosis of Alzheimer’s disease. Alzheimers Res. Ther. 11, 34 (2019).
Lewczuk, P. et al. Cerebrospinal fluid Aβ 42/40 corresponds better than Aβ 42 to amyloid PET in Alzheimer’s disease. J. Alzheimers Dis. 55, 813–822 (2017).
Palmqvist, S., Mattsson, N. & Hansson, O. Cerebrospinal fluid analysis detects cerebral amyloid-β accumulation earlier than positron emission tomography. Brain 139, 1226–1236 (2016).
Mattsson, N., Palmqvist, S., Stomrud, E., Vogel, J. & Hansson, O. Staging β-amyloid pathology with amyloid positron emission tomography. JAMA Neurol. 76, 1319–1329 (2019).
Schindler, S. E. et al. Cerebrospinal fluid biomarkers measured by Elecsys assays compared to amyloid imaging. Alzheimers Dement. 14, 1460–1469 (2018).
Wittenberg, R., Knapp, M., Karagiannidou, M., Dickson, J. & Schott, J. M. Economic impacts of introducing diagnostics for mild cognitive impairment Alzheimer’s disease patients. Alzheimers Dement. 5, 382–387 (2019).
Soleimani-Meigooni, D. N. et al. 18F-flortaucipir PET to autopsy comparisons in Alzheimer’s disease and other neurodegenerative diseases. Brain 143, 3477–3494 (2020).
Schöll, M. et al. PET imaging of tau deposition in the aging human brain. Neuron 89, 971–982 (2016).
Delaby, C. et al. Development and validation of dried matrix spot sampling for the quantitative determination of amyloid β peptides in cerebrospinal fluid. Clin. Chem. Lab. Med. 52, 649–655 (2013).
T.K.K. was funded by the Swedish Research Council (Vetenskapsrådet #2021-03244), an Alzheimer’s Association Research Fellowship (#AARF-21-850325), the BrightFocus Foundation (#A2020812F), an International Society for Neurochemistry’s Career Development Grant, the Swedish Alzheimer Foundation (Alzheimerfonden; #AF-930627), the Swedish Brain Foundation (Hjärnfonden; #FO2020-0240), the Swedish Dementia Foundation (Demensförbundet), the Swedish Parkinson Foundation (Parkinsonfonden), the Gamla Tjänarinnor Foundation, the Aina (Ann) Wallströms and Mary-Ann Sjöbloms Foundation, the Agneta Prytz-Folkes & Gösta Folkes Foundation (#2020-00124), the Gun and Bertil Stohnes Foundation, and the Anna Lisa and Brother Björnsson’s Foundation. N.J.A. was supported by the Swedish Alzheimer Foundation (Alzheimerfonden; #AF-931009), Hjärnfonden and the Swedish Dementia Foundation (Demensförbundet). M.S.-C. receives funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (grant agreement no. 948677); the Instituto de Salud Carlos III (PI19/00155); and the Spanish Ministry of Science, Innovation and Universities (Juan de la Cierva Programme grant IJC2018-037478-I). H.Z. is a Wallenberg Scholar supported by grants from the Swedish Research Council (#2018-02532), the European Research Council (#681712), Swedish State Support for Clinical Research (#ALFGBG-720931), the Alzheimer Drug Discovery Foundation (ADDF), USA (#201809-2016862), and the UK Dementia Research Institute at University College London. K.B. is supported by the Swedish Research Council (#2017-00915), the Alzheimer Drug Discovery Foundation (ADDF), USA (#RDAPB-201809-2016615), the Swedish Alzheimer Foundation (#AF-742881), Hjärnfonden, Sweden (#FO2017-0243), the Swedish state under the agreement between the Swedish government and the County Councils, the ALF-agreement (#ALFGBG-715986), and the European Union Joint Programme on Neurodegenerative Disease Research (JPND2019-466-236). The funders had no role in data collection, analysis or decision to publish.
H.Z. has served on scientific advisory boards for CogRx, Denali, Pinteon Therapeutics, Roche Diagnostics, Samumed, Siemens Healthineers and Wave, and has given lectures in symposia sponsored by Alzecure, Biogen and Fujirebio. H.Z. is also a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program (outside submitted work). K.B. has served as a consultant, on advisory boards, or on data monitoring committees for Abcam, Axon, Biogen, Julius Clinical, Lilly, MagQu, Novartis, Roche Diagnostics and Siemens Healthineers, and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program (outside submitted work). M.S.-C. has served as a consultant and on advisory boards for Roche Diagnostics International Ltd and has given lectures in symposia sponsored by Roche Diagnostics, S.L.U and Roche Farma, S.A. The other authors report no competing interests.
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Part of a whole; for example, the soluble and insoluble parts of tau together form the pool of tau in the brain.
Peptides generated after a longer peptide or protein is incubated with the enzyme trypsin, to cleave the molecule at the amino acids lysine or arginine except when followed by a proline.
- Single molecule array (Simoa)
An ultrasensitive immunoassay technology platform that allows small quantities of target analytes to be detected in biological fluids (for example, blood) that are remote from the brain.
- Ethylenediaminetetraacetic acid (EDTA)-plasma
A clear component of blood obtained by collecting whole blood into a tube containing a known concentration of the chelating agent and anticoagulant EDTA for a defined amount of time and centrifuging the mixture to separate the upper layer of plasma from the heavier cellular components.
Blood matrix prepared by adding a clotting-preventing citrate compound to whole blood for a fixed amount of time, and centrifuging to separate the clear liquid layer from the cellular material.
The clear liquid component of blood obtained by adding heparin salt anticoagulant to whole blood to induce the separation of the upper layer of interest from the more dense cellular components.
The state of having abnormal levels of amyloid plaques in the brain, as determined at autopsy or measured in vivo using Aβ PET or the CSF Aβ1–42 to Aβ1–40 ratio.
The state of having normal amounts of amyloid plaques in the brain, either determined post mortem or analysed using Aβ PET or the CSF Aβ1–42 to Aβ1–40 ratio according to predefined thresholds.
- Round-robin studies
Interlaboratory studies in which the same tests are independently performed at multiple centres or laboratories on identical samples and the results compared to assess variability of the assay.
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Karikari, T.K., Ashton, N.J., Brinkmalm, G. et al. Blood phospho-tau in Alzheimer disease: analysis, interpretation, and clinical utility. Nat Rev Neurol (2022). https://doi.org/10.1038/s41582-022-00665-2