Time course of phosphorylated-tau181 in blood across the Alzheimer’s disease spectrum

Moscoso, Alexis; Grothe, Michel J.; Ashton, Nicholas J.; Karikari, Thomas K.; Lantero‐Rodriguez, Juan; Snellman, Anniina; Suárez‐Calvet, Marc; Zetterberg, Henrik; Blennow, Kaj; Schöll, Michael; Initiative, Alzheimer’s Disease Neuroimaging

doi:10.1093/brain/awaa399

Cited by 159 publications

(175 citation statements)

References 72 publications

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“…We also noticed that participants in A-T-N- and A-T-N + showed elevating levels of plasma p-tau181. The analysis of longitudinal trajectories of plasma p-tau181 by Moscoso A might explained it as they found earliest elevations of plasma p-tau181 levels occurred before PET and CSF biomarkers of amyloid reached their respective abnormality thresholds [ 25 ]. Small sample sizes of certain groups (e.g.…”

Section: Discussionmentioning

confidence: 99%

Longitudinal plasma phosphorylated tau 181 tracks disease progression in Alzheimer’s disease

et al. 2021

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To assess plasma phosphorylated tau181 (p-tau181) as a progression biomarker in Alzheimer’s disease (AD), we examined longitudinal plasma p-tau181 of 1184 participants (403 cognitively normal (CN), 560 patients with mild cognitive impairment (MCI), and 221 with AD dementia) from Alzheimer’s Disease Neuroimaging Initiative (ADNI). The plasma p-tau level was increased at baseline for MCI and AD dementia (mean: CN, 15.4 pg/mL; MCI, 18.4 pg/mL; AD dementia, 23.7 pg/mL; P < 0.001) and increased significantly over time at preclinical (Aβ-positive CN), prodromal (Aβ-positive MCI), and dementia (Aβ-positive dementia) stage of AD. A longitudinal increase of plasma p-tau181 was associated with abnormal cerebrospinal fluid biomarker levels (low Aβ42, high phosphorylated tau, and high total tau, all P < 0.001), amyloid accumulation (P < 0.001) and hypometabolism (P = 0.002) on positron emission tomography, atrophy in structure imaging (small hippocampal (P = 0.030), middle temporal (P = 0.008), and whole brain (P = 0.027) volume, and large ventricular volume (P = 0.008)), and deteriorated cognitive performance (global cognition and memory, language, executive function, and visuospatial function, all P < 0.050) at baseline. Furthermore, longitudinal plasma p-tau181 correlated with concurrent changes of nearly all these AD-related hallmarks and faster increase in plasma p-tau181 correlated with faster worsening cognition in all diagnostic groups. Importantly, most associations remained significant in Aβ-positive group and became non-significant in Aβ-negative group. Longitudinal analyses of plasma p-tau181 suggest its potential as a noninvasive biomarker to track disease progression in AD and to monitor effects of disease-modifying therapeutics in clinical trials.

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Section: Discussionmentioning

confidence: 99%

Longitudinal plasma phosphorylated tau 181 tracks disease progression in Alzheimer’s disease

et al. 2021

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“…P-tau, however, is a highly specific pathological biomarker of AD and the diagnostic capabilities of CSF p-tau at threonine 181 (p-tau181) [ 12 ] have been widely replicated in blood. Plasma p-tau181 can differentiate AD from non-AD neurodegenerative disorders [ 10 , 25 , 27 , 29 , 34 , 60 ], detect AD neuropathology [ 25 , 34 , 60 ], identifies individuals with increased Aβ and tau PET retention [ 25 , 27 , 29 , 41 , 60 ], strongly associates with imminent grey matter atrophy [ 57 ] and predicts progression to AD dementia, to the same degree as CSF p-tau181 [ 25 , 27 , 44 ]. Furthermore, findings of CSF p-tau at threonine 217 (p-tau217), which suggests stronger associations with AD pathology than standard CSF p-tau181 biomarkers [ 6 , 26 , 28 ], have also been replicated in plasma [ 38 , 48 ].…”

Section: Introductionmentioning

confidence: 99%

Plasma p-tau231: a new biomarker for incipient Alzheimer’s disease pathology

et al. 2021

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The quantification of phosphorylated tau in biofluids, either cerebrospinal fluid (CSF) or plasma, has shown great promise in detecting Alzheimer’s disease (AD) pathophysiology. Tau phosphorylated at threonine 231 (p-tau231) is one such biomarker in CSF but its usefulness as a blood biomarker is currently unknown. Here, we developed an ultrasensitive Single molecule array (Simoa) for the quantification of plasma p-tau231 which was validated in four independent cohorts (n = 588) in different settings, including the full AD continuum and non-AD neurodegenerative disorders. Plasma p-tau231 was able to identify patients with AD and differentiate them from amyloid-β negative cognitively unimpaired (CU) older adults with high accuracy (AUC = 0.92–0.94). Plasma p-tau231 also distinguished AD patients from patients with non-AD neurodegenerative disorders (AUC = 0.93), as well as from amyloid-β negative MCI patients (AUC = 0.89). In a neuropathology cohort, plasma p-tau231 in samples taken on avergae 4.2 years prior to post-mortem very accurately identified AD neuropathology in comparison to non-AD neurodegenerative disorders (AUC = 0.99), this is despite all patients being given an AD dementia diagnosis during life. Plasma p-tau231 was highly correlated with CSF p-tau231, tau pathology as assessed by [18F]MK-6240 positron emission tomography (PET), and brain amyloidosis by [18F]AZD469 PET. Remarkably, the inflection point of plasma p-tau231, increasing as a function of continuous [18F]AZD469 amyloid-β PET standardized uptake value ratio, was shown to be earlier than standard thresholds of amyloid-β PET positivity and the increase of plasma p-tau181. Furthermore, plasma p-tau231 was significantly increased in amyloid-β PET quartiles 2–4, whereas CSF p-tau217 and plasma p-tau181 increased only at quartiles 3–4 and 4, respectively. Finally, plasma p-tau231 differentiated individuals across the entire Braak stage spectrum, including Braak staging from Braak 0 through Braak I–II, which was not observed for plasma p-tau181. To conclude, this novel plasma p-tau231 assay identifies the clinical stages of AD and neuropathology equally well as plasma p-tau181, but increases earlier, already with subtle amyloid-β deposition, prior to the threshold for amyloid-β PET positivity has been attained, and also in response to early brain tau deposition. Thus, plasma p-tau231 is a promising novel biomarker of emerging AD pathology with the potential to facilitate clinical trials to identify vulnerable populations below PET threshold of amyloid-β positivity or apparent entorhinal tau deposition.

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“…Mass spectrometric assays for plasma Aβ 42 or Aβ ratio have demonstrated high accuracy in detecting cerebral Aβ pathology ( Nakamura et al, 2018 ; Schindler et al, 2019 ). Blood p-tau is a highly specific pathological blood biomarker for AD pathology and encompasses all diagnostic capabilities of CSF p-tau ( Benussi et al, 2020 ; Karikari et al,2020a,b ; Lantero Rodriguez et al, 2020 ; Moscoso et al, 2020 ; O’Connor et al, 2020 ; Ashton et al, 2021 ). Nonetheless, while blood biomarkers are considerably less complexed than CSF and molecular imaging, venipuncture is still required to extract the sample that may still limit some populations.…”

Section: Introductionmentioning

confidence: 99%

Saliva Neurofilament Light Chain Is Not a Diagnostic Biomarker for Neurodegeneration in a Mixed Memory Clinic Population

Gleerup

Sanna

Høgh

et al. 2021

Front. Aging Neurosci.

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Neurodegeneration and axonal injury result in an increasing release of neurofilament light chain (NfL) into bodily fluids, including cerebrospinal fluid (CSF) and blood. Numerous studies have shown that NfL levels in CSF and blood are increased in neurodegenerative disorders and monitor neurodegeneration. Saliva is an easily accessible biofluid that could be utilized as a biofluid measurement of Alzheimer’s disease (AD) biomarkers. In this study, for the first time, salivary NfL was measured and compared to plasma NfL in a consecutive cohort of patients referred to cognitive assessments. In two mixed memory clinic cohorts, saliva samples were taken from 152 patients, AD (n = 49), mild cognitive impairment (MCI) (n = 47), non-AD (n = 56), and also 17 healthy controls. In addition, 135 also had a matching plasma sample. All saliva and plasma samples were analyzed for NfL, and the association between saliva and plasma NfL and CSF levels of total tau (t-tau), phosphorylated tau (p-tau), and beta amyloid 1–42 (Aβ42) were investigated. In total, 162/169 had quantifiable levels of salivary NfL by single molecule array (Simoa). No statistically significant differences were found in salivary NfL concentration across the diagnostic groups, but as expected, significant increases were found for plasma NfL in dementia cases (P < 0.0001). There was no association between saliva and plasma NfL levels. Furthermore, saliva NfL did not correlate with CSF Aβ42, p-tau, or tau concentrations. In conclusion, NfL is detectable in saliva but does not reflect neurodegeneration in the brain.

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Time course of phosphorylated-tau181 in blood across the Alzheimer’s disease spectrum

Cited by 159 publications

References 72 publications

Longitudinal plasma phosphorylated tau 181 tracks disease progression in Alzheimer’s disease

Longitudinal plasma phosphorylated tau 181 tracks disease progression in Alzheimer’s disease

Plasma p-tau231: a new biomarker for incipient Alzheimer’s disease pathology

Saliva Neurofilament Light Chain Is Not a Diagnostic Biomarker for Neurodegeneration in a Mixed Memory Clinic Population

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