Blood phosphorylated tau 181 as a biomarker for Alzheimer's disease: a diagnostic performance and prediction modelling study using data from four prospective cohorts

Karikari, Thomas K.; Pascoal, Tharick A.; Ashton, Nicholas J.; Bateman, Randall J.; Lantero‐Rodriguez, Juan; Chamoun, Mira; Savard, Mélissa; Kang, Min Su; Therriault, Joseph; Schöll, Michael; Massarweh, Gassan; Soucy, Jean Paul; Höglund, Kina; Brinkmalm, Gunnar; Mattsson, Niklas; Palmqvist, Sebastian; Gauthier, Serge; Stomrud, Erik; Zetterberg, Henrik; Hansson, Oskar; Rosa‐Neto, Pedro; Blennow, Kaj

doi:10.1016/s1474-4422(20)30071-5

Cited by 765 publications

(1,160 citation statements)

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“…We found that plasma p-tau181 was higher in males and in APOE ε4 carriers, which to our knowledge is a nding that has not been yet described. We also observed plasma p-tau181 to be signi cantly associated with older age, fewer years of education, elevated global cortical composite measure of Aβ-PET, and worse performance on cognitive scores, which, with the exception of education, concur with earlier studies on plasma p-tau181 [9][10][11][12]28]. As previously described, in our cross-sectional analyses, plasma p-tau181 was correlated with CSF p-tau181.…”

Section: Discussionsupporting

confidence: 92%

“…Plasma p-tau181 measurement Blood samples were collected, shipped, and stored as described by the ADNI Biomarker Core Laboratory [18]. Plasma p-tau181 was analyzed with the Single Molecule Array (Simoa) technique, using a clinically validated in-house assay described previously [9]. Plasma p-tau181 was measured on Simoa HD-X instruments (Quanterix, Billerica, MA, USA) in April 2020 at the Clinical Neurochemistry Laboratory, University of Gothenburg, Mölndal, Sweden.…”

Section: Study Participantsmentioning

confidence: 99%

“…plasma and serum) using ultrasensitive immunoassays [9][10][11][12][13] and mass spectrometry methods [14]. Plasma p-tau181 levels have been shown to be strongly associated with brain tau pathology, signi cantly elevated in AD, and differentiate AD from other neurodegenerative diseases [9][10][11][12][13]. However, to date the associations between plasma p-tau181 and AD-related brain metabolic dysfunction, a well-recognized pathophysiological process underlying AD, remains unknown.…”

Section: Introductionmentioning

confidence: 99%

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Plasma Levels of Phosphorylated Tau 181 Are Associated With Cerebral Metabolic Dysfunction in Cognitively Impaired Individuals

Lussier¹,

Benedet²,

Therriault³

et al. 2020

Preprint

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BackgroundAlzheimer’s disease (AD) biomarkers are primarily evaluated through MRI, PET, and CSF methods in order to diagnose and monitor disease. Recently, advances in the assessment of blood-based biomarkers have shown promise for simple, inexpensive, accessible, and minimally invasive tools with diagnostic and prognostic value for AD. Most recently, plasma phosphorylated tau181 (p-tau181) has shown excellent performance. The relationship between plasma p-tau181 and cerebral metabolic dysfunction assessed by [18F]FDG PET in AD is still unknown.MethodsThis study was performed on a total of 892 individuals (297 cognitively unimpaired; 595 cognitively impaired) from the ADNI cohort. Plasma p-tau181 was assessed using single molecular array (Simoa) technology and metabolic dysfunction was indexed by [18F]FDG PET. Cross-sectional associations between plasma and CSF p-tau181 and [18F]FDG were assessed using voxelwise linear regression models, with individuals stratified by diagnostic group and by Aβ status. Associations between baseline plasma p-tau181 and longitudinal rate of brain metabolic decline were also assessed in a subset (n=389) of individuals using correlations and voxelwise regression models.ResultsPlasma p-tau181 was elevated in Aβ+ and cognitively impaired individuals as well as in APOE ε4 carriers, and was significantly associated with age, worse cognitive performance, and CSF p-tau181. Cross-sectional analyses showed strong associations between plasma p-tau181 and [18F]FDG PET in Aβ+ and cognitively impaired individuals. Voxelwise longitudinal analyses showed that baseline plasma p-tau181 concentrations were significantly associated with annual rates of metabolic decline only in cognitively impaired individuals, bilaterally in the medial and lateral temporal lobes.ConclusionsThe associations between plasma p-tau181 and reduced brain metabolism, primarily in cognitively impaired and in Aβ+ individuals, supports the use of plasma p-tau181 as a simple, low-cost, minimally invasive, and accessible tool to both assess current and predict future metabolic dysfunction associated with AD, comparatively to PET, MRI, and CSF methods.

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Section: Discussionsupporting

confidence: 92%

Section: Study Participantsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Plasma Levels of Phosphorylated Tau 181 Are Associated With Cerebral Metabolic Dysfunction in Cognitively Impaired Individuals

Lussier¹,

Benedet²,

Therriault³

et al. 2020

Preprint

Self Cite

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“…Our < 65-year plasma NfL cut-offs (19.4 pg/mL, 21.5 pg/mL, 30.0 pg/mL) were substantially lower as to compared older cut-offs (38.0 pg/mL, 46.0 pg/mL, 54.8 pg/mL) and when this was applied, EOAD patients had the equivalent rate of abnormal plasma NfL as typical AD dementia -consistent with the reported literature on familial AD 56,57 . We also observed that age-related cut-offs may be more sensitive to neurodegeneration related to Aβ deposition, although it is clear that recent developments in plasma p-tau181 or p-tau217 would be a superior measure of Aβ and tau pathologies 10,11,14,15,51,58 . In individuals < 65 years, rates of abnormal plasma NfL were 3-fold higher in Aβ + controls as compared to Aβ-controls and also higher in MCI Aβ + than MCI Aβ-.…”

Section: Discussionmentioning

confidence: 75%

“…Recent advances in ultrasensitive immunological assays [10][11][12][13][14][15] and immunoprecipitation mass spectrometry (IPMS) methods [16][17][18] have been developed to measure neurodegenerative biomarkers in blood. NfL can be quanti ed at femtomolar concentrations in plasma or serum, which has enabled the reliable detection of NfL not only in symptomatic patients but also in cognitively unimpaired (CU) individuals of all ages 19 .…”

Section: Introductionmentioning

confidence: 99%

Diagnostic value of plasma neurofilament light: A multicentre validation study

Ashton

Bateman

Khleifat

et al. 2020

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Increased cerebrospinal fluid neurofilament light (NfL) is a recognized biomarker for neurodegeneration that can also be assessed in blood. Here, we investigate plasma NfL as a marker of neurodegeneration in fifteen neurodegenerative diseases from two multicenter cohorts: King’s College London (n = 847) and the Swedish BioFINDER study (n = 1464). Plasma NfL was significantly increased in all cortical neurodegenerative disorders, amyotrophic lateral sclerosis and atypical parkinsonian disorders. We further demonstrate that plasma NfL is clinically useful in identifying, i) atypical parkinsonian disorders in patients with parkinsonism, ii) dementia in individuals with Down Syndrome, iii) detect cases of frontotemporal dementia among psychiatric disorders such as moderate and severe depression, iv) identify frontotemporal dementia in patients with cognitive impairment. Data-driven cut-offs highlighted the fundamental importance of age-related plasma NfL cut-offs for disorders with a younger age of onset. Finally, our findings suggest that plasma NfL performs best when a concentration cut-off is applied to indicate no underlying neurodegeneration, with low false positives, in all age-related cut-offs.

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Association of Plasma and Cerebrospinal Fluid Alzheimer Disease Biomarkers With Race and the Role of Genetic Ancestry, Vascular Comorbidities, and Neighborhood Factors

et al. 2022

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ImportanceDifferences in cerebrospinal fluid (CSF) tau Alzheimer dementia (AD) biomarkers by self-identified race have been observed in prior studies. More recently, plasma biomarkers have been gaining recognition, but whether they exhibit similar differences is unclear. Furthermore, the underlying explanation for these differences in AD biomarkers is still unexplored.ObjectivesTo investigate differences in plasma biomarkers by race and genetic ancestry and explore potential underlying explanations for these differences.Design, Setting, and ParticipantsThis cross-sectional study used participant data from the Brain, Stress, Hypertension, and Aging Research Program (B-SHARP), an observational study conducted in the greater Atlanta metropolitan area. Participants were enrolled from March 1, 2016, to January 1, 2020.Main Outcomes and MeasuresMain outcomes were plasma and CSF amyloid-β (Aβ) 42, Aβ40, phosphorylated tau181 (p-tau181), and neurofilament light. General linear models were used for key comparisons.ExposuresMain independent variables were self-identified race and genetic ancestry. Additional variables were cardiovascular factors, APOE4, educational attainment, Area Deprivation Index, and C-reactive protein (reflecting systemic inflammation state).ResultsThis analysis included 617 participants (mean [SD] age, 66 [7.9] years; 300 [49%] African American and 317 [51%] White; 429 [70%] with mild cognitive impairment). On the basis of self-reported race, plasma levels of Aβ42 (adjusted mean difference, −1.20 pg/mL; 95% CI, −2.33 to −0.07 pg/mL), Aβ40 (adjusted mean difference, −37.78 pg/mL; 95% CI, −60.16 to −15.39 pg/mL), p-tau181 (adjusted mean difference, −4.66 pg/mL; 95% CI, −7.05 to −1.90 pg/mL), and neurofilament light (adjusted mean difference, −1.58; 95% CI, −2.83 to −0.19 pg/mL) were consistently lower in African American individuals after adjusting for demographic characteristics, educational attainment, cognition, APOE4, and cardiovascular factors. A similar pattern was observed in the CSF biomarkers except for Aβ42 and Aβ40. Although unadjusted analyses revealed an association between these biomarkers and African ancestry, these associations were not significant after adjusting for the same covariates. Differences by self-reported race were not explained by varied cardiovascular risk factors, C-reactive protein, educational attainment, or Area Deprivation Index.Conclusions and RelevanceIn this cross-sectional study of plasma biomarkers by race and genetic ancestry, the results indicated that plasma p-tau181, Aβ40, and NFL were lower in African American individuals based on self-reported race but not genetic ancestry. These differences were not explained by cardiovascular risks or clinical stage differences. These racial differences should be considered in clinical interpretations and clinical trial screenings to avoid an additional increase in underrepresentation of African American individuals in AD trials.

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Blood phosphorylated tau 181 as a biomarker for Alzheimer's disease: a diagnostic performance and prediction modelling study using data from four prospective cohorts

Cited by 765 publications

References 30 publications

Plasma Levels of Phosphorylated Tau 181 Are Associated With Cerebral Metabolic Dysfunction in Cognitively Impaired Individuals

Plasma Levels of Phosphorylated Tau 181 Are Associated With Cerebral Metabolic Dysfunction in Cognitively Impaired Individuals

Diagnostic value of plasma neurofilament light: A multicentre validation study

Association of Plasma and Cerebrospinal Fluid Alzheimer Disease Biomarkers With Race and the Role of Genetic Ancestry, Vascular Comorbidities, and Neighborhood Factors

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