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Association of plasma biomarkers with cerebrospinal fluid-defined amyloid and tauopathy status, age, sex, APOE ε4 carriership, renal function, body mass index and cognition. Forest plots show cerebrospinal fluid-defined amyloid and tauopathy status, age, sex, renal function, body mass index, clinical staging (mild cognitive impairment vs dementia) and MMSE standardized β linear regression coefficient with 95% confidence intervals predicting each plasma biomarker concentration. All regressors were adjusted for age and sex (in blue) and for age, sex and Aβ status (in red). *Linear regression β coefficient remained significant after Aβ status adjustment. Aβ, amyloid beta; T, CSF tauopathy status; p-tau181, tau phosphorylated at threonine 181; p-tau217, tau phosphorylated at threonine 217; eGFR, estimated glomerular filtration rate; BMI, body mass index; MCI, mild cognitive impairment; MMSE, Mini-Mental State Examination
Source publication
Plasma tau phosphorylated at threonine 181 (p-tau181) and 217 (p-tau217) have demonstrated high accuracy for Alzheimer’s disease (AD) diagnosis, defined by CSF/PET amyloid beta (Aβ) positivity, but most studies have been performed in research cohorts, limiting their generalizability. We studied plasma p-tau217 and p-tau181 for CSF Aβ status discrim...
Citations
... A significant difference was observed only in the comparison between p-tau217 and NfL (DeLong's p = 0.018), while comparisons between p-tau181 and GFAP were not significant [33]. [34][35][36][37]39], whereas IP-MS combines antibody-based immunoprecipitation with targeted mass spectrometry to achieve high peptide specificity and analytical sensitivity [40]. The cost-effectiveness, feasibility, and practical implementation of these testing approaches, and head-to-head comparisons of their diagnostic accuracy should be assessed in future studies. ...
Background
Plasma biomarkers offer a promising alternative to amyloid beta (Aβ) positron emission tomography (PET) or cerebrospinal fluid (CSF) biomarkers for diagnosing Alzheimer’s disease (AD). This cross-sectional study assessed the utility of multiple plasma biomarkers for diagnosing and staging AD in a Japanese cohort.
Methods
The assessed plasma biomarkers included Aβ42/40, phosphorylated tau (p-tau181 and p-tau217), glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL), individually and in combination. Aβ42/40 was measured using the HISCL® platform, while all other biomarkers were measured using the Simoa® platform. Participants were classified based on Aβ PET imaging and neuropsychological testing into healthy controls (HC), AD continuum (preclinical AD, mild cognitive impairment [AD-MCI], and mild dementia [AD-D]), and non-AD cognitive impairment (CI) groups. Receiver operating characteristic analyses were performed to predict the Aβ PET status, correlation with Centiloid (CL) values and cognitive scores, and biomarker comparisons across AD stages.
Results
Sixty-nine HC, 13 preclinical AD, 38 AD-MCI, 44 AD-D, and 79 non-AD CI participants were included. The area under the curves (AUCs) for predicting Aβ PET status were 0.937 (Aβ42/40), 0.926 (p-tau217), and 0.946 (p-tau217/Aβ42); results of pair-wise DeLong tests revealed no significant differences among these three metrics (all p > 0.05). In the cognitively normal group, the AUCs were 0.968 (Aβ42/40), 0.958 (p-tau217), and 0.979 (p-tau217/Aβ42), while in the cognitively impaired group, they were 0.919 (Aβ42/40), 0.893 (p-tau217), and 0.923 (p-tau217/Aβ42). Among HC and AD continuum participants, CL correlations were − 0.74 (Aβ42/40), 0.81 (p-tau217), and 0.83 (p-tau217/Aβ42). In the HC and AD continuum, Aβ42/40 levels showed a bimodal distribution (cutoff = 0.096), with a shift from high to low occurring at 19.3 CL, compared to the PET positivity threshold of 32.9 CL. P-tau217 exhibited a linear increase with disease progression. All biomarkers correlated strongly with logical memory scores.
Conclusions
Plasma biomarkers, Aβ42/40 and p-tau217, and particularly their ratio (p-tau217/Aβ42), show strong potential as Aβ PET alternatives for AD diagnosis. HISCL-based plasma Aβ42/40 detects Aβ accumulation earlier than Aβ PET visual reading threshold, underscoring its utility as an early diagnostic marker.
... However, p-tau217 has been established as the most promising plasma biomarker for several reasons [11,12]. It is a very specific AD biomarker that allows differentiating with great precision this pathology from other dementias [13][14][15] and its levels are related to cerebral deposition of both amyloid and p-tau [16,17]. Moreover, it begins to rise very early, almost at the same time as the amyloid ratio is altered in CSF and even before amyloid PET reaches pathological threshold [8]. ...
... Plasma p-tau217 has shown excellent results in detecting CSF amyloid and AD (A + T +) pathology with AUCs of 0.97 and 0.94, respectively. These results are similar to those previously reported [37,64], and place p-tau217 as the most accurate single marker for detecting brain amyloid pathology as it has consistently shown better results than the other plasma biomarkers [11,36], and comparable results than those of CSF biomarkers for detecting tau and amyloid PET positivity [15,65]. In addition, it has also shown high diagnostic accuracy in preclinical cohorts for detecting CSF A + subjects with an AUC of 0.85 [25]. ...
... By testing the previously proposed two-cutoff approach [56] we have seen that, depending on the selected thresholds, between 57.4-84.8% of subjects for plasma p-tau217, and 72.9-95.3% for plasma p-tau217/Aβ42 ratio fell outside the indeterminate zone, with overall accuracies > 90%, similar to those described in literature [15,56]. However, in clinical practice, patients in the intermediate zone would still generate diagnostic doubts and would be candidates for confirmatory tests such as LP or PET or a new determination during follow-up. ...
Background
Plasma biomarkers for Alzheimer's disease (AD) are a promising tool for accessible and accurate biological diagnostics. However, data in clinical practice are needed to better understand their diagnostic and prognostic ability in memory unit patients.
Methods
We analyzed plasma phosphorylated tau at threonine 217 (p-tau217) and neuroflament light chain (NfL) levels and AD cerebrospinal fluid (CSF) biomarkers in a group of 493 subjects using the Lumipulse G600II platform. The sample includes 340 patients from our memory unit (142 dementia, 186 mild cognitive impairment, and 12 with subjective complaints) and 153 cognitively unimpaired volunteers. We have correlated plasma and CSF biomarkers; we have analyzed plasma biomarker levels as a function of clinical diagnosis, cognitive status and amyloid status. We have also studied the ability of p-tau217 to discriminate between amyloid-positive and -negative subjects according to CSF using receiver operating characteristic curves.
Results
Plasma p-tau217 correlated significantly with CSF Aβ42/Aβ40 (Rho = -0.75; p-value < 0.001), p-tau181 (r = 0.66; p-value < 0.001), and t-tau (r = 0.59; p-value < 0.001). Plasma NfL correlated with CSF NfL (r = 0.48; p-value < 0.001). By clinical diagnosis, plasma p-tau217 levels showed to be higher in AD patients than in healthy controls (difference = 0.63 pg/ml; p-value < 0.001), FTD (difference = 0.60 pg/ml; p-value < 0.001), and nondegenerative dementias (difference = 0.61 pg/ml; p-value < 0.001). Plasma p-tau217 showed an area under the curve of 0.95 to discriminate between A + and A- subjects (95%CI 0.93–0.97).
Conclusion
Plasma p-tau217 shows excellent results for detecting amyloid pathology at brain level in a clinical setting with an AUC of 0.95. It is a highly specific marker of AD and increases progressively along the disease continuum. Using plasma p-tau217 as an initial diagnostic tool with cut-offs at sensitivities and specificities of 95 or 97.5% could save between 57.4–84.8% of LP/PETs with diagnostic accuracies of 95–97%. Plasma NfL increases progressively at different cognitive stages.
