Plasma phospho-tau in Alzheimer’s disease: towards diagnostic and therapeutic trial applications

Molecular Neurodegeneration, Journal Year: 2023, Volume and Issue: 18(1)

Published: March 16, 2023

As the leading cause of dementia, Alzheimer's disease (AD) is a major burden on affected individuals, their families and caregivers, healthcare systems. Although AD can be identified diagnosed by cerebrospinal fluid or neuroimaging biomarkers that concord with neuropathological evidence clinical symptoms, challenges regarding practicality accessibility hinder widespread availability implementation. Consequently, many people suspected cognitive impairment due to do not receive biomarker-supported diagnosis. Blood have capacity help expand access diagnostics worldwide. One such promising biomarker plasma phosphorylated tau (p-tau), which has demonstrated specificity versus non-AD neurodegenerative diseases, will extremely important inform diagnosis eligibility for therapies recently been approved. This review provides an update diagnostic prognostic performances p-tau181, p-tau217 p-tau231, associations in vivo autopsy-verified pathological hallmarks. Additionally, we discuss potential applications unanswered questions p-tau therapeutic trials, given recent addition toolbox participant screening, recruitment during-trial monitoring. Outstanding include assay standardization, threshold generation verification diverse cohorts reflective wider community attending memory clinics included trials.

Language: Английский

---

Specific associations between plasma biomarkers and postmortem amyloid plaque and tau tangle loads

EMBO Molecular Medicine, Journal Year: 2023, Volume and Issue: 15(5)

Published: March 13, 2023

Several promising plasma biomarkers for Alzheimer's disease have been recently developed, but their neuropathological correlates not yet fully determined. To investigate and compare independent associations between multiple (p-tau181, p-tau217, p-tau231, Aβ42/40, GFAP, NfL) neuropathologic measures of amyloid tau, we included 105 participants from the Arizona Study Aging Neurodegenerative Disorders (AZSAND) with antemortem samples a postmortem exam, 48 whom had longitudinal p-tau217 p-tau181. When simultaneously including plaque tangle loads, Aβ42/40 ratio p-tau231 were only associated plaques (ρAβ42/40 [95%CI] = -0.53[-0.65, -0.35], ρp-tau231 0.28[0.10, 0.43]), GFAP was tangles (ρGFAP 0.39[0.17, 0.57]), p-tau181 both (ρp-tau217 0.40[0.21, 0.56], ρp-tau181 0.36[0.15, 0.50]) 0.52[0.34, 0.66]; 0.36[0.17, 0.52]). A model combining showed highest accuracy predicting presence change (ADNC, AUC[95%CI] 0.89[0.82, 0.96]) load (R2 0.55), while alone optimal 0.45). Our results suggest that high-performing assays might be an combination to assess Alzheimer's-related pathology in vivo.

Language: Английский

---

Alzheimer's disease drug development pipeline: 2024

Alzheimer s & Dementia Translational Research & Clinical Interventions, Journal Year: 2024, Volume and Issue: 10(2)

Published: April 1, 2024

New therapies to prevent or delay the onset of symptoms, slow progression, improve cognitive and behavioral symptoms Alzheimer's disease (AD) are needed.

Language: Английский

---

CSF tau phosphorylation occupancies at T217 and T205 represent improved biomarkers of amyloid and tau pathology in Alzheimer’s disease

Nature Aging, Journal Year: 2023, Volume and Issue: 3(4), P. 391 - 401

Published: March 13, 2023

Cerebrospinal fluid (CSF) amyloid-β peptide (Aβ)42/Aβ40 and the concentration of tau phosphorylated at site 181 (p-tau181) are well-established biomarkers Alzheimer's disease (AD). The present study used mass spectrometry to measure concentrations nine five nonphosphorylated species phosphorylation occupancies (percentage phosphorylated/nonphosphorylated) ten sites. In we show that, in 750 individuals with a median age 71.2 years, CSF pT217/T217 predicted presence brain amyloid by positron emission tomography (PET) slightly better than Aβ42/Aβ40 (P = 0.02). Furthermore, for positive PET (n 263), was more strongly correlated amount (Spearman's ρ 0.69) (ρ -0.42, P < 0.0001). two independent cohorts participants symptoms AD dementia 55 n 90), pT205/T205 were measures p-tau181 concentration. These findings suggest that represent improved pathology AD.

Language: Английский

---

Equivalence of plasma p‐tau217 with cerebrospinal fluid in the diagnosis of Alzheimer's disease

Alzheimer s & Dementia, Journal Year: 2023, Volume and Issue: 19(11), P. 4967 - 4977

Published: April 20, 2023

Abstract INTRODUCTION Plasma biomarkers are promising tools for Alzheimer's disease (AD) diagnosis, but comparisons with more established needed. METHODS We assessed the diagnostic performance of p‐tau 181 , 217 and 231 in plasma CSF 174 individuals evaluated by dementia specialists amyloid‐PET tau‐PET. Receiver operating characteristic (ROC) analyses to identify tau‐PET positivity. RESULTS had lower dynamic ranges effect sizes compared p‐tau. (AUC = 76%) 82%) assessments performed inferior 87%) 95%) However, 91%) indistinguishable from 94%) DISCUSSION equivalent biomarker‐defined AD. Our results suggest that may help reduce need invasive lumbar punctures without compromising accuracy identification Highlights diagnosis AD, suggesting increased accessibility is not offset accuracy. mean fold‐changes between negative positive groups than CSF. greater when differentiating groups. worse AD diagnosis.

Language: Английский

---

Predicting amyloid PET and tau PET stages with plasma biomarkers

Brain, Journal Year: 2023, Volume and Issue: 146(5), P. 2029 - 2044

Published: Feb. 15, 2023

Abstract Staging the severity of Alzheimer’s disease pathology using biomarkers is useful for therapeutic trials and clinical prognosis. Disease staging with amyloid tau PET has face validity; however, this would be more practical plasma biomarkers. Our objectives were, first, to examine approaches and, second, prediction stages Participants (n = 1136) were enrolled in either Mayo Clinic Study Aging or Research Center; had a concurrent PET, blood draw; met criteria cognitively unimpaired 864), mild cognitive impairment 148) syndrome dementia 124). The latter two groups combined into impaired group 272). We used multinomial regression models estimate discrimination [concordance (C) statistics] among three (low, intermediate, high), four (Braak 0, 1–2, 3–4, 5–6) stage (none/low versus intermediate/high severity) as predictors separately within individuals. Plasma analytes, p-tau181, Aβ1–42 Aβ1–40 (analysed Aβ42/Aβ40 ratio), glial fibrillary acidic protein neurofilament light chain measured on HD-X Simoa Quanterix platform. p-tau217 was also subset 355) participants Lilly Meso Scale Discovery assay. Models all analytes along risk factors (age, sex APOE) most often provided best (C 0.78–0.82). p-tau181 similar 0.72–0.85 C 0.73–0.86). Discriminating proxy from none/low neuropathological change excellent but not better than only 0.88 0.87 0.91 0.90 impaired). outperformed assay discriminating high intermediate 0.85 0.74) did improve over model 0.83). can discriminate between surrogate accuracy acceptable range. Combinations are single many predictions exception that alone usually performed equivalently combinations discrimination.

Language: Английский

---

Acceptable performance of blood biomarker tests of amyloid pathology — recommendations from the Global CEO Initiative on Alzheimer’s Disease

Nature Reviews Neurology, Journal Year: 2024, Volume and Issue: 20(7), P. 426 - 439

Published: June 12, 2024

Anti-amyloid treatments for early symptomatic Alzheimer disease have recently become clinically available in some countries, which has greatly increased the need biomarker confirmation of amyloid pathology. Blood (BBM) tests pathology are more acceptable, accessible and scalable than PET or cerebrospinal fluid (CSF) tests, but highly variable levels performance. The Global CEO Initiative on Alzheimer's Disease convened a BBM Workgroup to consider minimum acceptable performance clinical use. Amyloid status was identified as reference standard. For use triaging test before subsequent confirmatory such CSF recommends that sensitivity ≥90% with specificity ≥85% primary care ≥75–85% secondary depending availability follow-up testing. without should equivalent — ~90%. Importantly, predictive values all vary according pre-test probability must be interpreted complete context. Use meet these standards could enable people receive an accurate timely diagnosis potentially benefit from new treatments. blood offer test. This Consensus Statement provides recommendations

Language: Английский

---

Plasma Aβ42/Aβ40 and phospho‐tau217 concentration ratios increase the accuracy of amyloid PET classification in preclinical Alzheimer's disease

Alzheimer s & Dementia, Journal Year: 2023, Volume and Issue: 20(2), P. 1214 - 1224

Published: Nov. 6, 2023

Abstract INTRODUCTION Incorporating blood‐based Alzheimer's disease biomarkers such as tau and amyloid beta (Aβ) into screening algorithms may improve efficiency. METHODS Plasma Aβ, phosphorylated (p‐tau)181, p‐tau217 concentration levels from AHEAD 3–45 study participants were measured using mass spectrometry. Tau ratios for each proteoform calculated to normalize inter‐individual differences. Receiver operating characteristic (ROC) curve analysis was performed biomarker against positivity, defined by > 20 Centiloids. Mixture of experts assessed the value including existing predictive algorithm positron emission tomography status. RESULTS The area under receiver (AUC) 0.87 Aβ42/Aβ40, 0.74 variant p‐tau181 ratio (p‐tau181/np‐tau181), 0.92 (p‐tau217/np‐tau217). Predicted Centiloid (PPC), a model p‐tau217/np‐tau217, age, apolipoprotein E improved AUC 0.95. DISCUSSION Including plasma p‐tau217/np‐tau217 along with Aβ42/Aβ40 in streamline preclinical individuals anti‐amyloid clinical trials. ClinicalTrials.gov Identifier: NCT04468659 Highlights addition (p‐tau217/np‐tau217) significantly identifying positivity. Prediction performance at higher NAV p‐tau217/np‐tau217. All models generated this are incorporated (PPC) app public use.

Language: Английский

---

Plasma Biomarkers of Alzheimer’s Disease: A Review of Available Assays, Recent Developments, and Implications for Clinical Practice

Journal of Alzheimer s Disease Reports, Journal Year: 2023, Volume and Issue: 7(1), P. 355 - 380

Published: April 25, 2023

Recently, low-sensitive plasma assays have been replaced by new ultra-sensitive such as single molecule enzyme-linked immunosorbent assay (Simoa), the Mesoscale Discovery (MSD) platform, and immunoprecipitation-mass spectrometry (IP-MS) with higher accuracy in determination of biomarkers Alzheimer's disease (AD). Despite significant variability, many studies established in-house cut-off values for most promising available biomarkers. We first reviewed used laboratory methods to measure AD Next, we review focused on diagnostic performance these identify cases, predict cognitive decline pre-clinical differentiate cases from other dementia. summarized data published until January 2023. A combination Aβ42/40 ratio, age, APOE status showed best diagnosing brain amyloidosis a liquid chromatography-mass (LC-MS) assay. Plasma p-tau217 has shown distinguishing Aβ-PET+ Aβ-PET-even cognitively unimpaired individuals. also different each biomarker when available. Recently developed undeniable importance research, improved analytical performance. Some extensively clinical trials are now clinically Nonetheless, several challenges remain their widespread use practice.

Language: Английский

---

Mass spectrometric simultaneous quantification of tau species in plasma shows differential associations with amyloid and tau pathologies

Nature Aging, Journal Year: 2023, Volume and Issue: 3(6), P. 661 - 669

Published: April 27, 2023

Abstract Blood phosphorylated tau (p-tau) biomarkers, at differing sites, demonstrate high accuracy to detect Alzheimerʼs disease (AD). However, knowledge on the optimal marker for identification across AD continuum and link pathology is limited. This partly due heterogeneity in analytical methods. In this study, we employed an immunoprecipitation mass spectrometry method simultaneously quantify six (p-tau181, p-tau199, p-tau202, p-tau205, p-tau217 p-tau231) two non-phosphorylated plasma peptides a total of 214 participants from Paris Lariboisière Translational Biomarkers Aging Dementia cohorts. Our results indicate that p-tau217, p-tau231 p-tau205 are forms best reflect AD-related brain changes, although with distinct emergences along course correlations features—amyloid tau. These findings support differential association blood p-tau variants pathology, our offers potential tool staging clinical trials.

Language: Английский

---