Clinical performance and head-to-head comparison of CSF p-tau235 with p-tau181, p-tau217 and p-tau231 in two memory clinic cohorts

Abstract

Background Cerebrospinal fluid (CSF) p-tau235 is a novel biomarker highly specific of Alzheimer’s disease (AD). However, CSF p-tau235 has only been studied in well-characterized research cohorts, which do not fully reflect the patient landscape found in clinical settings. Therefore, in this multicentre study, we investigated the performance of CSF p-tau235 to detect symptomatic AD in clinical settings and compared it with CSF p-tau181, p-tau217 and p-tau231. Methods CSF p-tau235 was measured using an in-house single molecule array (Simoa) assay in two independent memory clinic cohorts: Paris cohort (Lariboisière Fernand-Widal University Hospital Paris, France; n=212) and BIODEGMAR cohort (Hospital del Mar, Barcelona, Spain; n=175). Patients were classified by the syndromic diagnosis (cognitively unimpaired [CU], mild cognitive impairment [MCI] or dementia) and their biological diagnosis (amyloid-beta [Aβ]+ or Aβ $$-$$ - ). Both cohorts included detailed cognitive assessments and CSF biomarker measurements (clinically validated core AD biomarkers [Lumipulse CSF Aβ1–42/40 ratio, p-tau181 and t-tau] and in-house developed Simoa CSF p-tau181, p-tau217 and p-tau231). Results High CSF p-tau235 levels were strongly associated with CSF amyloidosis regardless of the clinical diagnosis, being significantly increased in MCI Aβ+ and dementia Aβ+ when compared with all other Aβ− groups (Paris cohort: P ˂0.0001 for all; BIODEGMAR cohort: P ˂0.05 for all). CSF p-tau235 was pronouncedly increased in the A+T+ profile group compared with A−T− and A+T− groups (P ˂0.0001 for all). Moreover, CSF p-tau235 demonstrated high diagnostic accuracies identifying CSF amyloidosis in symptomatic cases (AUCs=0.86 to 0.96) and discriminating AT groups (AUCs=0.79 to 0.98). Overall, CSF p-tau235 showed similar performances to CSF p-tau181 and CSF p-tau231 when discriminating CSF amyloidosis in various scenarios, but lower than CSF p-tau217. Finally, CSF p-tau235 associated with global cognition and memory domain in both cohorts. Conclusions CSF p-tau235 was increased with the presence of CSF amyloidosis in two independent memory clinic cohorts. CSF p-tau235 accurately identified AD in both MCI and dementia patients. Overall, the diagnostic performance of CSF p-tau235 was comparable to that of other CSF p-tau measurements, indicating its suitability to support a biomarker-based AD diagnosis in clinical settings.

A blood‐based multi‐pathway biomarker assay for early detection and staging of Alzheimer's disease across ethnic groups

“… 35 Accordingly, we optimized our 21‐protein biomarker assay specifically for the classification of AD and MCI in a population of European descent. We applied the 21‐protein biomarker assay to the Spanish BIODEGMAR cohort, 21 whose participants have undergone cognitive assessment by MMSE as well as CSF measurement of the Aβ42/40 ratio and t‐Tau (Table 1 and Figure S3 ). We then developed a European population‐specific AD risk scoring system based on the level changes of the 21 AD‐associated blood proteins in this cohort.…”

“…The Spanish BIODEGMAR cohort enrolled individuals visiting the Cognitive Decline and Movement Disorders Unit of Hospital del Mar, Barcelona, Spain. 21 The present study included 217 participants of the BIODEGMAR cohort, consisting of 129 individuals with Aβ+AD, 68 individuals with Aβ+MCI, and 20 Aβ−CN individuals. Participants donated a blood sample, underwent detailed neurological and neuropsychological evaluation, including the Mini‐Mental State Examination (MMSE), 22 brain MRI, and lumbar puncture for CSF collection for Aβ and tau biomarker measurement.…”

CSF p-tau205: a biomarker of tau pathology in Alzheimer’s disease

“…Participants were also stratified based on Aβ (A) and tau (T) status defined using Lumipulse CSF Aβ42/40 and p-tau181, respectively, into A−T− ( n = 82), A+T− ( n = 27) and A+T+ ( n = 99) (A−T+ [ n = 4] cases were considered suspected non-AD pathology [SNAP], and were therefore not included in the statistical analysis of the AT groups, but they are depicted in the AT boxplots) (Supplementary Table 2). Lumipulse cut-offs for Paris cohort are published elsewhere [ 21 ].…”

Fully synthetic phosphorylated Tau181, Tau217, and Tau231 calibrators for Alzheimer’s disease diagnosis

“…Biomarker-based detection approaches have advanced rapidly owing to the extensive investigation of Aβ and Tau proteins and the parallel advancement of ultrasensitive detection techniques. Remarkably, Tau with phosphorylation at threonines 231 (p-Tau231), 217 (p-Tau217), and 181 (p-Tau181) in cerebrospinal fluid (CSF) and blood are regarded as potent early biomarkers with high specificity and accuracy ( Janelidze et al, 2023 ; Lantero-Rodriguez et al, 2023 ).…”

“…Of which, GSK3β-induced Tau phosphorylation decreases its affinity to microtubules and leads to microtubule destabilization ( Uta et al, 1996 ; Rankin et al, 2007 ; Avila et al, 2012 ). Many immunoassays depend on the recombinant phosphorylated Tau-441 protein generated by the reaction of GSK3β in cells as a calibrator ( Karikari et al, 2021 ; Leuzy et al, 2021 ; Lantero-Rodriguez et al, 2023 ). However, the GSK3β-phosphorylated Tau-441 as a calibrator has been argued to have heterogeneity and inconsistency issues, including differences in phosphorylation sites and variability in kinase activity, which may have an impact on p-Tau calibrator standardization ( Liu et al, 2022 ).…”