Clinical value of plasma pTau181 to predict Alzheimer's disease pathology in a large real-world cohort of a memory clinic.

BACKGROUND

The identification of patients with an elevated risk of developing Alzheimer's disease (AD) dementia and eligible for the disease-modifying treatments (DMTs) in the earliest stages is one of the greatest challenges in the clinical practice. Plasma biomarkers has the potential to predict these issues, but further research is still needed to translate them to clinical practice. Here we evaluated the clinical applicability of plasma pTau181 as a predictive marker of AD pathology in a large real-world cohort of a memory clinic.

METHODS

Three independent cohorts (modelling [n = 991, 59.7% female], testing [n = 642, 56.2% female] and validation [n = 441, 55.1% female]) of real-world patients with subjective cognitive decline (SCD), mild cognitive impairment (MCI), AD dementia, and other dementias were included. Paired cerebrospinal fluid (CSF) and plasma samples were used to measure AT(N) CSF biomarkers and plasma pTau181.

FINDINGS

CSF and plasma pTau181 showed correlation in all phenotypes except in SCD and other dementias. Age significantly influenced the biomarker's performance. The general Aβ(+) vs Aβ(-) ROC curve showed an AUC = 0.77 [0.74-0.80], whereas the specific ROC curve of MCI due to AD vs non-AD MCI showed an AUC = 0.89 [0.85-0.93]. A cut-off value of 1.30 pg/ml of plasma pTau181 exhibited a sensitivity of 93.57% [88.72-96.52], specificity of 72.38% [62.51-79.01], VPP of 77.85% [70.61-83.54], and 8.30% false negatives in the subjects with MCI of the testing cohort. The HR of cox regression showed that patients with MCI up to this cut-off value exhibited a HR = 1.84 [1.05-3.22] higher risk to convert to AD dementia than patients with MCI below the cut-off value.

INTERPRETATION

Plasma pTau181 has the potential to be used in the memory clinics as a screening biomarker of AD pathology in subjects with MCI, presenting a valuable prognostic utility in predicting the MCI conversion to AD dementia. In the context of a real-world population, a confirmatory test employing gold-standard procedures is still advisable.

FUNDING

This study has been mainly funded by Ace Alzheimer Center Barcelona, Instituto de Salud Carlos III (ISCIII), Biomedical Research Networking Centre in Neurodegenerative Diseases (CIBERNED), Spanish Ministry of Science and Innovation, Fundación ADEY, Fundación Echevarne and Grífols S.A.

Informations de copyright

Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of interests Alberto Lleó received personal fees for service on the advisory boards from Biogen, Eisai, Fujirebio-Europe, Lilly, Novartis, NovoNordisk, Nutricia, Otsuka Pharmaceutical, and Zambón, and received speaker honoraria from Lilly, Biogen, KRKA and Zambon. Juan Fortea received personal fees for service on the advisory boards, adjudication committees or speaker honoraria from AC Immune, Lilly, Lundbeck, Roche, Fujirebio and Biogen, outside the submitted work. D.A., A.L. and J.F. report holding a patent for markers of synaptopathy in neurodegenerative disease (licensed to Adx, EPI8382175.0). Marta Marquié received personal fees for service on the advisory boards from Araclon Biotech–Grifols, S.A. Marta Marquié received grants or contracts from Instituto de Salud Carlos III (ISCIII) Accion Estrategica en Salud, integrated in the Spanish National RCDCI Plan and financed by ISCIII-Subdireccion General de Evaluacion and the Fondo Europeo de Desarrollo Regional (FEDER—Una manera de hacer Europa) grant PI19/00335. Daniel Alcolea received personal fees for service on the advisory boards from Fujirebio-Europe, Roche Diagnostics, Nutricia, Krka Farmacéutica S.L., Zambon S.A.U., Grifols, S.A., Lilly, and Esteve Pharmaceuticals S.A.