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Diagnostic performance of plasma Aβ42/40 ratio, p-tau181, GFAP, and NfL along the continuum of Alzheimer's disease and non-AD dementias : An international multi-center study

Doecke, James D. ; Bellomo, Giovanni ; Vermunt, Lisa ; Alcolea, Daniel ; Halbgebauer, Steffen ; in ’t Veld, Sjors ; Mattsson-Carlgren, Niklas LU orcid ; Veverova, Katerina ; Fowler, Christopher J. and Boonkamp, Lynn , et al. (2025) In Alzheimer's and Dementia 21(6).
Abstract

INTRODUCTION: Plasma phosphorylated tau (p-tau)181, glial fibrillary acidic protein (GFAP), neurofilament light chain (NfL), and amyloid beta ratio (Aβ42/40) may have diagnostic and prognostic value in Alzheimer's disease (AD). Here we assess which markers can best identify AD from controls and other non-AD dementias in a large international multi-center study. METHODS: Plasma samples (n = 1298) were collected from six international centers. Aβ40, Aβ42, GFAP, NfL, and p-tau181 were measured using single molecule array. In each group, AD diagnosis/co-pathology was defined according to cerebrospinal fluid biomarkers or amyloid positron emission tomography. Validations were performed in three separate cohorts via single and dual cut-off... (More)

INTRODUCTION: Plasma phosphorylated tau (p-tau)181, glial fibrillary acidic protein (GFAP), neurofilament light chain (NfL), and amyloid beta ratio (Aβ42/40) may have diagnostic and prognostic value in Alzheimer's disease (AD). Here we assess which markers can best identify AD from controls and other non-AD dementias in a large international multi-center study. METHODS: Plasma samples (n = 1298) were collected from six international centers. Aβ40, Aβ42, GFAP, NfL, and p-tau181 were measured using single molecule array. In each group, AD diagnosis/co-pathology was defined according to cerebrospinal fluid biomarkers or amyloid positron emission tomography. Validations were performed in three separate cohorts via single and dual cut-off models. RESULTS: p-tau181 showed the best area under the curve value to separate AD from frontotemporal dementia, controls, and Aβ– dementia with Lewy bodies. However, this discriminative power could not be reproduced by applying pre-defined cut-offs. DISCUSSION: p-tau181 was the best single plasma marker for detecting AD at any stage. Specific cut-offs are needed to maximize diagnostic performances. Highlights: Phosphorylated tau (p-tau)181 provided a clear differentiation between controls and Alzheimer's disease (AD) participants, with evidence of increased levels in the preclinical stage of AD. Plasma biomarkers demonstrated that when amyloid co-pathology is removed from dementia with Lewy bodies (DLB), only glial fibrillary acidic protein and neurofilament light chain remain to predict DLB. Given the low prevalence of amyloid co-pathology in frontotemporal dementia (FTD), p-tau181 and its ratio with amyloid beta 42 are strong biomarkers to differentiate FTD from AD.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Alzheimer's disease, amyloid beta, dementia with Lewy bodies, frontotemporal dementia, plasma biomarkers
in
Alzheimer's and Dementia
volume
21
issue
6
article number
e14573
publisher
Wiley
external identifiers
  • scopus:105009271550
  • pmid:40551285
ISSN
1552-5260
DOI
10.1002/alz.14573
language
English
LU publication?
yes
additional info
Publisher Copyright: © 2025 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.
id
0fdd2c29-9f78-471c-923e-275281f2967c
date added to LUP
2025-12-22 14:40:46
date last changed
2025-12-23 03:00:03
@article{0fdd2c29-9f78-471c-923e-275281f2967c,
  abstract     = {{<p>INTRODUCTION: Plasma phosphorylated tau (p-tau)181, glial fibrillary acidic protein (GFAP), neurofilament light chain (NfL), and amyloid beta ratio (Aβ42/40) may have diagnostic and prognostic value in Alzheimer's disease (AD). Here we assess which markers can best identify AD from controls and other non-AD dementias in a large international multi-center study. METHODS: Plasma samples (n = 1298) were collected from six international centers. Aβ40, Aβ42, GFAP, NfL, and p-tau181 were measured using single molecule array. In each group, AD diagnosis/co-pathology was defined according to cerebrospinal fluid biomarkers or amyloid positron emission tomography. Validations were performed in three separate cohorts via single and dual cut-off models. RESULTS: p-tau181 showed the best area under the curve value to separate AD from frontotemporal dementia, controls, and Aβ– dementia with Lewy bodies. However, this discriminative power could not be reproduced by applying pre-defined cut-offs. DISCUSSION: p-tau181 was the best single plasma marker for detecting AD at any stage. Specific cut-offs are needed to maximize diagnostic performances. Highlights: Phosphorylated tau (p-tau)181 provided a clear differentiation between controls and Alzheimer's disease (AD) participants, with evidence of increased levels in the preclinical stage of AD. Plasma biomarkers demonstrated that when amyloid co-pathology is removed from dementia with Lewy bodies (DLB), only glial fibrillary acidic protein and neurofilament light chain remain to predict DLB. Given the low prevalence of amyloid co-pathology in frontotemporal dementia (FTD), p-tau181 and its ratio with amyloid beta 42 are strong biomarkers to differentiate FTD from AD.</p>}},
  author       = {{Doecke, James D. and Bellomo, Giovanni and Vermunt, Lisa and Alcolea, Daniel and Halbgebauer, Steffen and in ’t Veld, Sjors and Mattsson-Carlgren, Niklas and Veverova, Katerina and Fowler, Christopher J. and Boonkamp, Lynn and Houtkamp, Isabel M. and Koel-Simmerlink, Marleen and Verberk, Inge M.W. and Gaetani, Lorenzo and Toja, Andrea and Wojdała, Anna Lidia and Fortea, Juan and Pijnenburg, Yolande and Lemstra, Afina and van der Flier, Wiesje and Hort, Jakub and Otto, Markus and Hansson, Oskar and Parnetti, Lucilla and Masters, Colin L. and Lleó, Alberto and González-Escalante, Armand and Contador, José and Suárez-Calvet, Marc and Fernández-Lebrero, Aida and Puig-Pijoan, Albert and Ortiz-Romero, Paula and Jiménez-Moyano, Esther and Minguillón, Carolina and del Campo, Marta and Teunissen, Charlotte}},
  issn         = {{1552-5260}},
  keywords     = {{Alzheimer's disease; amyloid beta; dementia with Lewy bodies; frontotemporal dementia; plasma biomarkers}},
  language     = {{eng}},
  number       = {{6}},
  publisher    = {{Wiley}},
  series       = {{Alzheimer's and Dementia}},
  title        = {{Diagnostic performance of plasma Aβ42/40 ratio, p-tau181, GFAP, and NfL along the continuum of Alzheimer's disease and non-AD dementias : An international multi-center study}},
  url          = {{http://dx.doi.org/10.1002/alz.14573}},
  doi          = {{10.1002/alz.14573}},
  volume       = {{21}},
  year         = {{2025}},
}