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Multicenter Study
. 2025 Jun;21(6):e14573.
doi: 10.1002/alz.14573.

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

James D Doecke  1 , Giovanni Bellomo  2 , Lisa Vermunt  3   4 , Daniel Alcolea  5 , Steffen Halbgebauer  6 , Sjors In 't Veld  3   7 , Niklas Mattsson-Carlgren  8   9   10 , Katerina Veverova  11 , Christopher J Fowler  12 , Lynn Boonkamp  3 , Isabel M Houtkamp  3   7 , Marleen Koel-Simmerlink  3 , Inge M W Verberk  3 , Lorenzo Gaetani  2 , Andrea Toja  2 , Anna Lidia Wojdała  3 , Juan Fortea  5 , Yolande Pijnenburg  4 , Afina Lemstra  4 , Wiesje van der Flier  4 , Jakub Hort  11 , Markus Otto  6 , Oskar Hansson  8   13 , Lucilla Parnetti  2 , Colin L Masters  12 , Alberto Lleó  5 , Armand González-Escalante  14   15   16 , José Contador  14   15   17 , Marc Suárez-Calvet  14   15   16   18 , Aida Fernández-Lebrero  14   15   16 , Albert Puig-Pijoan  15   16 , Paula Ortiz-Romero  14   15 , Esther Jiménez-Moyano  14   15 , Carolina Minguillón  14   15   18   19 , Marta Del Campo  3   14   15   17 , Charlotte Teunissen  3
Affiliations
Multicenter Study

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

James D Doecke et al. Alzheimers Dement. 2025 Jun.

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 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.

Keywords: Alzheimer's disease; amyloid beta; dementia with Lewy bodies; frontotemporal dementia; plasma biomarkers.

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Conflict of interest statement

J.D., E.J.M., P.O.R., A.F.L., J.C., A.G.E., C.M., Y.P., A.T., M.K.S., I.H., L.B., C.F., K.V., S.I.V., and S.H. have no conflicts of interest to declare. G.B. has grants or contracts from the Parkinson's Foundation, Fujirebio, and the Alzheimer's Association. L.V. has grants or contracts from NWO VENI and Amsterdam UMC, ZonMw, Olink Dioraphte, Roche Diagnostics, Ely Lilly, Alzheimer's Association, Alzheimer Nederland, and Dutch Dementia researchers conference committee. D.A. has support from the Instituto de Salud Carlos III, and the Department of Health Generalitat de Catalunya PERIS program, and funding from Grfols S.A., Lily, Fujirebio, Roche Diagnostics, Nutricia, Krka Farmaceutical SL, Zambon SAU, Esteve Pharmaceuticals, and Neuraxpharm. N.M.C. received support from the Swedish Alzheimer Foundation, Family Ronnstrom Foundation, Swedish Brain Foundation, Kock Foundation, WASP and DDLS joint call for research projects, Konug Gustaf V:s och Drottning Victorias Frimurarestiftelse, the Swedish Research Council, Biogen, and Owkin. I.V. has grants, funding, or contracts from the Amsterdam UMC starter grant, and the TKI grant Health‐Holland, Neurogen Biomarking, and Quanterix. L.G. has received grants or contracts from AirAlzh Foundation; received consulting fees from Fujirebio and Eli Lilly; has payment or honoraria from Fujirebio, Eli Lilly, and Eisai; and support for attending meetings and/or travel from Fujirebio, Eli Lilly, and Novartis. L.G. also participates on a data safety monitoring board or advisory board for Eli Lilly. A.W. received support from Quanterix and a grant from the European Union's Horizon 2020 research and innovation program under the Marie Skłodowska‐ Curie. J.F. received support from Fondo de Investigaciones Sanitario (FIS); Instituto de Salud Carlos III, Spain; National Institutes of Health (NIH), USA; Generalitat de Catalunya, Spain; Fundació Tatiana Pérez de Guzmán el Bueno, Spain; Alzheimer ´s Association, USA; Brightfocus, USA; and Horizon 2020 (European Commission). J.F. received consulting fees from Lundbeck, Ionis, and AC Immune, and payments or honoraria from Roche Diagnostics, Esteve, Biogen, Laboratorios Canot, MKI, Eisai, Lilly, and Adamed. J.F. has patent issued; WO2019175379 A1 Markers of synaptopathy in neurodegenerative disease. J.F. participates on a data safety monitoring board or advisory board for AC Immune, Alzheon, Zambon, Lilly, Roche Diagnostics, Eisai, and Perha. J.F. has leadership or fiduciary roles in the Spanish Neurological Society, T21 Research Society, Lumind Foundation, Jerome‐Lejeune Foundation, Alzheimer's Association, Health Research Board, Dementia Trials Ireland, European Commission, National Institutes of Health, USA, and the Instituto de Salud Carlos III, Spain. J.F. has receipt of equipment, materials, drugs, medical writing, gifts. or other services from Life Molecular Imaging (LMI). M.O. received grants or contracts from the BMBF – FTLD consortium, moodmarker, the ALS association, and EU_MIRIADE, and funding from Biogen, Axon, Roche Diagnostics, and Grifols. M.O. participates on a data safety monitory or advisory board from the Biogen ATLAS trial, and has a leadership or fiduciary role in the German Society for CSF diagnostics and neurochemistry, as a speaker for the FTLD consortium, and for the Society for CSF diagnostics and neurochemistry. A.L. has grants or contracts from Hersenstichting and ZOnMW, and has a leadership or fiduciary role on the Steering Committee E‐DLB and the Dutch Neurology Society. W.F. has grants or contracts from ZonMW, NWO, EU‐FP7, EU‐JPND, Alzheimer Nederland, Hersenstichting CardioVascular Onderzoek Nederland, Health∼Holland, Topsector Life Sciences & Health, stichting Dioraphte, Gieskes‐Strijbis fonds, stichting Equilibrio, Noaber Foundation, Edwin Bouw fonds, Pasman stichting, Stichting Steun Alzheimercentrum Amsterdam, Philips, Biogen MA Inc, Novartis‐NL, Life‐MI, AVID, Roche BV, Fujifilm, Eisai, Combinostics. W.F. holds the Pasman chair. W.F. is recipient of ABOARD, which is a public–private partnership receiving funding from ZonMW (#73305095007) and Health∼Holland, Topsector Life Sciences & Health (PPP‐allowance; #LSHM20106). W.F. is recipient of TAP‐dementia, ZonMw #10510032120003. W.F. is recipient of IHI‐AD‐RIDDLE (#101132933), a project supported by the Innovative Health Initiative Joint Undertaking (IHI JU). W.F. is consultant to Oxford Health Policy, Forum CIC, Roche Diagnostics, Eisai, and Biogen MA Inc. W.F. has been an invited speaker at Boehringer Ingelheim, Biogen MA Inc, Danone, Eisai, WebMD Neurology (Medscape), NovoNordisk, Springer Healthcare, European Brain Council. W.F. participated on advisory boards of Biogen MA Inc, Roche Diagnostics, and Eli Lilly. WF is member of the steering committee of Novonordisk's Evoke/Evoke+ phase 3 trials. W.F. is member of the steering committee of PAVE, and Think Brain Health. W.F. was associate editor of Alzheimer, Research & Therapy in 2020/2021. W.F. is associate editor at Brain. J.H. has funding from SAB Eli Lilly and has stock in Alzheom company. O.H. has consulting fees from AC, Immune, BioArctic, Biogen, Bristol, Meyer, Squibb, C2N Diagnostics institute, Eisai, Eli Lilly, Fujirebio, Merck, Novartis, Novo, Nordisk, Roche Diagnostics, Sanofi, and Siemens. L.P. has funding from JPco‐fuND‐2: Multinational research projects on Personalised Medicine for Neurodegenerative Diseases (CUP number J99C18000210005). L.P. has grants or contracts European Union—Next Generation EU – PNRR M6C2 ‐ Investimento 2.1 Valorizzazione e potenziamento della ricerca biomedica del SSN (PNRR‐MAD‐2022‐12376035) and Fujirebio. A.L.B. had support from Fondo de Investigaciones Sanitario (FIS), Institution de Salud Carlos III AC19/00103; has grants or contracts from CIBERNED program (Program 1, Alzheimer Disease); has received consulting fees for Grifols S.A. and Lilly; and has patents planned issued or pending; WO2019175379 A1 Markers of synaptopathy in neurodegenerative disease. M.S.C. has grants or contracts from Roche Diagnostics, consulting fees from Roche Diagnostics, and has received funding from Roche, Almirall, Eli Lilly, and Novo Nordisk. M.S.C. has participated on data safety monitoring board or advisory boards for Roche Diagnostics, Grifols, and Eli Lilly. M.S.C. has received equipment, materials, drugs, medical writing gifts, or other services from Roche Diagnostics, Avid Radiopharmaceuticals, Inc. (Eli Lilly and company), Janssen Research and Development, ADx Neurosciences, Alamar Biosciences, Fujirebio, Meso Scale Discovery, and ALZpath. M.S.C. has other financial or non‐financial interests with Roche Diagnostics. A.P.P. has support from Laboratoris Esteve, Nutricia Ltd, and participates on a data safety monitory board or advisory board for Schwabe Farma Iberica. C.M. has grants or contracts from EuFingers JPND research grant, and the ADDF digital biomarkers research grant. M.d.C. has support from the JPND‐Bpride project funding, and grants or contracts from Alzheimer's research and therapy, Attraction Talent Comunidad de Madrid, and PROYECTOS I+D+I – 2020″‐ Retos de investigación from the Ministerio Español de Ciencia e innovación; has received payment or honoraria from Novonordisk and Springer Healthcare; and has a leadership or fiduciary role in BBB‐PIA chair AA and is Scientific advisor for ADPD. C.E.T. has research contracts with Acumen, ADx Neurosciences, AC‐Immune, Alamar, Aribio, Axon Neurosciences, Beckman‐Coulter, BioConnect, Bioorchestra, Brainstorm Therapeutics, Celgene, Cognition Therapeutics, EIP Pharma, Eisai, Eli Lilly, Fujirebio, Instant Nano Biosensors, Novo Nordisk, Olink, PeopleBio, Quanterix, Roche, Toyama, Vivoryon. She is editor in chief of Alzheimer Research and Therapy, and serves on editorial boards of Molecular Neurodegeneratoin, Neurology: Neuroimmunology & Neuroinflammation, Medidact Neurologie/Springer, and serves on committee to define guidelines for Cognitive disturbances, and one for acute Neurology in the Netherlands. She had consultancy/speaker contracts for Aribio, Biogen, Beckman‐Coulter, Cognition Therapeutics, Eli Lilly, Merck, Novo Nordisk, Olink, Roche, and Veravas. Author disclosures are available in the supporting information.

Figures

FIGURE 1
FIGURE 1
Box and whisker plots of plasma biomarkers over the disease continuums for AD, DLB, and FTD. (A) Aβ42/40, (B) p‐tau181, (C) GFAP, and (D) NfL. – P > 0.05, * P < 0.05, ** P < 0.01, *** P < 0.001, **** P < 0.0001 versus controls. Values shown for Aβ42, GFAP, NfL, and p‐tau181 are in pg/mL. Aβ, amyloid beta; AD, Alzheimer's disease; DLB, dementia with Lewy bodies; FTD, frontotemporal dementia; GFAP, glial fibrillary acidic protein; MCI, mild cognitive impairment; NfL, neurofilament light chain; preAD, pre‐clinical AD; p‐tau, phosphorylated tau; sMCI, stable MCI
FIGURE 2
FIGURE 2
Internal cross‐validation AUC (95% CI) values for the AD continuum and for AD versus other dementia. Other dementia: includes participants with DLB or FTD. Multivariate model included the interaction Aβ40 × p‐tau181, and ratios Aβ42/GFAP and Aβ42/p‐tau181. AD, Alzheimer's disease; AUC, area under the curve; CI, confidence interval; DLB, dementia with Lewy bodies; FTD, frontotemporal dementia; GFAP, glial fibrillary acidic protein; MCI, mild cognitive impairment; NfL, neurofilament light chain; preAD, pre‐clinical AD; p‐tau, phosphorylated tau
FIGURE 3
FIGURE 3
Internal cross‐validation AUC (95% CI) values for the DLB Aβ‐ and DLB Aβ+ versus controls, and between DLB & AD. Aβ, amyloid beta; AD, Alzheimer's disease; AUC, area under the curve; CI, confidence interval; DLB, dementia with Lewy bodies; GFAP, glial fibrillary acidic protein; NfL, neurofilament light chain; p‐tau, phosphorylated tau
FIGURE 4
FIGURE 4
Internal cross‐validation AUC (95% CI) values for the FTD continuum and for FTD versus AD. Aβ, amyloid beta; AD, Alzheimer's disease; AUC, area under the curve; CI, confidence interval; FTD, frontotemporal dementia; GFAP, glial fibrillary acidic protein; NfL, neurofilament light chain; p‐tau, phosphorylated tau
FIGURE 5
FIGURE 5
Biomarker cut‐offs for controls versus preAD and controls versus AD. Density plots for each biomarker with cut‐offs taken from the ROC calculated using controls versus AD. Percent of participants in gray zone calculated as the number of participants whose plasma biomarker concentration falls within the gray zone divided by the total number of participants. Blue line represents Youden index. Values shown for Aβ42, GFAP, NfL, and p‐tau181 are in pg/mL. Aβ, amyloid beta; AD, Alzheimer's disease; GFAP, glial fibrillary acidic protein; NfL, neurofilament light chain; preAD, pre‐clinical Alzheimer's disease; p‐tau, phosphorylated tau; Sens., sensitivity; Spec., specificity.
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