Diagnostic performance of plasma Aß42/40 ratio, p-tau181, GFAP, and NfL along the continuum of Alzheimer's disease and non-AD dementias: an international multi-center study

Abstract

Introduction: Plasma phosphorylated tau (p-tau)181, glial fibrillary acidic protein (GFAP), neurofilament light chain (NfL), and amyloid beta ratio (Aß42/40) 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. Aß40, Aß42, 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 Aß- 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.

O.H. has acquired research support (for the institution) from AVID Radiopharmaceuticals, Biogen, C2N Diagnostics, Eli Lilly, Eisai, Fujirebio, GE Healthcare, and Roche. In the past 2 years, he has received consultancy/speaker fees from Alzpath, BioArctic, Biogen, Bristol Meyer Squibb, Eisai, Eli Lilly, Fujirebio, Merck, Novartis, Novo Nordisk, Roche, Sanofi, and Siemens. L.G. participated on advisory boards for, and received writing honoraria and travel grants from, Almirall, Biogen, Euroimmun, Fujirebio, Lilly, Merck, Mylan, Novartis, Roche, Sanofi, Siemens Healthineers, and Teva. Work at Lund University was supported by the European Research Council (ADG-101096455), Alzheimer's Association (ZEN24-1069572, SG-23-1061717), GHR Foundation, Swedish Research Council (2022-00775), ERA PerMed (ERAPERMED2021-184), Knut and Alice Wallenberg foundation (2022-0231), Strategic Research Area MultiPark (Multidisciplinary Research in Parkinson's disease) at Lund University, Swedish Alzheimer Foundation (AF-980907), Swedish Brain Foundation (FO2021-0293), Parkinson foundation of Sweden (1412/22), Cure Alzheimer's fund, Rönström Family Foundation, Konung Gustaf V:s och Drottning Victorias Frimurarestiftelse, Skåne University Hospital Foundation (2020-O000028), Regionalt Forskningsstöd (2022-1259), and Swedish federal government under the ALF agreement (2022-Projekt0080). The ALFA+ Study has received funding from “la Caixa” Foundation (ID 100010434), under agreement LCF/PR/GN17/50300004, the Alzheimer's Association, and an international anonymous charity foundation through the TriBEKa Imaging Platform project (TriBEKa-17-519007). Additional support has been received from the Universities and Research Secretariat, Ministry of Business and Knowledge of the Catalan Government under the grant no. 2021 SGR 00913. M.S.-C. receives funding from the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation program (Grant agreement No. 948677); ERA PerMed (ERAPERMED2021-184); Project “PI19/00155” and ‘‘PI22/00456, funded by Instituto de Salud Carlos III (ISCIII) and co-funded by the European Union; and from a fellowship from “la Caixa” Foundation (ID 100010434) and from the European Union's Horizon 2020 research and innovation program under the Marie Skłodowska-Curie grant agreement No 847648 (LCF/BQ/PR21/11840004). Research of C.E.T. is supported by the European Commission (Marie Curie International Training Network), grant agreement No 860197 (MIRIADE), Innovative Medicines Initiatives 3TR (Horizon 2020, grant no 831434) EPND (IMI 2 Joint Undertaking [JU], grant No. 101034344) and JPND (bPRIDE), European Partnership on Metrology, co-financed from the European Union's Horizon Europe Research and Innovation Programme and by the Participating States (22HLT07 NEuroBioStand), CANTATE project funded by the Alzheimer Drug Discovery Foundation, Alzheimer Association, Health Holland, the Dutch Research Council (ZonMW), Alzheimer Drug Discovery Foundation, The Selfridges Group Foundation, Alzheimer Netherlands. C.T. 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). C.T. is recipient of TAP-dementia, a ZonMw funded project (#10510032120003) in the context of the Dutch National Dementia Strategy.