Diagnostic utility of plasma ptau217, ptau181, GFAP for Alzheimer disease in a heterogeneous younger onset dementia clinical cohort

Objective We investigated diagnostic utility of phosphorylated tau 217 and 181 (ptau217, ptau181), glial fibrillary acidic protein (GFAP), amyloid beta 42 and 40 (Aβ42, Aβ40), neurofilament light (NfL) to distinguish AD from non-AD conditions, in a heterogenous clinical cohort of younger people. Methods Plasma biomarkers were analysed using ultrasensitive technology, and compared in patients with CSF Alzheimer disease profiles (A+T+) to other profiles (OtherAT). Results Seventy-nine patients were included, median age 60.8 years: 16 A+T+, 63 OtherAT. Ptau217, ptau181, GFAP were significantly elevated in A+T+ compared to OtherAT (3.67 vs 1.12pg/mL, 3.87 vs 1.79pg/mL, 189 vs 80pg/mL, respectively). ptau217 distinguished AD from OtherAT with 90% accuracy (88% specificity, 100% sensitivity) Conclusions Plasma ptau217 has strong diagnostic utility to diagnose AD in a clinically relevant, younger cohort of people with symptoms, adding further weight for a simple diagnostic blood test for AD as a cause of a patient’s symptoms. ### Competing Interest Statement ACKNOWLEDGEMENTS AND FUNDING SOURCES HZ is a Wallenberg Scholar and a Distinguished Professor at the Swedish Research Council supported by grants from the Swedish Research Council 202300356 202201018 and 201902397 the European Unions Horizon Europe research and innovation programme under grant agreement No 101053962 Swedish State Support for Clinical Research ALFGBG71320 the Alzheimer Drug Discovery Foundation ADDF USA 2018092016862 the AD Strategic Fund and the Alzheimers Association ADSF21831376C ADSF21831381C ADSF21831377C and ADSF241284328C the Bluefield Project Cure Alzheimers Fund the Olav Thon Foundation the ErlingPersson Family Foundation Stiftelsen fr Gamla Tjnarinnor Hjrnfonden Sweden FO20220270 the European Unions Horizon 2020 research and innovation programme under the Marie SkodowskaCurie grant agreement No 860197 MIRIADE the European Union Joint Programme Neurodegenerative Disease Research JPND202100694 the National Institute for Health and Care Research University College London Hospitals Biomedical Research Centre and the UK Dementia Research Institute at UCL UKDRI1003 MK is supported by the Research Training Program Scholarship from the Department of Psychiatry University of Melbourne with contributions from the Australian Commonwealth Government and the Ramsay Hospital Research Foundation Acknowledgements Funding KB is supported by the Swedish Research Council 201700915 and 202200732 the Swedish Alzheimer Foundation AF930351 AF939721 AF968270 and AF994551 Hjrnfonden Sweden FO20170243 and ALZ20220006 the Swedish state under the agreement between the Swedish government and the County Councils the ALFagreement ALFGBG715986 and ALFGBG965240 the European Union Joint Program for Neurodegenerative Disorders JPND2019466236 the Alzheimers Association 2021 Zenith Award ZEN21848495 the Alzheimers Association 20222025 Grant SG231038904 QC La Fondation Recherche Alzheimer FRA Paris France the Kirsten and Freddy Johansen Foundation Copenhagen Denmark and Familjen Rnstrms Stiftelse Stockholm Sweden Finally the authors would like to thank all the current and past Neuropsychiatry Centre clinicians and most importantly patients and their families for their participation The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication DECLARATION OF INTERESTS AND FINANCIAL DISCLOSURES HZ has served at scientific advisory boards andor as a consultant for Abbvie Acumen Alector Alzinova ALZPath Amylyx Annexon Apellis Artery Therapeutics AZTherapies Cognito Therapeutics CogRx Denali Eisai Merry Life Nervgen Novo Nordisk Optoceutics Passage Bio Pinteon Therapeutics Prothena Red Abbey Labs reMYND Roche Samumed Siemens Healthineers Triplet Therapeutics and Wave has given lectures in symposia sponsored by Alzecure Biogen Cellectricon Fujirebio Lilly Novo Nordisk and Roche and is a cofounder of Brain Biomarker Solutions in Gothenburg AB BBS which is a part of the GU Ventures Incubator Program outside submitted work SL has received honorarium from Lundbeck and Otsuka AHE has received honoraria from Abbvie STADA Seqirus and Ipsen KB has served as a consultant and at advisory boards for Abbvie AC Immune ALZPath AriBio BioArctic Biogen Eisai Lilly Moleac Pte Ltd Novartis Ono Pharma Prothena Roche Diagnostics and Siemens Healthineers has served at data monitoring committees for Julius Clinical and Novartis has given lectures produced educational materials and participated in educational programs for AC Immune Biogen Celdara Medical Eisai and Roche Diagnostics and is a cofounder of Brain Biomarker Solutions in Gothenburg AB BBS which is a part of the GU Ventures Incubator Program outside the work presented in this paper All the other authors have nothing to disclose ### Funding Statement Australian Government NHMRC Ideas Grant ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Ethics committee/IRB of The Royal Melbourne Hospital and others gave ethical approval for this work: This study, part of The Markers in Neuropsychiatric Disorders Study (The MiND Study, https://themindstudy.org), was approved by the Human Research Ethics Committees at Melbourne Health (2016.038, 2017.090, 2018.371, 2020.142), University of Melbourne (1341074), St. Vincent's Hospital (028-06), and the Florey Institute of Neurosciences and Mental Health (1648441.1). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors