INTRODUCTION We validated plasma p-tau217 cut-points for Alzheimer’s disease (AD) diagnosis using two commercial assays in two biomarker-defined cohorts and examined influences of pre-analytical factors and chronic kidney disease (CKD) on p-tau217 concentrations.

METHODS Lumipulse (Fujirebio) and ALZpath (Quanterix) assays quantified plasma p-tau217 in symptomatic patients (AD status definition CSF n=257; amyloid PET n=76). ROC analyses established ≥95% sensitivity/specificity cut-points. In separate cohorts we evaluated the impact of pre-analytical handling/transport variations (n=40/10) and cognitively normal (CN)-CKD individuals (n=58).

RESULTS Diagnostic accuracy was similar (AUROC Lumipulse 0.947; ALZpath 0.940). Lumipulse p-tau217 achieved 95% sensitivity and 97% specificity using dual cut-points (0.153/0.422 pg/mL), producing indeterminate results in 19.4% (CSF-defined) and 34.2% (PET-defined). P-tau217 concentrations were stable across handling conditions and kit lots, and mostly in the low-to-intermediate range in CN-CKD.

DISCUSSION Lumipulse plasma p-tau217, now available in our UKAS-accredited clinical NHS laboratory, will be used in a randomized trial of p-tau217 result disclosure in memory services.

AK has received consulting fees from Eli Lilly Ltd and is an executive committee member for the Biofluid Biomarkers Professional Interest Area of ISTAART (unpaid role). She is supported by the NIHR University College London Hospitals Biomedical Research Centre. RW is supported by an NIHR Academic Clinical Fellowship (Grant Ref: ACF-2024-17-002). MH is supported by the University College London Hospitals NIHR Biomedical Research Centre. MPL is supported by the University College London Hospitals NIHR Biomedical Research Centre. NICL has a time-limited unrestricted staff salary grant from Eli Lilly Ltd to support a member of scientific staff to assist with biomarker R&D and clinical service. MCBD is a Clinical Research Training Fellow funded by the Medical Research Council (MRC) (Grant Ref: MR/W016095/1). AJH has undertaken paid consultancy work for Quanterix Corp. HZ has served at scientific advisory boards and/or as a consultant for Abbvie, Acumen, Alector, Alzinova, ALZpath, Amylyx, Annexon, Apellis, Artery Therapeutics, AZTherapies, Cognito Therapeutics, CogRx, Denali, Eisai, Enigma, LabCorp, Merck Sharp & Dohme, Merry Life, Nervgen, Novo Nordisk, Optoceutics, Passage Bio, Pinteon Therapeutics, Prothena, Quanterix, Red Abbey Labs, reMYND, Roche, Samumed, ScandiBio Therapeutics AB, Siemens Healthineers, Triplet Therapeutics, and Wave, has given lectures sponsored by Alzecure, BioArctic, Biogen, Cellectricon, Fujirebio, LabCorp, Lilly, Novo Nordisk, Oy Medix Biochemica AB, Roche, and WebMD, is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program, and is a shareholder of CERimmune Therapeutics (outside submitted work). NCF has received consulting fees from Eisai, F. Hoffmann-La Roche, Eli Lilly, and Biogen, and is an advisory board member for Biogen and Abbvie. PM participates on an independent data safety monitoring board for Johnson & Johnson. He is a trustee of the Alzheimer Society and is the National Institute for Health and Care Research (NIHR) Research Development Network National Specialty Lead for Dementia and Neurodegeneration. He has grant funding from NIHR, Alzheimer's Research UK, Federation Internationale de Football Association, Football Association, LifeArc, Dementias Platform UK, Medical Research Council, UK Dementia Research Institute. JMS has received personal fees from Eli Lilly, Roche, Biogen, MSD, and GE Healthcare; nonfinancial support from Alamar Bioscience; and royalties from Oxford University Press and Henry Stewart Talks. He is a NIHR senior investigator and is supported by the NIHR University College London Hospitals Biomedical Research Centre and the UCL Centre of Research Excellence, an initiative funded by British Heart Foundation. He has grant funding from Alzheimer's Research UK, LifeArc, Brain Research UK, Weston Brain Institute, Medical Research Council, British Heart Foundation, Wolfson Foundation, UK Dementia Research Institute, and Alzheimer's Association. KW, IG-B, KT, LR, OS-A, PW and DPG have no disclosures.

The ADAPT study is funded by the Blood Biomarker Challenge grant ARUK-BBC2023-002 (funding partners Alzheimer's Society, Alzheimer's Research UK, Postcode Innovation Trust, People's Postcode Lottery, the National Institute for Health and Social Care Research), AK, MH, MPL, NCF, HZ and JMS acknowledge the support of the UCLH NIHR Biomedical Research Centre. The Fluid Biomarker Laboratory at UCL is supported by the UK Dementia Research Institute (UKDRI-1003) and the National Institute for Health and Care Research University College London Hospitals Biomedical Research Centre.

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

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The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

REC of London Queen Square gave ethical approval for this work (Wolfson CSF study 12/0344, PI Schott). REC of London Camden and Kings Cross gave ethical approval for this work (the Imperial Amyloid PET Cohort Study 20/LO/0442, PI Malhotra) REC of Institute of Child Health/Great Ormond Street Hospital gave ethical approval for this work (the Polycystic Kidney Disease (PKD) Biobank, sponsored by PKD Charity at Royal Free 05/Q0508/6). REC of London Queen Square gave ethical approval for this work (Biomarkers and Genetics in Dementia study, 03/N049, PI Fox).

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