Alzheimer’s Disease Biological PET Staging Using Plasma P217+tau

Background Plasma phospho-tau biomarkers, such as p217+tau, excel at identifying Alzheimer’s Disease (AD) neuropathology. However, questions remain regarding their capacity to inform AD biological PET stages at group level and maintain the same precision at individual patient level. Method Participants included 248 cognitively unimpaired (CU) and 227 cognitively impaired (CI) individuals, with Janssen plasma p217+tau Simoa® assay, 18F-NAV4694 Aβ PET (A) and 18F-MK6240 tau PET (T) data. Biological PET stages were defined based on the draft NIA-AA Revised Criteria (July 2023): Initial (A+T-), Early (A+TMTL+), Intermediate (A+TMOD+), and Advanced (A+THIGH+). We used thresholds for A+ of 25 Centiloid and for THIGH of 80 Centaur (2.68 SUVRtemporo-parietal). Adding an A-T- stage for comparison, we assessed the performance of p217+tau in discriminating between these stages at the group level using Receiver Operating Characteristic (ROC) analysis and at the individual level using logistic regression. Results Plasma p217+tau concentrations increased across the stages, with significant differences between them, except for the Initial and Early stages. Screening for Advanced ( vs . lower stages), combined Intermediate/Advanced ( vs . lower stages), or all stages ( vs . A-T-), p217+tau showed good group-level discriminations (AUC 0.91, 0.92 and 0.92; CI only: AUC 0.83, 0.89, 0.93, respectively). At the individual level, the likelihood of PET stage vs . p217+tau level showed good discrimination of A-T- vs any A+ stage and of combined Intermediate/Advanced disease stage vs lower stages in the CI. Conclusion In addition to accurately screening for A+ individuals, plasma p217+tau shows promise for separating persons with either Intermediate or Advanced stage AD from those at a lower stage, providing prognostic information and informing better selection for trials and disease modifying therapies. ### Competing Interest Statement Christopher C. Rowe has received research grants from NHMRC, Enigma Australia, Biogen, Eisai and Abbvie. He is on the scientific advisory board for Cerveau Technologies and has consulted for Prothena, Eisai, Roche, and Biogen Australia. Victor L. Villemagne is and has been a consultant or paid speaker at sponsored conference sessions for Eli Lilly, Life Molecular Imaging, GE Healthcare, IXICO, Abbvie, Lundbeck, Shanghai Green Valley Pharmaceutical Co Ltd, AC Immune and Hoffmann La Roche. Ziad S. Saad, Gallen Triana-Baltzer, and Hartmuth C. Kolb are employees of Janssen Pharmaceuticals. Simon M. Laws is a scientific advisor for Cytox Ltd. The other authors did not report any conflict of interest. ### Funding Statement The study was supported by the Australian Federal Government through NHMRC grants APP1132604, APP1140853 and APP1152623 and by a grant from Enigma Australia. Janssen Pharmaceuticals paid a commercial data access fee to the AIBL study of ageing. ### 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: Institutional ethics review committees of the AIBL and ADNeT studies gave ethical approval for this work. 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, after obtaining approval from AIBL and ADNeT.