Clarifications and response to “Validating plasma biomarkers for distinguishing neurodegenerative and psychiatric disorders” by Boccardi et al.

We thank Boccardi and colleagues for their timely commentary, and for the opportunity to respond. We agree with their central message that blood biomarkers should be translated through rigorous, context-specific, incremental validation and with explicit attention to real-world implementation. We also agree that no single study should be interpreted as the endpoint of clinical translation. We would like to take this opportunity to clarify several points to ensure our study is interpreted accurately. Context-of-use in our study was explicitly defined in detail in the methods section, addressing difficult differential diagnosis in a specialist setting.1 While we focused on specific diagnostic categories, like another recent study published in this journal by another group,2 this study, as well as our broader work, has focused on unselected patients in real-world specialist clinical settings. We completely agree with the need for future research validating our findings in other memory clinics, and expanding to more diverse settings, especially primary care and primary psychiatric settings, a point we emphasized in the research in context section: “Future directions: Future research should validate these findings in larger, more diverse cohorts, develop multimodal diagnostic algorithms, and evaluate the clinical utility and cost-effectiveness of implementing blood biomarker testing in psychiatric, primary care, and memory clinic settings.”1 In addition, it is important to clarify that diagnostic categorization was independent of the plasma biomarkers: “Diagnostic group categorization was determined based on the most recent diagnosis, at longitudinal follow-up, based on established diagnostic criteria, blinded to plasma biomarker levels”. This methodological separation is central to our design and was intended to minimize bias. We would like to reiterate that this study, as described in the Methods section, is a follow-up to our previous study, titled “Plasma and CSF neurofilament light chain distinguish neurodegenerative from primary psychiatric conditions in a clinical setting”, published in the same journal.3 It is worth reading our current study and Boccardi et al.’s comments in the context of this previous work,3 and another recent study of ours “Strong diagnostic performance of plasma ptau217 for CSF biomarker-defined young-onset Alzheimer disease in a diagnostically heterogeneous clinical cohort”.4 Collectively, those two studies and the current study, addresses, in a defined unselected real-world clinical cohort, a defined specialist-care problem that is increasingly recognized in current guidance and implementation literature. Furthermore, it is important to consider the current study, and the comments, as part of a larger program of work, that has been more specifically focused on diagnostic and broader performance of ptau217 and neurofilament light chain (NfL) in diverse disorders and settings, moving from early pilot to more definitive studies and longitudinal diagnostic prediction, with much ongoing work, in particular regarding broader clinical settings and implementation3-18. We agree that it is useful to consider the five-phase roadmap perspective.19-22 If mapped to that framework, our study is a late clinical-validation to early implementation bridge in specialist care, with Phase-5-type questions (pathway impact, outcomes, and health economics) being the next priority. We respect the roadmap's contribution, while acknowledging that the evidence base has advanced rapidly since these publications, with substantial progress and converging evidence across multiple phases of this roadmap, without necessarily requiring explicit mapping on to that framework. Very strongly performing biomarkers with a lot of independent replication studies will require less strict adherence to frameworks and will move faster from discovery to clinical translation. For ptau217, evidence has accumulated for the strong diagnostic performance for Alzheimer's disease (AD) versus other disorders in multiple settings,2, 4, 23-29 support for clinically actionable use in structured pathways and specialist-care guideline recommendations,30, 31 and identifying future research needs,32 high-performance automated-platform studies across primary and secondary care,33 and two-step workflows that explicitly manage uncertainty zones.34 AD-specific biomarkers and ptau217 were not the only focus in this study and our broader work, but on NfL translational signal as well. For NfL, the evidence remains compelling that it discriminates neurodegenerative from primary psychiatric disorders, while requiring careful interpretation in psychiatric and non-specialized settings. Beyond our program of work so far,3, 5-11 multiple independent groups now report convergent findings for distinguishing neurodegenerative disorders such as AD and behavioral variant frontotemporal demetia (bvFTD) from primary psychiatric disorders, in a range of settings.35-38 At the same time, we3, 39 and others38, 40-43 rightly emphasize the need for attention to various analytical, reference range, and implementation pitfalls, particularly in psychiatric disorders and settings. We have acknowledged other important limitations in our study in the discussion, including subgroup size constraints, and incomplete gold-standard biomarker confirmation for all participants, as well as other limitations, analytical and other issues. Future directions, particularly with regard to NfL, were identified and discussed in detail in our other recent publications.3, 4 These are real constraints and issues, and they motivate the next phase of work, including larger multisite pathway studies, assay harmonization, calibration across age and case mix, prospective impact outcomes, health-economic analyses, and other implementation and global equity issues as described by others.32, 44-46.We are well underway now on such important future work, for example, biomarker performance in psychiatric and primary care settings,11, 12 factors contributing to biomarker false positives and negatives, addressing analytical and reference ranges and precision interpretation issues we have identified, improved technologies,47 and health economic and cost-effectiveness analyses. We once again thank Boccardi et al.’s commentary and share their emphasis on rigor. We appreciate the opportunity to discuss both the importance of rigor and frameworks, as well as the practical realities of advancing blood biomarkers toward clinical use in specialist and real-world settings. We believe the most accurate interpretation is that our study contributes clinically relevant evidence within a broader, rapidly evolving ptau217 and NfL translational framework–one that is now supported by converging external literature and is progressing toward implementation-oriented outcomes. The authors have nothing to report. H.Z. 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 MicThera (outside submitted work). The other authors have nothing to disclose. Author disclosures are available in the supporting information. No funding supported this paper. 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