Clinical value of plasma ALZpath pTau217 immunoassay in the assessment of mild cognitive impairment

Objectives We sought to compare two of the most promising plasma biomarkers for Alzheimer disease: pTau181 and pTau217. Methods pTau181 and pTau217 were quantified using SIMOA Quanterix and ALZpath assays in the well characterized prospective multicentre BALTAZAR cohort of mild cognitive impairment (MCI) participants. Results Among MCI participants, 55% were Aβ+ and 29% developed dementia due to AD. pTau181 and pTau217 were higher in the Aβ+ population with fold-change of 1.5 and 2.7 respectively. Concentration were also higher in MCI that converted to AD versus with hazard ratio of 1.38 (1.26-1.51) for pTau181 compared to 8.22 (5.45-12.39) for pTau217. The AUC for predicting Aβ+ was 0.783 (95%CI: 0.721-0.836; cut-point 2.75 pg/mL) for pTau181 and 0.914 (95%CI: 0.868-0.948; cut-point 0.44 pg/mL) for pTau217. The predictive power of pTau217 was not improved by adding age, sex, and APOEε4 status in a logistic model. The confounding factors of age, APOEε4 or renal dysfunction were associated with both pTau levels, but pTau217 clinical performance was only marginally modified by these comorbidities. Using a two cut-point approach, a 95% positive predictive value for Aβ+ corresponded to pTau217 > 0.8 ng/mL and a 95% negative predictive value at <0.23 ng/mL. At these two cut-points, the percentages of MCI conversion were 56.8% and 9.7% respectively, while the annual rates of decline in MMSE were -2.32 versus -0.65. Conclusions Plasma pTau217 and pTau181 both correlate with AD, but the fold-change in pTau217 make it better to diagnose cerebral amyloidosis, and predict cognitive decline and conversion to AD dementia. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement The French ministry of Health (Programme Hospitalier de Recherche Clinique), Grant/Award Numbers:PHRC2009/01-04,PHRC-13-0404; The Foundation Plan Alzheimer; Fondation pour la Recherche Medicale (FRM); The Gerontopole Ile de France (GERONDIF). None of the funding bodies had any role in study design, in the collection, analysis, and interpretation of data, in the writing of the report or in the decision to submit the paper for publication. ### 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: All participants gave written informed consent to be part of the study. The BALTAZAR study was approved by the Paris ethics committee (CPP Ile de France IV Saint-Louis Hospital). Clinical trial registration: [NCT01315639][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 Data and informed consent form are available upon request after publication (APHP, Paris). Requests will be considered by each study investigator, based on the information provided by the requester, regarding the study and analysis plan. If the use is appropriate, a data sharing agreement will be put in place before distributing a fully de-identified version of the dataset, including the data dictionary used for analysis with individual participant data. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01315639&atom=%2Fmedrxiv%2Fearly%2F2024%2F01%2F22%2F2024.01.21.24301570.atom