Diagnostic performance of plasma Aβ1-42, Aβ1-40 and pTau181 in the LUMIPULSE automated platform for the detection of Alzheimer disease

BACKGROUND: Recently-developed blood markers for Alzheimer's (AD) detection have high accuracy but usually require ultra-sensitive analytic tools not commonly available in clinical laboratories. METHODS: We analyzed plasma samples from 367 consecutive participants in the SPIN cohort, comprising 302 euploid participants (67 cognitively unimpaired, 136 participants with mild cognitive impairment, and 99 with dementia) and 65 with Down Syndrome (46 non-demented and 19 with AD dementia). Participants were classified according to CSF biomarkers status using the AT(N) system. Plasma AB1-42, AB1-40 and pTau181 were measured in the fully-automated LUMIPULSE platform. We used ANOVA to compare plasma biomarkers concentrations between AT(N) groups, evaluated Spearman's correlation between plasma and CSF and performed ROC analyses to assess their diagnostic accuracy to detect AD. RESULTS: Plasma pTau181 concentration was higher in A+T+ than A+T- and A-T-, and in A+T- and A-T+ than A-T[ndash]. The plasma AB1-42/AB1-40 ratio was lower in A+T+ and A+T- compared to A-T-. pTau181 and the AB1-42/AB1-40 ratio showed moderate correlation between plasma and CSF (Rho=0.66 and 0.65, respectively). The areas under the ROC curve (AUC) to discriminate A+T+ from A-T- participants were 0.91 for pTau181 and 0.86 for AB1-42/AB1-40. The combination of both measures yielded an AUC=0.94. Chronic kidney disease (CKD) was related to increased plasma biomarker concentrations, but ratios were not significantly affected. CONCLUSION: The feasibility and performance of plasma-based biomarker measurements on an automated platform showed high diagnostic accuracy and hold great promise for the diagnostic process of AD. ### Competing Interest Statement Daniel Alcolea is employed by Hospital de la Santa Creu i Sant Pau and received research grants from Pla Estrategic de Recerca i Innovacio en Salut (PERIS SLT006/17/125), and from Instituto de Salud Carlos III (PI18/00435 and INT19/00016). He participated in advisory boards from Fujirebio-Europe and Roche Diagnostics and received speaker honoraria from Fujirebio-Europe, Roche Diagnostics, Nutricia, Zambon S.A.U., Esteve, and from Krka Farmaceutica S.L. Javier Arranz is employed by Biomedical Research Institute Sant Pau. He is funded by a Rio Hortega research grant from the Institute of Health Carlos III. Declarations of interest: none Nuole Zhu is employed by Biomedical Research Institute Sant Pau. He is funded by a Rio Hortega research grant from the Institute of Health Carlos III. Declarations of interest: none Sara Rubio-Guerra is employed by Hospital de la Santa Creu i Sant Pau. Declarations of interest: none Inigo Rodriguez-Baz is employed by Biomedical Research Institute Sant Pau. He is funded by a Rio Hortega research grant from the Institute of Health Carlos III. Declarations of interest: none. Maria Carmona-Iragui is employed by Hospital de la Santa Creu i Sant Pau. Declarations of interest: none. Isabel Barroeta is employed by Hospital de la Santa Creu i Sant Pau. Declarations of interest: none. Drs Illan-Gala is a senior Atlantic Fellows for Equity in Brain Health at the Global Brain Health Institute (GBHI), and is supported with funding from GBHI, Alzheimer's Association, and Alzheimer's Society (GBHI ALZ UK-21-720973 and AACSF-21-850193). Dr Illan-Gala was also supported by the Juan Rodes Contract (JR20/0018) from Instituto de Salud Carlos III. This work was supported by Fondo de Investigaciones Sanitario, Instituto de Salud Carlos III (PI21/00791 to Dr IllanGala). Ignacio Illan-Gala reported receiving personal fees from Nutricia, Esteve, UCB, and Neuraxpharm Spain outside the submitted work. Miguel Santos-Santos is employed by Hospital de la Santa Creu i Sant Pau. His research is supported by funding from from the Spanish Institute of Health Carlos III (Juan Rodes research grant JR18-00018; Fondo de investigacion sanitaria grant PI19/00882), the Alzheimer's Association clinician scientist fellowship (AACSF-22-972945), and the National Institutes of Health (R01AG080470). Juan Fortea is employed by Hospital de la Santa Creu i Sant Pau and received research grants from Institute of Health Carlos III, National Institutes of Health, Fundacio La Marato de TV3, and Pla Estrategic de Recerca i Innovacio en Salut (PERIS). Dr. Fortea has served as a consultant for Novartis and Lundbeck, has received honoraria for lectures from Roche, NovoNordisk, Esteve and Biogen and served at advisory boards for AC Immune, Zambon and Lundbeck. Alberto Lleo is employed by Hospital de la Santa Creu i Sant Pau and received research grants from CIBERNED, Institute of Health Carlos III, Generalitat de Catalunya (PERIS and AGAUR) and Fundacion Tatiana and BBVA. He participated in advisory boards from Biogen, Eisai, Fujirebio-Europe, Novartis, Novo ### Funding Statement This study was supported by the Fondo de Investigaciones Sanitario (FIS), Instituto de Salud Carlos III (PI14/01126, PI17/01019 and PI20/01473 to JF, PI13/01532 and PI16/01825 to RB, PI18/00335 to MCI, PI19/00882 to MS-S, PI18/00435 and INT19/00016 to DA, PI17/01896 and AC19/00103to AL) and the CIBERNED program (Program 1, Alzheimer Disease to AL), jointly funded by Fondo Europeo de Desarrollo Regional, Unión Europea, ″Una manera de hacer Europa″. This work was also supported by the National Institutes of Health (NIA grants 1R01AG056850-01A1; R21AG056974; and R01AG061566 to JF), by Generalitat de Catalunya (2017-SGR-547, SLT006/17/125 to DA, SLT006/17/119 to JF, SLT002/16/408 to AL) and ″Marató TV3″ foundation grants 20141210 to JF, 044412 to RB and 20142610 to AL. This work was also supported by a grant from the Fundació Bancaria La Caixa to RB (DABNI project). Fundació Catalana Síndrome de Down and Fundació Víctor Grífols i Lucas partly supported this work. Horizon 21 Consortium is partly funded by Jèrôme Lejeune Foundation (Clinical and trial outcome measures for dementia in individuals with Down syndrome). The reagents necessary to complete the study were funded by Fujirebio-Europe. The sponsors of the study did not take part in the design and conduct of the study; collection, management, analysis, and interpretation of the data; writing and review of the report; or the decision to submit the article 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: The ethics committee of Hospital Sant Pau approved all procedures included in this study following the standards for medical research in humans recommended by the Declaration of Helsinki. All participants or their legally authorised representative gave written informed consent before enrolment in the study. 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 Raw anonymized data and code for statistical analysis are available upon reasonable request. All requests should be sent to the corresponding author detailing the study hypothesis and statistical analysis plan. The steering committee of this study will decide whether data/code sharing is appropriate based on the novelty and scientific rigor of the proposal. All applicants will be asked to sign a data access agreement.