Restricted accessResearch articleFirst published online 2025-11
Comparison of diagnostic accuracy of Alzheimer's disease cerebrospinal fluid core biomarkers using INNOTEST,Lumipulse G,and Elecsys assays: Insights from the PUMCH dementia cohort study
Cerebrospinal fluid (CSF) core biomarkers play a pivotal role in the biological diagnosis of Alzheimer's disease (AD). While various commercial assays and kits are available for quantifying these biomarkers, their performance across diverse clinical settings remains insufficiently evaluated.
Objective
This study aimed to compare the diagnostic accuracy of AD core biomarkers using four measurement methods in a Chinese population and to establish method-specific cutoff values tailored to different clinical scenarios.
Methods
A total of 309 participants were enrolled from the PUMCH dementia cohort, comprising 176 AD, 114 non-AD dementia cases, and 19 cognitively normal controls (CN). For biomarker quantification, we employed one manual immunoassay (INNOTEST, conducted in two independent laboratories) and two fully automated immunoassay platforms (Lumipulse G and Roche Elecsys). These methods were used to measure CSF Aβ1–40, Aβ1–42, t-tau, and p-tau181, and to calculate three biomarker ratios (Aβ1–42/Aβ1–40, t-tau/Aβ1–42, and p-tau181/Aβ1–42).
Results
Our findings provide method-specific and clinical context-optimized cutoff values for each application scenario including clinically diagnosed AD versus non-AD dementia, amyloid PET-positive versus PET-negative dementia, and AD versus CN. The accuracy of differential diagnosis was higher using biomarker ratios (Aβ1–42/Aβ1–40, t-tau/Aβ1–42, p-tau181/Aβ1–42) than absolute values. Most of the high accuracy was achieved using automated assays especially Lumipulse G rather than manual assays.
Conclusions
In this first comparative study of three immunoassays in a Chinese cohort, automated assays demonstrated superior performance compared to manual assays. We established assay-specific cutoff values tailored to different clinical contexts in a Chinese population.
JackCRJr.BennettDABlennowK, et al.NIA-AA Research framework: toward a biological definition of Alzheimer's disease. Alzheimers Dement2018; 14: 535–562.
2.
JackCRJr.AndrewsJSBeachTG, et al.Revised criteria for diagnosis and staging of Alzheimer's disease: Alzheimer's Association Workgroup. Alzheimers Dement2024; 20: 5143–5169.
3.
BlennowK. CSF Biomarkers for Alzheimer's disease: use in early diagnosis and evaluation of drug treatment. Expert Rev Mol Diagn2005; 5: 661–672.
4.
KangJHKoreckaMToledoJB, et al.Clinical utility and analytical challenges in measurement of cerebrospinal fluid amyloid-β(1-42) and τ proteins as Alzheimer disease biomarkers. Clin Chem2013; 59: 903–916.
5.
OosthoekMVermuntLde WildeA, et al.Utilization of fluid-based biomarkers as endpoints in disease-modifying clinical trials for Alzheimer's disease: a systematic review. Alzheimers Res Ther2024; 16: 93.
6.
SeeburgerJLHolderDJCombrinckM, et al.Cerebrospinal fluid biomarkers distinguish postmortem-confirmed Alzheimer's disease from other dementias and healthy controls in the OPTIMA cohort. J Alzheimers Dis2015; 44: 525–539.
7.
SalvadóGLarssonVCodyKA, et al.Optimal combinations of CSF biomarkers for predicting cognitive decline and clinical conversion in cognitively unimpaired participants and mild cognitive impairment patients: a multi-cohort study. Alzheimers Dement2023; 19: 2943–2955.
8.
PanneeJGobomJShawLM, et al.Round robin test on quantification of amyloid-β 1-42 in cerebrospinal fluid by mass spectrometry. Alzheimers Dement2016; 12: 55–59.
9.
KollhoffALHowellJCHuWT. Automation vs. experience: measuring Alzheimer's beta-amyloid 1-42 peptide in the CSF. Front Aging Neurosci2018; 10: 253.
10.
DakterzadaFLópez-OrtegaRAriasA, et al.Assessment of the concordance and diagnostic accuracy between Elecsys and Lumipulse fully automated platforms and Innotest. Front Aging Neurosci2021; 13: 604119.
11.
HanssonOBatrlaRBrixB, et al.The Alzheimer's Association international guidelines for handling of cerebrospinal fluid for routine clinical measurements of amyloid β and tau. Alzheimers Dement2021; 17: 1575–1582.
12.
McKhannGMKnopmanDSChertkowH, et al.The diagnosis of dementia due to Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement2011; 7: 263–269.
13.
McKhannGMAlbertMSGrossmanM, et al.Clinical and pathological diagnosis of frontotemporal dementia: report of the Work Group on Frontotemporal Dementia and Pick's Disease. Arch Neurol2001; 58: 1803–1809.
14.
SachdevPKalariaRO'BrienJ, et al.Diagnostic criteria for vascular cognitive disorders: a VASCOG statement. Alzheimer Dis Assoc Disord2014; 28: 206–218.
15.
McKeithIGBoeveBFDicksonDW, et al.Diagnosis and management of dementia with Lewy bodies: fourth consensus report of the DLB consortium. Neurology2017; 89: 88–100.
16.
EmreMAarslandDBrownR, et al.Clinical diagnostic criteria for dementia associated with Parkinson's disease. Mov Disord2007; 22: 1689–1707. quiz 1837.
17.
MinoshimaSDrzezgaAEBarthelH, et al.SNMMI Procedure standard/EANM practice guideline for amyloid PET imaging of the Brain 1.0. J Nucl Med2016; 57: 1316–1322.
18.
WillemseEAJTijmsBMvan BerckelBNM, et al.Comparing CSF amyloid-beta biomarker ratios for two automated immunoassays, Elecsys and Lumipulse, with amyloid PET status. Alzheimers Dement (Amst)2021; 13: e12182.
19.
BlennowKStomrudEZetterbergH, et al.Second-generation elecsys cerebrospinal fluid immunoassays aid diagnosis of early Alzheimer's disease. Clin Chem Lab Med2023; 61: 234–244.
20.
NiemantsverdrietEValckxSBjerkeM, et al.Alzheimer's disease CSF biomarkers: clinical indications and rational use. Acta Neurol Belg2017; 117: 591–602.
21.
HampelHToschiNBaldacciF, et al.Alzheimer's disease biomarker-guided diagnostic workflow using the added value of six combined cerebrospinal fluid candidates: aβ(1–42), total-tau, phosphorylated-tau, NFL, neurogranin, and YKL-40. Alzheimers Dement2018; 14: 492–501.
22.
ShawLMAriasJBlennowK, et al.Appropriate use criteria for lumbar puncture and cerebrospinal fluid testing in the diagnosis of Alzheimer's disease. Alzheimers Dement2018; 14: 1505–1521.
23.
LeeJJangHKangSH, et al.Cerebrospinal fluid biomarkers for the diagnosis and classification of Alzheimer's disease spectrum. J Korean Med Sci2020; 35: e361.
24.
HennemanWJVrenkenHBarnesJ, et al.Baseline CSF p-tau levels independently predict progression of hippocampal atrophy in Alzheimer disease. Neurology2009; 73: 935–940.
25.
LachnoDRRomeoMJSiemersER, et al.Validation of ELISA methods for quantification of total tau and phosporylated-tau181 in human cerebrospinal fluid with measurement in specimens from two Alzheimer's disease studies. J Alzheimers Dis2011; 26: 531–541.
26.
LachnoDREvertBAMaloneyK, et al.Validation and clinical utility of ELISA methods for quantification of amyloid-β of peptides in cerebrospinal fluid specimens from Alzheimer’s disease studies. J Alzheimers Dis2015; 45: 527–542.
27.
DumurgierJVercruysseOPaquetC, et al.Intersite variability of CSF Alzheimer's disease biomarkers in clinical setting. Alzheimers Dement2013; 9: 406–413.
28.
GobomJParnettiLRosa-NetoP, et al.Validation of the LUMIPULSE automated immunoassay for the measurement of core AD biomarkers in cerebrospinal fluid. Clin Chem Lab Med2022; 60: 207–219.
29.
LeitãoMJSilva-SpínolaASantanaI, et al.Clinical validation of the lumipulse G cerebrospinal fluid assays for routine diagnosis of Alzheimer's disease. Alzheimers Res Ther2019; 11: 91.
30.
BayartJLHanseeuwBIvanoiuA, et al.Analytical and clinical performances of the automated Lumipulse cerebrospinal fluid Aβ(42) and T-Tau assays for Alzheimer's disease diagnosis. J Neurol2019; 266: 2304–2311.
31.
MoonSKimSMankhongS, et al.Alzheimer's cerebrospinal biomarkers from lumipulse fully automated immunoassay: concordance with amyloid-beta PET and manual immunoassay in Koreans : CSF AD biomarkers measured by Lumipulse in Koreans. Alzheimers Res Ther2021; 13: 22.
32.
AlcoleaDPeguerolesJMuñozL, et al.Agreement of amyloid PET and CSF biomarkers for Alzheimer's disease on Lumipulse. Ann Clin Transl Neurol2019; 6: 1815–1824.
33.
NojimaHItoSKushidaA, et al.Clinical utility of cerebrospinal fluid biomarkers measured by LUMIPULSE(®) system. Ann Clin Transl Neurol2022; 9: 1898–1909.
34.
HanssonOSeibylJStomrudE, et al.CSF Biomarkers of Alzheimer's disease concord with amyloid-β PET and predict clinical progression: a study of fully automated immunoassays in BioFINDER and ADNI cohorts. Alzheimers Dement2018; 14: 1470–1481.
35.
SchindlerSEGrayJDGordonBA, et al.Cerebrospinal fluid biomarkers measured by Elecsys assays compared to amyloid imaging. Alzheimers Dement2018; 14: 1460–1469.
36.
DoeckeJDWardLBurnhamSC, et al.Elecsys CSF biomarker immunoassays demonstrate concordance with amyloid-PET imaging. Alzheimers Res Ther2020; 12: 36.
37.
GrotheMJMoscosoAAshtonNJ, et al.Associations of fully automated CSF and novel plasma biomarkers with Alzheimer disease neuropathology at autopsy. Neurology2021; 97: e1229–e1242.
38.
FaullMChingSYJarmolowiczAI, et al.Comparison of two methods for the analysis of CSF aβ and tau in the diagnosis of Alzheimer's disease. Am J Neurodegener Dis2014; 3: 143–151.
39.
Monge-ArgilésJAMuñoz-RuizCSánchez-PayáJ, et al.Comparison of two analytical platforms for CSF biomarkers of Alzheimer's disease. Biomed Res Int2014; 2014: 765130.
40.
SchipkeCGProkopSHeppnerFL, et al.Comparison of immunosorbent assays for the quantification of biomarkers for Alzheimer's disease in human cerebrospinal fluid. Dement Geriatr Cogn Disord2011; 31: 139–145.
41.
KeshavanAWellingtonHChenZ, et al.Concordance of CSF measures of Alzheimer's pathology with amyloid PET status in a preclinical cohort: a comparison of Lumipulse and established immunoassays. Alzheimers Dement (Amst)2021; 13: e12131.
42.
ToombsJFoianiMSWellingtonH, et al.Amyloid β peptides are differentially vulnerable to preanalytical surface exposure, an effect incompletely mitigated by the use of ratios. Alzheimers Dement (Amst)2018; 10: 311–321.
43.
WillemseEvan UffelenKBrixB, et al.How to handle adsorption of cerebrospinal fluid amyloid β (1–42) in laboratory practice? Identifying problematic handlings and resolving the issue by use of the Aβ(42)/Aβ(40) ratio. Alzheimers Dement2017; 13: 885–892.
44.
DursunEAlayliogluMBilgicB, et al.Amyloid beta adsorption problem with transfer plates in amyloid beta 1–42 IVD kits. J Mol Neurosci2019; 67: 534–539.
45.
ToombsJPatersonRWSchottJM, et al.Amyloid-beta 42 adsorption following serial tube transfer. Alzheimers Res Ther2014; 6: 5.
46.
VandersticheleHMJanelidzeSDemeyerL, et al.Optimized standard operating procedures for the analysis of cerebrospinal fluid Abeta42 and the ratios of Abeta isoforms using low protein binding tubes. J Alzheimers Dis2016; 53: 1121–1132.
47.
HanssonOLehmannSOttoM, et al.Advantages and disadvantages of the use of the CSF Amyloid β (Aβ) 42/40 ratio in the diagnosis of Alzheimer's disease. Alzheimers Res Ther2019; 11: 34.
48.
BaldeirasISantanaILeitãoMJ, et al.Addition of the Aβ42/40 ratio to the cerebrospinal fluid biomarker profile increases the predictive value for underlying Alzheimer's disease dementia in mild cognitive impairment. Alzheimers Res Ther2018; 10: 33.
49.
Peña-BautistaCÁlvarez-SánchezLPascualR, et al.Clinical usefulness of cerebrospinal fluid biomarkers in Alzheimer's disease. Eur J Clin Invest2023; 53: e13910.
50.
ParkSAChaeWSKimHJ, et al.Cerebrospinal fluid biomarkers for the diagnosis of Alzheimer disease in South Korea. Alzheimer Dis Assoc Disord2017; 31: 13–18.
51.
JanelidzeSPanneeJMikulskisA, et al.Concordance between different amyloid immunoassays and visual amyloid positron emission tomographic assessment. JAMA Neurol2017; 74: 1492–1501.
52.
GaetaniLChiasseriniDPaolini PaolettiF, et al.Required improvements for cerebrospinal fluid-based biomarker tests of Alzheimer's disease. Expert Rev Mol Diagn2023; 23: 1195–1207.
53.
DelabyCTeunissenCEBlennowK, et al.Clinical reporting following the quantification of cerebrospinal fluid biomarkers in Alzheimer's disease: an international overview. Alzheimers Dement2022; 18: 1868–1879.
54.
ZwanMDRinneJOHasselbalchSG, et al.Use of amyloid-PET to determine cutpoints for CSF markers: a multicenter study. Neurology2016; 86: 50–58.
55.
ToledoJBBrettschneiderJGrossmanM, et al.CSF Biomarkers cutoffs: the importance of coincident neuropathological diseases. Acta Neuropathol2012; 124: 23–35.
56.
ForlenzaOVRadanovicMTalibLL, et al.Cerebrospinal fluid biomarkers in Alzheimer's disease: diagnostic accuracy and prediction of dementia. Alzheimers Dement (Amst)2015; 1: 455–463.
57.
Puig-PijoanAGarcía-EscobarGFernández-LebreroA, et al.The CORCOBIA study: cut-off points of Alzheimer's disease CSF biomarkers in a clinical cohort. Neurologia (Engl Ed)2024; 39: 756–765.
58.
OrellanaAGarcía-GonzálezPValeroS, et al.Establishing in-house cutoffs of CSF Alzheimer's disease biomarkers for the AT(N) stratification of the Alzheimer center Barcelona cohort. Int J Mol Sci2022; 23: 6891.
Supplementary Material
Please find the following supplemental material available below.
For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.
For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.
