Thimet oligopeptidase as a potential CSF biomarker for Alzheimer's disease: A cross-platform validation study.

Introduction: Our previous antibody-based cerebrospinal fluid (CSF) proteomics study showed that Thimet oligopeptidase (THOP1), an amyloid beta (Aβ) neuropeptidase, was increased in mild cognitive impairment with amyloid pathology (MCI-Aβ+) and Alzheimer's disease (AD) dementia compared with controls and dementia with Lewy bodies (DLB), highlighting the potential of CSF THOP1 as an early specific biomarker for AD. We aimed to develop THOP1 immunoassays for large-scale analysis and validate our proteomics findings in two independent cohorts.
Methods: We developed in-house CSF THOP1 immunoassays on automated Ella and Simoa platforms. The performance of the different assays were compared using Passing-Bablok regression analysis in a subset of CSF samples from the discovery cohort ( n = 72). Clinical validation was performed in two independent cohorts (cohort 1: n = 200; cohort 2: n = 165) using the Ella platform.
Results: THOP1 concentrations moderately correlated between proteomics analysis and our novel assays ( Rho  > 0.580). In both validation cohorts, CSF THOP1 was increased in MCI-Aβ+ (>1.3-fold) and AD (>1.2-fold) compared with controls; and between MCI-Aβ+ and DLB (>1.2-fold). Higher THOP1 concentrations were detected in AD compared with DLB only when both cohorts were analyzed together. In both cohorts, THOP1 correlated with CSF total tau (t-tau), phosphorylated tau (p-tau), and Aβ40 ( Rho  > 0.540) but not Aβ42.
Discussion: Validation of our proteomics findings underpins the potential of CSF THOP1 as an early specific biomarker associated with AD pathology. The use of antibody-based platforms in both the discovery and validation phases facilitated the translation of proteomics findings, providing an additional workflow that may accelerate the development of biofluid-based biomarkers.
Competing Interests: Y.S.H., K.B., D.R., A.W.L., and M.C. report no conflicts of interest. D.A. participated in advisory boards from Fujirebio‐Europe and Roche Diagnostics and received speaker honoraria from Fujirebio‐Europe, Roche Diagnostics, Nutricia, Krka Farmacéutica S.L., Zambon S.A.U., and Esteve Pharmaceuticals S.A., D.A. declares a filed patent application (WO2019175379 A1 Markers of synaptopathy in neurodegenerative disease). A.L. participated in advisory boards from Fujirebio‐Europe, Grifols, Eisai, Novartis, Roche Diagnostics, Otsuka Pharmaceutical, Nutricia, Zambón S.A.U., and Biogen, and received speaker honoraria from Eli Lilly, Biogen, KRKA, and Zambon. A.L. declares a filed patent application (WO2019175379 A1 Markers of synaptopathy in neurodegenerative disease). Research programs of W.F. have been funded by ZonMW, NWO, EU‐FP7, EU‐JPND, Alzheimer Nederland, Hersenstichting CardioVascular Onderzoek Nederland, Health∼Holland, Topsector Life Sciences & Health, stichting Dioraphte, Gieskes‐Strijbis fonds, stichting Equilibrio, Edwin Bouw fonds, Pasman stichting, stichting Alzheimer & Neuropsychiatrie Foundation, Philips, Biogen MA Inc, Novartis‐NL, Life‐MI, AVID, Roche BV, Fujifilm, Eisai, and Combinostics. W.F. holds the Pasman chair. W.F. is recipient of ABOARD, which is a public‐private partnership receiving funding from ZonMW (#73305095007) and Health∼Holland, Topsector Life Sciences & Health (PPP‐allowance; #LSHM20106). W.F. has been an invited speaker at Biogen MA Inc, Danone, Eisai, WebMD Neurology (Medscape), NovoNordisk, Springer Healthcare, NovoNordisk, and European Brain Council. W.F. is a consultant to Oxford Health Policy Forum CIC, Roche, and Biogen MA Inc. W.F. participated in advisory boards of Biogen MA Inc, Roche, and Eli Lilly. All funding is paid to her institution. W.F. is member of the steering committee of PAVE and Think Brain Health. W.F. was associate editor of Alzheimer's Research & Therapy in 2020/2021. W.F. is associate editor at Brain. C.T. has a collaboration contract with ADx Neurosciences, Quanterix, and Eli Lilly, and performed contract research or received grants from AC‐Immune, Axon Neurosciences, Bioconnect, Bioorchestra, Brainstorm Therapeutics, Celgene, EIP Pharma, Eisai, Grifols, Novo Nordisk, PeopleBio, Roche, Toyama, and Vivoryon. C.T. serves on editorial boards of Medidact Neurologie/Springer, Alzheimer's Research & Therapy, and Neurology: Neuroimmunology & Neuroinflammation and is editor of a Neuromethods book (Springer). She had speaker contracts for Roche, Grifols, and Novo Nordisk. Author disclosures are available in the supporting information.
(© 2023 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals, LLC on behalf of Alzheimer's Association.)