Thimet Oligopeptidase is a potential CSF biomarker for Alzheimer’s Disease

Abstract

AbstractBackgroundUsing antibody‐based Olink proteomics, we recently established that Thimet Oligopeptidase (THOP1) is a potential cerebrospinal fluid (CSF) biomarker for Alzheimer’s Disease (AD). THOP1 is a neuropeptidase able to degradate Aβ peptides. Here, we aimed to develop specific THOP1 immunoassays for further clinical validation and to enable future implementation of this biomarker.MethodWe developed and compared novel immunoassays for CSF THOP1 analysis on automated Ella™ and Simoa™ platforms. After analytical validation, THOP1 levels were measured in a selection of CSF samples from the original discovery study (24 cognitively unimpaired controls, 24 AD and 24 dementia with Lewy bodies (DLB) patients) on both platforms. Passing bablok‐regression analysis showed that platforms were comparable and thus we selected the Ella platform for further validation in two independent cohorts (Amsterdam Dementia cohort (ADC) including 56 controls, 45 mild cognitive impairment with amyloid pathology (MCI‐Aβ+), 55 AD and 55 DLB patients; Sant Pau Initiative on Neurodegeneration (SPIN) cohort including 53 controls, 50 MCI‐Aβ+, 47 AD and 50 DLB patients). Differences in THOP1 levels between diagnostic groups and correlations to the AD CSF biomarkers were tested by ANCOVA (corrected for sex) and Spearman correlation analyses.ResultTHOP1 levels moderately correlated between proteomics analysis and the novel assays (Olink‐Ella: rho=0.720; Olink‐Simoa: rho=0.584; Ella‐Simoa rho=0.713; figure 1). Consistent with results obtained on the Olink proteomics platform, THOP1 levels were significantly increased in AD compared to DLB patients (Ella: 1.6‐fold; Simoa: 1.7‐fold) and controls (Ella: 1.8‐fold; Simoa: p>0.05). We next showed increased THOP1 levels in both MCI‐Aβ+ (ADC: 1.2‐fold, p<0.05; SPIN: 1.4‐fold, p<0.001) and AD patients (ADC: 1.03‐fold, p>0.05; SPIN: 1.4‐fold, p<0.001) compared to controls (Figure 2). THOP1 levels correlated moderately with levels of t‐Tau (ADC: rho=0.644; SPIN: rho=0.721), p‐Tau (ADC: rho=0.480; SPIN: rho=0.712) and Aβ40 (ADC: not available; SPIN: rho=0.625) but not with Aβ42 (ADC: rho=0.110; SPIN: rho=‐0.09).ConclusionWe show increased CSF THOP1 levels in amyloid positive AD and MCI patients and correlation with CSF Aβ40, which together with literature showing colocalization of THOP1 with Aβ plaques suggests a relationship with Aβ‐production. The association of THOP1 to tau pathologies highlights the potential of this protein as a disease monitoring biomarker.