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DOPA Decarboxylase (DDC) has been proposed as a cerebrospinal fluid (CSF) biomarker with increased concentrations in Lewy body disorders (LBDs) and highest levels in patients receiving dopaminergic treatment. Here we evaluate plasma DDC, measured by proximity extension assay, and the effect of dopaminergic treatment in three independent LBD (with a focus on dementia with Lewy bodies (DLB) and Parkinson's disease (PD)) cohorts: an autopsy-confirmed cohort (n = 71), a large multicenter, cross-dementia cohort (n = 1498) and a longitudinal cohort with detailed treatment information (n = 66, median follow-up time[IQR] = 4[4, 4] years). Plasma DDC was not altered between different LBDs and other disease groups or controls in absence of treatment. DDC levels increased over time in PD, being significantly associated to higher dosages of dopaminergic treatment. This emphasizes the need to consider treatment effect when analyzing plasma DDC, and suggests that plasma DDC, in contrast to CSF DDC, is of limited use as a diagnostic biomarker for LBD, but could be valuable for treatment monitoring., Competing Interests: Competing interests: D.A. participated in advisory boards from Fujirebio-Europe, Roche Diagnostics, Grifols S.A. and Lilly, and received speaker honoraria from Fujirebio-Europe, Roche Diagnostics, Nutricia, Krka Farmacéutica S.L., Zambon S.A.U. and Esteve Pharmaceuticals S.A. L.G, participated on advisory boards for, and received writing honoraria and travel grants from Almirall, Biogen, Euroimmun, Fujirebio, Lilly, Merck, Mylan, Novartis, Roche, Sanofi, Siemens Healthineers and Teva. A.L. participated in advisory boards from Almirall, Biogen, Eisai, Fujirebio-Europe, Grifols, Novartis, Roche, Otsuka Pharmaceutical, Nutricia, Zambón, y NovoNordisk. C.E.T. has a collaboration contract with ADx Neurosciences, Quanterix, and Eli Lilly, performed contract research or received grants from AC-Immune, Axon Neurosciences, BioConnect, Bioorchestra, Brainstorm Therapeutics, Celgene, EIP Pharma, Eisai, Fujirebio, Grifols, Instant Nano Biosensors, Merck, Novo Nordisk, PeopleBio, Roche, Siemens, Toyama, Vivoryon. She is editor of Alzheimer Research and Therapy and serves on editorial boards of Medidact Neurologie/Springer, and Neurology: Neuroimmunology & Neuroinflammation. She had speaker contracts for Roche, Grifols, and Novo Nordisk. The remaining authors declare no competing interests., (© 2025. The Author(s).)

Background and Objectives: Plasma β-amyloid-1-42/1-40 (Aβ42/40), phosphorylated-tau (P-tau), glial fibrillary acidic protein (GFAP), and neurofilament light (NfL) have been widely examined in Alzheimer disease (AD), but little is known about their reflection of copathologies, clinical importance, and predictive value in dementia with Lewy bodies (DLB). We aimed to evaluate associations of these biomarkers with CSF amyloid, cognition, and core features in DLB., Methods: This cross-sectional multicenter cohort study with prospective component included individuals with DLB, AD, and healthy controls (HCs), recruited from 2002 to 2020 with an annual follow-up of up to 5 years, from the European-Dementia With Lewy Bodies consortium. Plasma biomarkers were measured by single-molecule array (Neurology 4-Plex E kit). Amyloid status was determined by CSF Aβ42 concentrations, and cognition was assessed by Mini-Mental State Examination (MMSE). Biomarker differences across groups, associations with amyloid status, and clinical core features were assessed by analysis of covariance. Associations with cognitive impairment and decline were assessed by linear regression and linear mixed-effects models., Results: In our cohort consisting of 562 individuals (HC n = 89, DLB n = 342, AD n = 131; 250 women [44.5%], mean [SD] age of 71 [8] years), sex distribution did not differ between groups. Patients with DLB were significantly older, and had less years of education and worse baseline cognition than HC, but not AD. DLB participants stratified for amyloid status differed significantly in plasma Aβ42/40 ratio (decreased in amyloid abnormal: β = -0.008, 95% CI -0.016 to -0.0003, p = 0.01) and P-tau (increased in amyloid abnormal, P-tau181: β = 0.246, 95% CI 0.011-0.481; P-tau231: β = 0.227, 95% CI 0.035-0.419, both p < 0.05), but not in GFAP (β = 0.068, 95% CI -0.018 to 0.153, p = 0.119), and NfL (β = 0.004, 95% CI -0.087 to 0.096, p = 0.923) concentrations. Higher baseline GFAP, NfL, and P-tau concentrations were associated with lower MMSE scores in DLB, and GFAP and NfL were associated with a faster cognitive decline (GFAP: annual change of -2.11 MMSE points, 95% CI -2.88 to -1.35 MMSE points, p < 0.001; NfL: annual change of -2.13 MMSE points, 95% CI -2.97 to -1.29 MMSE points, p < 0.001). DLB participants with parkinsonism had higher concentrations of NfL (β = 0.08, 95% CI 0.02-0.14, p = 0.006) than those without., Discussion: Our study suggests a possible utility of plasma Aβ42/40, P-tau181, and P-tau231 as a noninvasive biomarkers to assess amyloid copathology in DLB, and plasma GFAP and NfL as monitoring biomarkers for cognitive symptoms in DLB.

INTRODUCTION: We aimed to evaluate informal caregivers' attitudes toward undergoing and future implementation of blood‐based biomarkers (BBBM) testing for Alzheimer's disease (AD). METHODS: We explored caregivers' perspectives, by combining an online survey (n = 107) with a subsequent focus group (n = 7). We used descriptive statistics and thematic content analysis to identify common themes in answers to open‐ended survey questions and focus group data. RESULTS: Most caregivers (72.0%) favored BBBM for AD diagnosis. Provided with hypothetical scenarios, confidence in a normal result decreased significantly if experienced symptoms were more severe (mild: 78.5% vs. severe: 48.6%). Caregivers' attitudes toward BBBM for screening purposes significantly improved with prospect of treatment (53.3% vs. 92.5%). Concerns toward BBBM testing included treatment unavailability, increased/prolonged distress, and AD‐related stigma. Potential benefits were actionability, explanation for symptoms, and opportunities for better care and future treatment. DISCUSSION: Emerging AD treatment and reduction of AD‐related stigma could profoundly increase public interest in BBBM testing for AD. Highlights: Most informal caregivers would want blood‐based biomarker (BBBM) testing for Alzheimer's disease (AD) diagnosis.Perceived (dis)advantages were related to diagnosing AD early.With severe symptoms, there was less confidence in normal BBBM results.Treatment availability would significantly increase interest in BBBM testing for AD.Informal caregivers showed uncertainty regarding the meaning of the term "AD." [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Proteomics studies have shown differential expression of numerous proteins in dementias but have rarely led to novel biomarker tests for clinical use. The Marie Curie MIRIADE project is designed to experimentally evaluate development strategies to accelerate the validation and ultimate implementation of novel biomarkers in clinical practice, using proteomics-based biomarker development for main dementias as experimental case studies. We address several knowledge gaps that have been identified in the field. First, there is the technology-translation gap of different technologies for the discovery (e.g., mass spectrometry) and the large-scale validation (e.g., immunoassays) of biomarkers. In addition, there is a limited understanding of conformational states of biomarker proteins in different matrices, which affect the selection of reagents for assay development. In this review, we aim to understand the decisions taken in the initial steps of biomarker development, which is done via an interim narrative update of the work of each ESR subproject. The results describe the decision process to shortlist biomarkers from a proteomics to develop immunoassays or mass spectrometry assays for Alzheimer's disease, Lewy body dementia, and frontotemporal dementia. In addition, we explain the approach to prepare the market implementation of novel biomarkers and assays. Moreover, we describe the development of computational protein state and interaction predictionmodels to support biomarker development, such as the prediction of epitopes. Lastly, we reflect upon activities involved in the biomarker development process to deduce a best-practice roadmap for biomarker development. [ABSTRACT FROM AUTHOR]