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. 2025 Feb 13;17(1):42.
doi: 10.1186/s13195-025-01696-9.

Plasma Hepcidin as a potential informative biomarker of Alzheimer disease and vascular dementia

Constance Delaby #  1   2 , Daniel Alcolea #  3   4 , Germain Busto  5 , Audrey Gabelle  5 , Xavier Ayrignac  5 , Karim Bennys  5 , Elena Muiño  6   7 , Paula Villatoro  8 , Israel Fernández-Cadenas  8 , Nicolas Pradeilles  9 , Shaima El Bounasri  3 , Soraya Torres  3 , Christophe Hirtz  9 , Henrik Zetterberg  10   11   12   13   14   15 , Alberto Lleó  3   4 , Juan Fortea #  3   4 , Sylvain Lehmann #  9
Affiliations

Plasma Hepcidin as a potential informative biomarker of Alzheimer disease and vascular dementia

Constance Delaby et al. Alzheimers Res Ther. .

Abstract

Background: Blood-based assays are expected to be integrated into clinical routines across various contexts, including Alzheimer's disease (AD). Vascular dementia (VaD), which is the second most common cause leading to dementia after AD, could also significantly benefit from this advancement. However, no informative fluid biomarker has been identified for VaD. Given the disruption of iron homeostasis in both AD and VaD, this study aims to characterize the potential of the iron-related hormone Hepcidin as a biomarker for these two conditions. We will compare its added value to established AT(N) blood biomarkers.

Methods: Blood biomarkers (amyloid-composite, p-Tau181, Neurofilament Light Chain [NfL] and Hepcidin) levels in blood were analyzed in two independent cohorts and compared between AD patients and non-AD individuals. Additionally, blood Hepcidin and NfL were evaluated in the contexts of VaD and CADASIL, with their relative diagnostic value assessed.

Results: Blood Hepcidin and NfL do not significantly increase the AUC obtained with both p-Tau181 and amyloid composite in the context of AD. In contrast, AUC for VaD diagnosis is significantly higher when combining these two blood biomarkers compared to NfL alone. Hepcidin was not significantly modified in CADASIL patients compared to control subjects.

Conclusion: Blood Hepcidin and NfL have limited interest in the clinical context of AD but determination of these biomarkers shows to be highly informative for the diagnosis of VaD. This result could have important implications for diagnosis and implementation of clinical trials.

Keywords: Alzheimer’s disease; Blood biomarkers; Diagnosis; Hepcidin; NfL; Vascular dementia.

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Conflict of interest statement

Declarations. Ethics approval and consent to participate: All the patients at each clinical centre gave their written informed consent to participating in clinical research on CSF biomarkers, which was approved by the respective Ethics Committees. The committee responsible in Montpellier was the regional Ethics Committee of the Montpellier University Hospital and Montpellier CSF-Neurobank #DC-2008–417 at the certified NFS 96–900 CHU resource center BB-0033–00031, www.biobanques.eu . Authorization to handle personal data was granted by the French Data Protection Authority (CNIL) under the number 1709743 v0. Competing interests: H.Z has served at scientific advisory boards and/or as a consultant for Abbvie, Acumen, Alector, Alzinova, ALZpath, Amylyx, Annexon, Apellis, Artery Therapeutics, AZTherapies, Cognito Therapeutics, CogRx, Denali, Eisai, LabCorp, Merry Life, Nervgen, Novo Nordisk, Optoceutics, Passage Bio, Pinteon Therapeutics, Prothena, Quanterix, Red Abbey Labs, reMYND, Roche, Samumed, Siemens Healthineers, Triplet Therapeutics, and Wave, has given lectures sponsored by Alzecure, BioArctic, Biogen, Cellectricon, Fujirebio, Lilly, Novo Nordisk, Roche, and WebMD, and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program (outside submitted work). 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., Neuraxpharm, Alter Medica, Lilly and Esteve Pharmaceuticals S.A. D.A. declares a filed patent application (WO2019175379 A1 Markers of synaptopathy in neurodegenerative disease). 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., Neuraxpharm, Alter Medica, Lilly and Esteve Pharmaceuticals S.A. D.A. declares a filed patent application (WO2019175379 A1 Markers of synaptopathy in neurodegenerative disease).

Figures

Fig. 1
Fig. 1
Evaluation of plasma biomarkers’ Informativity in non-AD subjects versus AD patients (cohort 1): Panels (A) and (B) show comparison of plasma level of Hepcidin and p-Tau181 respectively (for non-AD subjects, the SCI subjects are in blue, DLB in orange, FTD in green, PSP in black, MS in gray, and OND in white). Results were adjusted by age and sex. Results are presented as boxplots, where the central box represents the values from the lower to upper quartile (25 to 75 percentile). The middle line represents the median. The horizontal line extends from the minimum to the maximum value, excluding outside and far out values which are displayed as separate points. Clinical groups were compared through analysis of covariance adjusting by age and sex; *: p = 0.05, **p: 0.001. Results were analysed by the non-parametric Kruskal–Wallis test and the post hoc pairwise Mann–Whitney-test. Panel (C) compares receiving operator characteristics (ROC) analysis adjusted for age and sex of Aβ composite (Aβ compo, dark blue line), p-Tau181 (green line), Hepcidin (red line), regression model combining p-Tau181 and Aβ composite (orange line) and regression model combining the 3 biomarkers (Aβ composite, p-Tau181 and Hepcidin, light blue line) between non-AD and AD groups
Fig. 2
Fig. 2
Plasma Hepcidin and NfL variation in patients with various neurodegenerative diseases (cohort2): Panel (A) and B respectively show plasma level of Hepcidin and neurofilament light (NfL) in control participants and patients with dementia: Alzheimer Disease (AD) slow and fast decliners, Frontotemporal Dementia (FTD), Dementia with Lewy Bodies (DLB) and Vascular Dementia (VaD). Results were adjusted by age and sex, and are presented as boxplots, where the central box represents the values from the lower to upper quartile (25 to 75 percentile). The middle line represents the median. The horizontal line extends from the minimum to the maximum value, excluding outside and far out values which are displayed as separate points. Clinical groups were compared through analysis of covariance adjusting by age and sex; *: p = 0.05. Results were analysed by the non-parametric Kruskal–Wallis test and the post hoc pairwise Mann–Whitney-test
Fig. 3
Fig. 3
Evaluation of plasma biomarkers’ informativity in patients with Vascular Dementia and CADASIL patients (cohort 2): Panel (A) compares receiving operator characteristics (ROC) analysis adjusted for age and sex of Hepcidin (dark blue line), NfL (green line), and regression model combining both biomarkers (red line) between control participants and VaD patients. Panel (B) compares receiving operator characteristics (ROC) analysis adjusted for age and sex of Hepcidin (dark blue line), NfL (green line), and regression model combining both biomarkers (red line) between control participants and CADASIL patients
Fig. 4
Fig. 4
Plasma Hepcidin and NfL variation in CADASIL patients: Panels (A) and B respectively show plasma level of Hepcidin and neurofilament light (NfL) in control participants and patients with CADASIL. Results were adjusted by age and sex. Results are presented as boxplots, where the central box represents the values from the lower to upper quartile (25 to 75 percentile). The middle line represents the median. The horizontal line extends from the minimum to the maximum value, excluding outside and far out values which are displayed as separate points. Clinical groups were compared through analysis of covariance adjusting by age and sex; *: p = 0.05. Results were analysed by the non-parametric Kruskal–Wallis test and the post hoc pairwise Mann–Whitney-test
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