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. 2025 Mar;21(3):e70116.
doi: 10.1002/alz.70116.

Novel blood-based proteomic signatures across multiple neurodegenerative diseases

Robert Durcan  1 , Amanda Heslegrave  2 , Peter Swann  3 , Julia Goddard  1   4 , Leonidas Chouliaras  3 , Alexander G Murley  1 , George Savulich  3 , W Richard Bevan-Jones  3 , Owen Swann  2 , Nicholas J Ashton  5   6   7 , Kaj Blennow  5   8 , William McEwan  4 , Henrik Zetterberg  2   5   8   9   10   11 , James B Rowe  1   12 , John T O'Brien  3 , Maura Malpetti  1   4
Affiliations

Novel blood-based proteomic signatures across multiple neurodegenerative diseases

Robert Durcan et al. Alzheimers Dement. 2025 Mar.

Abstract

Introduction: Blood-based biomarkers have the potential to support early and accurate diagnoses of neurodegenerative diseases, which are sensitive to molecular pathology and are predictive of outcome. We evaluated a novel multiplex proteomic method in people with diverse neurodegenerative diseases.

Methods: Serum from people with Alzheimer's disease (N = 36), Lewy body dementia (N = 34), frontotemporal dementia (N = 36), and progressive supranuclear palsy (N = 36) and age-matched controls (N = 30) was analyzed with the nucleic acid linked immuno-sandwich assay (NULISA) central nervous system panel (≈ 120 analytes) and inflammation panel (250 analytes). Biomarkers were compared across groups and included as predictors of survival.

Results: The NULISA panels demonstrated high sensitivity and reliability for detecting multiple biomarkers across neurodegenerative disorders. There were condition-specific proteomic biomarkers, while neurofilament light chain, corticotropin-releasing hormone, CD276, and a data-driven inflammation pattern were significant transdiagnostic outcome predictors.

Discussion: The sensitive NULISA multiplex approach supports differential diagnosis and target identification, with prognostically informative dementia-related biomarkers.

Highlights: We tested the novel technology nucleic acid linked immuno-sandwich assay (NULISA) in people with diverse neurodegenerative diseases, which demonstrated high sensitivity and reliability for detecting multiple biomarkers in serum samples. We compared the NULISA central nervous system serum results to single molecule array (Simoa) plasma assays for phosphorylated tau (p-tau)217, p-tau231, neurofilament light chain (NfL), and glial fibrillary acidic protein, finding strong correlations. Increased levels of serum NfL were identified across all patient groups and most elevated in the frontotemporal dementia (FTD) and progressive supranuclear palsy (PSP) cohorts, while p-tau epitopes were the most significant markers in patients with Alzheimer's disease (AD) and Lewy body dementia. Patients with FTD and PSP showed upregulation of many inflammation markers, compared to controls and patients with AD. We found condition-specific proteomic biomarkers, while NfL, corticotropin-releasing hormone, CD276, and data-driven immune signatures were significant transdiagnostic predictors of clinical outcomes (survival rates).

Keywords: blood‐based biomarkers; dementia; multiplex assays; non–Alzheimer's disease neurodegenerative diseases; nucleic acid linked immuno‐sandwich assay.

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Conflict of interest statement

The authors have no conflicts of interest to report related to this work. Unrelated to this work, J.T.O. has received honoraria for work as DSMB chair or member for TauRx, Axon, Eisai, and Novo Nordisk; has acted as a consultant for Biogen and Roche; and has received research support from Alliance Medical and Merck. J.B.R. is a non‐remunerated trustee of the Guarantors of Brain, Darwin College, and the PSP Association (UK). He provides consultancy unrelated to the current work to Asceneuron, Astronautx, Astex, Curasen, CumulusNeuro, Wave, and SVHealth and has research grants from AZ‐Medimmune, Janssen, and Lilly as industry partners in the Dementias Platform UK. M.M. has acted as a consultant for Astex Pharmaceuticals. W.M. is an academic co‐founder and consultant to Trimtech Therapeutics and has a research grant funded by Takeda Pharmaceuticals. H.Z. has served on 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, Red Abbey Labs, reMYND, Roche, Samumed, Siemens Healthineers, Triplet Therapeutics, and Wave; has given lectures in symposia sponsored by Alzecure, Biogen, Cellectricon, Fujirebio, Lilly, Novo Nordisk, and Roche; 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). A.H. has served as a consultant for Quanterix and been a paid panel member for Lilly. Author disclosures are available in the supporting information.

Figures

FIGURE 1
FIGURE 1
Validation of the dementia‐relevant single markers on the CNS panel. A, Associations between NULISA serum‐based markers and Simoa plasma‐based markers, considering like‐for‐like proteins. B, Group comparisons on dementia‐relevant single markers from the NULISA CNS panel. AD, Alzheimer's disease; CNS, central nervous system; FTD, frontotemporal dementia; GFAP, glial fibrillary acidic protein; LBD, Lewy body disease; MCI, mild cognitive impairment; NfL, neurofilament light chain; NULISA, nucleic acid linked immuno‐sandwich assay; PSP, progressive supranuclear palsy; ptau, phosphorylated tau; Simoa; single molecule array.
FIGURE 2
FIGURE 2
Comparisons between each patient group and controls on CNS markers. For each comparison, the panel on the right represents markers that are increased in patients compared to controls, while the panel on the left represents markers reduced in patients. Orange dots represent comparisons with p < 0.05, and red dots with p < 0.05 corrected for multiple comparisons. AD, Alzheimer's disease; CNS, central nervous system; FDR, false discovery rate; FTD, frontotemporal dementia; LBD, Lewy body disease; MCI, mild cognitive impairment; PSP, progressive supranuclear palsy.
FIGURE 3
FIGURE 3
Prognostic markers on CNS panel. A, Final model by the backward stepwise selection on predictors in the survival analysis, including eight CNS markers (differentiating patients and controls at FDR‐corrected level), age, sex, and diagnosis. B, The final model was selected on survival predictors, including 24 CNS markers (differentiating patients and controls, p uncorrected), age, sex, and diagnosis. For each variable, the hazard ratio on survival is plotted. Cand D, Kaplan–Meier survival curves of NfL and CRH, respectively, divided on the median of each marker (C). AD, Alzheimer's disease; CI, confidence interval; CNS, central nervous system; CRH, corticotropin‐releasing hormone; FDR, false discovery rate; FTD, frontotemporal dementia; GFAP, glial fibrillary acidic protein; LBD, Lewy body disease; NfL, neurofilament light chain; NULISA, nucleic acid linked immuno‐sandwich assay; PSP, progressive supranuclear palsy.
FIGURE 4
FIGURE 4
Comparisons between each patient group and controls on inflammation markers. For each comparison, the panel on the right represents markers that are increased in patients compared to controls, while the panel on the left represents markers reduced in patients. Orange dots represent comparisons to p < 0.05, and red dots with p < 0.05 corrected for multiple comparisons. AD, Alzheimer's disease; FDR, false discovery rate; FTD, frontotemporal dementia; LBD, Lewy body disease; MCI, mild cognitive impairment; PSP, progressive supranuclear palsy.
FIGURE 5
FIGURE 5
Inflammation prognostic markers. A, Kaplan–Meier survival curves of CD276 divided on the median and (B) final model by the backward stepwise selection on predictors in the survival analysis, including 12 inflammatory markers (differentiating patients and controls at FDR‐corrected level), age, sex, and diagnosis. C, The final model was selected on survival predictors, including 57 inflammatory markers (differentiating patients and controls, p uncorrected), age, sex, and diagnosis. For each variable, the hazard ratio on survival is plotted. AD, Alzheimer's disease; AREG, amphiregulin; CI, confidence interval; FDR, false discovery rate; FTD, frontotemporal dementia; LBD, Lewy body disease; NULISA, nucleic acid linked immuno‐sandwich assay; PSP, progressive supranuclear palsy.
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