Biomarker discovery in Alzheimer's and neurodegenerative diseases using Nucleic Acid Linked Immuno-Sandwich Assay.

Kaj Blennow, Chiara Tolassi, Matilde Bongianni, Laia Montoliu-Gaya, Joel Simrén, Kubra Tan, Jonathan Schott, Federica Anastasi, Guglielmo Di Molfetta, Andrea L Benedet, Andrea Pilotto, Alessandro Padovani, Marc Suárez-Calvet, Bárbara Fernandes Gomes, Henrik Zetterberg, Nicholas J Ashton, Ilaria Pola, Barbara Borroni, Valentina Cantoni, Aida Fernández-Lebrero, Albert Puig-Pijoan, Gianluigi Zanusso, Antonella Alberici, Richard Isaacson, Ashvini Keshavan

Journal: Alzheimer's & dementia : the journal of the Alzheimer's Association 2025;21(5):e14621

PMID: 40401628

Abstract

INTRODUCTION

Recent advancements in immunological methods accurately quantify biofluid biomarkers for Alzheimer's disease (AD) pathology. Despite progress, more biomarkers, ideally in blood, are needed for effective disease monitoring for AD and other neurodegenerative proteinopathies.

METHODS

We used the Nucleic Acid Linked Immuno-Sandwich Assay (NULISA) central nervous system panel for biomarker quantification in plasma, serum, and cerebrospinal fluid of patients with AD, mild cognitive impairment, Lewy body dementia, progranulin (GRN) mutation carriers.

RESULTS

NULISA identified phosphorylated tau217 and neurofilament light chain as the most deregulated biomarkers in the AD continuum and GRN mutation carriers, respectively. Importantly, numerous novel proteomic changes were observed in each disease endophenotype, which included synaptic processing, inflammation, microglial reactivity, TAR DNA-binding protein 43, and α-synuclein pathology.

DISCUSSION

We underline the potential of next-generation biomarker identification tools to detect novel proteomic features that also incorporate established biomarkers. These findings highlight the importance of continued biomarker discovery to improve treatment decisions and help us better understand the complexities of neurodegenerative disorders.

HIGHLIGHTS

The, direct, or indirect, measures in blood that complement phosphorylated tau (p-tau)217 for other proteinopathies or disease progression are urgently needed. Significant novel proteomic changes were observed in each disease endophenotype in plasma, serum, and cerebrospinal fluid, which included proteins involved in synaptic processing, inflammation, microglial reactivity, TAR DNA-binding protein 43, and α-synuclein pathology. Nucleic Acid Linked Immuno-Sandwich Assay continued to unbiasely highlight p-tau217 and neurofilament light chain as the most significantly deregulated blood biomarkers in the Alzheimer's disease continuum and progranulin mutation carriers, respectively.

© 2025 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.

Address: Department of Psychiatry and Neurochemistry, Institute of Neuroscience & Physiology, the Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden.; Banner Alzheimer's Institute and University of Arizona, Phoenix, Arizona, USA.; Banner Sun Health Research Institute, Sun City, Arizona, USA.; Department of Psychiatry and Neurochemistry, Institute of Neuroscience & Physiology, the Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden.; Hospital del Mar Research Institute, Barcelona, Spain.; Barcelonaβeta Brain Research Center (BBRC), Pasqual Maragall Foundation, Barcelona, Spain.; Hospital del Mar Research Institute, Barcelona, Spain.; Barcelonaβeta Brain Research Center (BBRC), Pasqual Maragall Foundation, Barcelona, Spain.; Servei de Neurologia, Hospital del Mar, Barcelona, Spain.; Department of Medicine and Life Sciences, Universitat Pompeu Fabra, Barcelona, Spain.; Hospital del Mar Research Institute, Barcelona, Spain.; Servei de Neurologia, Hospital del Mar, Barcelona, Spain.; Department of Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain.; Dementia Research Centre, UCL Queen Square Institute of Neurology, University College London, London, UK.; Dementia Research Centre, UCL Queen Square Institute of Neurology, University College London, London, UK.; UK Dementia Research Institute at UCL, London, UK.; Department of Neurology, Weill Cornell Medicine and New York Presbyterian, New York, New York, USA.; Department of Neurology, Florida Atlantic University, Charles E. Schmidt College of Medicine, Boca Raton, Florida, USA.; Department of Neurosciences, Biomedicine, and Movement Sciences, Policlinico G. B. Rossi, University of Verona, Verona, Italy.; Clinical Investigation in Laboratory, Maggiore Hospital ASST-Crema, Crema, Italy.; Department of Clinical and Experimental Sciences, Neurology Unit, University of Brescia, Brescia, Italy.; Department of Clinical and Experimental Sciences, Neurology Unit, University of Brescia, Brescia, Italy.; Department of Continuity of Care and Frailty, Azienda Socio Sanitaria Territoriale (ASST) Spedali Civili, Brescia, Italy.; Laboratory of Digital Neurology and Biosensors, University of Brescia, Brescia, Italy.; Brain Health Center, University of Brescia, Brescia, Italy.; Department of Neuroscience, Biomedicine and Movement Sciences, University of Verona, Verona, Italy.; Department of Clinical and Experimental Sciences, Neurology Unit, University of Brescia, Brescia, Italy.; Department of Continuity of Care and Frailty, Azienda Socio Sanitaria Territoriale (ASST) Spedali Civili, Brescia, Italy.; Hospital del Mar Research Institute, Barcelona, Spain.; Barcelonaβeta Brain Research Center (BBRC), Pasqual Maragall Foundation, Barcelona, Spain.; Servei de Neurologia, Hospital del Mar, Barcelona, Spain.; Centro de Investigación Biomédica en Red de Fragilidad y Envejecimiento Saludable (CIBERFES), Madrid, Spain.; Department of Psychiatry and Neurochemistry, Institute of Neuroscience & Physiology, the Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden.; Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden.; Paris Brain Institute, ICM, Pitié-Salpêtrière Hospital, Sorbonne University, Hôpital Pitié, Paris, France.; Neurodegenerative Disorder Research Center, Division of Life Sciences and Medicine, and Department of Neurology, Institute on Aging and Brain Disorders, University of Science and Technology of China and First Affiliated Hospital of USTC, Hefei, P. R. China.; Department of Psychiatry and Neurochemistry, Institute of Neuroscience & Physiology, the Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden.; Dementia Research Centre, UCL Queen Square Institute of Neurology, University College London, London, UK.; UK Dementia Research Institute at UCL, London, UK.; Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden.; Hong Kong Center for Neurodegenerative Diseases, Hong Kong, China.; Wisconsin Alzheimer's Disease Research Center, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin, USA.
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