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

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.