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 identifying Alzheimers pathology and neurodegeneration. Despite this progress, more biomarkers, ideally in blood, are needed for effective patient management and disease monitoring for Alzheimers disease (AD) and other neurodegenerative proteinopathies. METHODS: We employed the Nucleic Acid-Linked Immuno-Sandwich Assay (NULISA) central nervous system (CNS) panel for biomarker quantification in plasma, serum and cerebrospinal fluid (CSF) of patients with AD, mild cognitive impairment, Lewy body dementia, progranulin (GRN) mutation carriers and matched controls. RESULTS: NULISA identified p-tau217 and NfL as the most significantly deregulated plasma biomarkers in the AD continuum and GRN mutation carriers, respectively. Importantly, numerous novel and significant proteomic changes were observed in each disease comparison, which included proteins involved in synaptic processing, inflammation, microglial reactivity, TDP-43 and alpha-synuclein pathology. Plasma and serum act as complimentary biofluids. CONCLUSION: We highlight the potential of next-generation biomarker identification tools, such as NULISA, to detect novel proteomic features that incorporate established biomarkers like p-tau217 and NfL. These findings highlight the importance of continued biomarker discovery to enhance patient management, improve treatment decisions, and better understand the complexities of neurodegenerative disorders