Phosphorylated tau-217 (p-tau217) and glial fibrillary acidic protein (GFAP) showed the strongest associations with amyloid beta (Aβ) pathology in plasma samples from an ethnically diverse cohort.
identified several plasma biomarkers linked to Alzheimer's disease (AD), including p-tau217, GFAP, and p-tau231.
Markers related to neuroinflammation, such as C-C motif ligand 2 (CCL2), chitotriosidase 1 (CHIT1), and interleukin-8 (CXCL8), were also associated with .
Astrocytic protein chitinase-3-like protein 1 (CHI3L1) and brain-derived neurotrophic factor (BDNF) were linked to cortical thickness.
Moderate to strong correlations between NULISA and established immunoassay methods were observed for various biomarkers.
Plasma biomarker levels may be influenced by factors like age, sex, apolipoprotein E (APOE) genotype, and self-identified race.
Simplified
INTRODUCTION: Proteomic evaluation of plasma samples could accelerate the identification of novel Alzheimer's disease (AD) biomarkers. We evaluated the novel NUcleic acid Linked Immuno-Sandwich Assay () proteomic method in an ethnically diverse cohort.
METHODS: Plasma biomarkers were measured with NULISA in the Human Connectome Project, a predominantly preclinical biracial community cohort in southwestern Pennsylvania. Selected biomarkers were additionally measured using Simoa and Quest immunoassays and compared.
RESULTS: On NULISA, phosphorylated tau (p-tau217, p-tau231, and p-tau181), glial fibrillary acidic protein (GFAP), and microtubule-associated protein tau (MAPT-tau) showed the top significant association with amyloid beta (Aβ) positron emission tomography (PET) status, followed by the neuroinflammation markers C-C motif ligand 2 (CCL2), chitotriosidase 1 (CHIT1) and interleukin-8 (CXCL8), and the synaptic marker neurogranin (NRGN). Biomarkers associated with cortical thickness included astrocytic protein chitinase-3-like protein 1 (CHI3L1), cytokine CD40 ligand (CD40LG), brain-derived neurotrophic factor (BDNF), the Aβ-associated metalloprotein TIMP3 (tissue inhibitor of metalloprotein 3), and ficolin 2 (FCN2). Furthermore, moderate to strong between-platform correlations were observed for various assays.
DISCUSSION: NULISA multiplexing advantage allowed concurrent assessment of established and novel plasma biomarkers of and .
HIGHLIGHTS: Classical Alzheimer's disease (AD) biomarkers measured using the NUcleic acid Linked Immuno-Sandwich Assay (NULISA) with next-generation sequencing readout (NULISAseq) CNS panel showed strong concordance with those measured using established immunoassay methods from Quanterix and Quest, with glial fibrillary acidic protein (GFAP) and neurofilament light (NfL) exhibiting the strongest correlation. NULISAseq proteomic analysis identified several plasma biomarkers strongly associated with AD pathology in a biracial community cohort of older adults. Notably, phosphorylated tau-217 (p-tau217), GFAP, and p-tau231 displayed the strongest association with amyloid beta (Aβ) pathology, whereas brain-derived neurotrophic factor (BDNF) was strongly associated with neurodegeneration. We demonstrate that plasma biomarker levels could be influenced by age, sex, apolipoprotein E (APOE) genotype, and self-identified race. Specifically, GFAP, NfL, and surfactant protein D (SFTPD) showed a strong association with age; CD63 and S100 calcium-binding protein B (S100B) with self-identified race; synaptosomal-associated protein 25 (SNAP25) with APOE genotype; and serum amyloid A1 (SAA1) and superoxide dismutase 1 (SOD1) with significant sex differences.
Key numbers
108%
Increase in p-tau217 in A+ individuals
Average increase in Aβ PET-positive participants compared to negative controls.
88
Participants in the study
Total number of participants from the Human Connectome Project.
14
Significant associations with
Number of biomarkers significantly associated with Aβ PET status.
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