Targeted proteomic biomarker profiling using NULISA in a cohort enriched with risk for Alzheimer's disease and related dementias.

INTRODUCTION

Targeted proteomic assays may be useful for diagnosing and staging Alzheimer's disease and related dementias (ADRD). We evaluated the performance of a 120-marker central nervous system (CNS) NUcleic acid Linked Immuno-Sandwich Assay (NULISA) panel in samples spanning the Alzheimer's disease (AD) spectrum.

METHODS

Cross-sectional plasma samples (n = 252) were analyzed using NULISAseq CNS panel from Alamar Biosciences. Receiver-operating characteristic (ROC) analyses demonstrated the accuracy from NULISAseq-tau phosphorylated at threonine 217 (pTau217) in detecting amyloid (A) and tau (T) positron emission tomography (PET) positivity. Differentially expressed proteins were identified using volcano plots.

RESULTS

NULISAseq-pTau217 accurately classified A/T PET status with ROC areas under the curve of 0.92/0.86; pTau217 was upregulated in A+, T+, and impaired groups with log2-fold changes of 1.21, 0.57, and 4.63, respectively, compared to A-. Of interest, TAR DNA-binding protein 43 (TDP-43) phosphorylated at serine 409 (pTDP43-409) was also upregulated in the impaired group and correlated with declining hippocampal volume and cognitive trajectories.

DISCUSSION: This study shows the potential of a targeted proteomics panel for characterizing brain changes pertinent to ADRD. The promising pTDP43-409 findings require further replication.

HIGHLIGHTS: The NULISAseq pTau217 assay was comparable to the Simoa pTau217 assay, both utilizing the ALZpath antibody, in detecting amyloid positron emission tomography (PET) positivity, each with areas under the curve greater than 90%. Nineteen proteins were differentially expressed in participants with mild cognitive impairment (MCI) compared to those who were unimpaired. Markers of non-AD proteinopathies such as pTDP43-409, oligomeric alpha-synuclein, and huntingtin (HTT), were among those upregulated in MCI. High levels of plasma pTDP43-409 were associated with worsening hippocampal atrophy and cognitive decline, clinical indicators of limbic-predominant age-related TDP-43 encephalopathy (LATE), compared to those with low pTDP43-409.