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bioRxiv · 10.1101/2025.06.10.658994

Multiplex Proteomics of Lewy Body Dementia Reveals Cerebrospinal Fluid Biomarkers of Disease Pathology and Progression

Higginbotham, L.·Shantaraman, A.·Guo, Q.·Fox, E. J.·Bagchi, P.·Wu, F.·Lah, J. J.·Levey, A. I.·Seyfried, N. T.
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Abstract

Lewy body dementia (LBD), which encompasses Parkinsons disease dementia (PDD) and Dementia with Lewy bodies (DLB), lacks established biofluid markers of its complex clinical and neuropathological heterogeneity. Multiplex proteomic tools, such as the recently developed NUcleic acid Linked ImmunoSandwich Assay (NULISATM), can assess a diverse array of neurodegenerative targets and address these biomarker gaps. We used this platform to analyze 852 baseline and longitudinal cerebrospinal fluid (CSF) samples from control, PD, and DLB subjects from the Parkinsons Disease Biomarker Program (PDBP). We then examined LBD protein signatures across different clinical diagnoses, patterns of cognitive progression, and underlying neuropathologies. Of the 124 markers analyzed, 54 were significantly altered in PD with cognitive impairment and/or DLB compared to controls, many serving as informative clinical classifiers in machine learning models. We also identified 15 proteins with significant baseline and/or longitudinal changes linked to cognitive progression. To identify neuropathological signatures, we stratified 209 cases by the presence of underlying synuclein and amyloid-beta (A{beta}) pathology using CSF alpha-synuclein seed amplification assay (Syn-SAA) results and NULISA pTau-217 levels, respectively. Select synaptic markers were decreased relative to synucleinopathy but increased relative to A{beta} accumulation, complicating their interpretation in cases with co-pathology. These neuropathological analyses were replicated in an independent cohort of 917 cases from the Alzheimers Disease Neuroimaging Initiative (ADNI). Overall, these results highlight the utility of multiplex proteomic analysis in the identification of candidate CSF biomarkers of disease heterogeneity in LBD. One Sentence SummaryThis multiplex proteomic analysis using the recently released NULISA platform revealed unique targets of Lewy body dementia progression and neuropathology.

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Higginbotham, L., Shantaraman, A., Guo, Q., Fox, E. J., Bagchi, P., Wu, F., Lah, J. J., Levey, A. I., Seyfried, N. T.. 2025-06-13. Multiplex Proteomics of Lewy Body Dementia Reveals Cerebrospinal Fluid Biomarkers of Disease Pathology and Progression. https://doi.org/10.1101/2025.06.10.658994

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