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Alzheimer’s & Dementia

Integrated Proteomic Analysis of Alzheimer and Mild Cognitive Impairment in Biofluid using Mass Spectrometry and NULISA™ Technology

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  • January 9, 2025
  • Yao Chen, et al., Sanofi
Topic/Product:
CNS Disease Panel 120, Neurology
Disease Area:
Alzheimer's Disease
Sample Type:
CSF, Plasma

Abstract

Background

One hypothesis of lack of effectiveness in most current clinical trials for the AD (Alzheimer’s disease) is the advanced stages of the disease at the time of pharmacological intervention. To aim a robust effect from disease‐modifying therapies, there is an urgent need for biomarkers that can identify patients with MCI and early stages of AD. In this study, we combined in‐house large‐scale LC‐MS and new emerging highly sensitive NULISA proteomics analysis on a medium sized AD cohort sample, aiming an early‐stage protein biomarker discovery in MCI and AD.

Method

59 AD set plasma and 65 AD set CSF were purchased from the vendor. Donor classification strictly followed the disease inclusion/exclusion criteria. One aliquot from each sample were sent to Alamar Bioscience for NULISAseq analysis on ARGOTM system using 120‐plex CNS disease panel. In house LC‐MS was performed on the same set of samples.

Result

Of 59 AD set plasma samples (19 HC, 22 MCI AND 18 AD), 3 significantly up‐regulated protein in MCI and 16 significantly down‐regulated protein in AD and MCI were identified by NULISAseq 120plex CNS panel. One significantly up‐regulated protein in MCI and 3 significantly down‐regulated proteins in AD were also confirmed by in house LC‐MS. Of 65 AD set CSF samples (19 HC, 22 MCI and 24 AD), 12 significantly up‐regulated proteins and 11 significant down‐regulated protein in AD and MCI were identified by NULISAseq 120plex CNS panel. CSF protein profiling by in house LC‐MS is still pending. 5 (3 from plasma, and 2 from CSF) significantly up‐regulated novel proteins in MCI and CD have been reported to be associated with neuronal connectivity, neuro inflammation or acting as a neuromodulator. Sample correlation in CSF between NULISAseq and Simoa (Single Molecule Array) was also verified by NFL and pTau181. Both proteins displayed excellent correlation (R2 was 0.88 and 0.92).

Conclusion

5 novel significantly upregulated protein biomarkers in MCI and AD were identified by combined in house MS and new emerging NULISAseq technologies. The integrated proteomic method could be a powerful tool to identify the molecular signature and pathological pathways associated with AD and MCI.

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Authors & Affiliations

 1,✉,  1,  1,  1

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Steve Williams, MD, PhD

CSO

Dr. Willams serves as the company’s Chief Scientific Officer. He was previously Chief Medical Officer at Standard Biotools and at SomaLogic where he pioneered the discipline for discovery and validation of predictive, diagnostic and prognostic models using machine-learning applied to large-plex proteomics. 20 such tests were used for drug characterization, safety and efficacy when incorporated in clinical drug trials at Pharma/Biotech and 17 different multivariate tests were validated and translated into regulated healthcare uses. Prior to SomaLogic, Dr. Williams was at Pfizer in the UK and the USA as a clinical triallist in Translational Medicine, and subsequently as VP, Global Clinical Technology. He sat on the National Advisory Council for the National Institute of Biomedical Imaging and Bioengineering, the Executive Committee for the FNIH Biomarkers Consortium, and worked with FDA and PhRMA on developing evidentiary standards for biomarker qualification. Dr. William’s medical training was in London, at Charing Cross and Westminster Medical School, followed by a PhD in medicine/physiology at the same institution and training in Radiology at the University of Newcastle Upon Tyne. Steve is co-inventor on 26 proteomics patents and author/coauthor on multiple foundational proteomics manuscripts.

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Justin McAnear

CFO

Mr. McAnear serves as the company’s Chief Financial Officer. He brings over 25 years of operational and financial leadership experience across various sectors and was instrumental in taking 10x Genomics public in 2019, serving as its CFO for over five years. Mr. McAnear served for over 3 years as Tesla’s VP of Worldwide Finance and Operations, supporting landmark initiatives such as the Model X and Model 3 launches and Solar City acquisition.  He also held various roles at Apple and J&J earlier in his career and served as a naval officer and aviator for over 9 years.