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medRxiv

Exploratory Blood Biomarker Patterns in a Mixed Dementia Cohort

  • November 8, 2024
  • Bedia Samanci, et al., Istanbul University
Product:
CNS Disease Panel 120
Topic:
Neurology
Disease Area:
Alzheimer's Disease, Dementia
Sample Type:
CSF
Back to Publications​
  • November 8, 2024
  • Bedia Samancı, et al. Istanbul University
Topic/Product:
CNS Disease Panel 120
Disease Area:
Alzheimer's Disease, Dementia
Sample Type:
CSF

Abstract

Alzheimer’s disease (AD) diagnosis is challenging due to overlapping symptoms with other dementias. Current diagnostic methods are invasive and costly, highlighting the need for accessible biomarkers. This study investigates the diagnostic performance and pathophysiological implications of a novel plasma biomarker panel in a mixed dementia cohort, aiming to enhance diagnosis and elucidate underlying pathogenic mechanisms.

120 plasma biomarkers were analyzed using the NULISA™ platform in a well-characterized mixt dementia. CSF biomarkers were measured via ELISA. Statistical analyses employed ANOVA, and Kruskal-Wallis tests for group comparisons. Spearman correlations assessed relationships between CSF and plasma biomarkers. Diagnostic accuracy was evaluated using regression models and ROC curves. Feature importance and selection were performed using random forest analysis. Protein interactions assessed with GO enrichment analysis.

We evaluated 248 subjects (130 females, 118 males) with 117 AD, 50 MCI, 39 FTD, 25 DLB, and 17 other dementias. Plasma pTau were significantly elevated in AD compared to other groups, and in DLB compared to MCI. Plasma Aβ42 was highest in DLB, while NfL was highest in FTD. Plasma GFAP was highest in AD and elevated in DLB compared to MCI and FTD.

Plasma pTau levels showed a negative correlation with CSF Aβ42 and a positive correlation with CSF pTau in the entire cohort. CSF and plasma NfL levels were also highly correlated. These correlations were stronger in DLB and amyloid-positive MCI groups but weaker or absent in the AD group. Plasma pTau, GFAP, and NfL were negatively correlated with MMSE in AD, while GFAP showed a negative correlation with MMSE in FTD and DLB.

Plasma pTau217 demonstrated the best diagnostic accuracy for AD, DLB, FTD diagnosis and CSF amyloid positivity (AUCs 0.9, 0.84, 0.79, and 0.87, respectively). pTau181, pTau217, pTau231, total-tau and GFAP had lower odds in DLB and FTD compared to AD. AGRN, CXCL1, SCNB, TEK, and UCHL1 had higher odds in DLB compared to AD. SNAP25 had lower odds ratio in FTD compared to AD and DLB. pTau181, pTau217, pTau231, GFAP, MAPT, SNAP25 and PGF is related to AD progression.

Random forest analysis incorporating all plasma biomarkers, age, and gender yielded an AUCs of 0.85 for AD, 0.84 for FTD, and 0.75 for DLB. Refining the model by including biomarkers identified as significant in regression model improved performance, resulting in AUCs of 0.88 for AD, 0.87 for FTD, and 0.81 for DLB. This demonstrates potential for enhancing diagnostic accuracy through targeted biomarker panel refinement.

Read the Pre-print

Authors & Affiliations

Haşim Gezegen, Merve Alaylıoğlu, Erdi Şahin, Owen Swann, Elena Veleva, Gamze Güven, Umran Yaman, Derviş A. Salih, Başar Bilgiç, Haşmet Hanağası, Hakan Gürvit, Murat Emre, Duygu Gezen-Ak, Erdinç Dursun, Henrik Zetterberg, John Hardy, Amanda Heslegrave, Maryam Shoai, Bedia Samancı

  1. Behavioural Neurology and Movement Disorders Unit, Department of Neurology, Istanbul
    Faculty of Medicine, Istanbul University, Istanbul, Turkey
  2. Brain and Neurodegenerative Disorders Research Laboratories, Department of
    Neuroscience, Institute of Neurological Sciences, Istanbul University-Cerrahpasa, Istanbul,
    Turkey
  3. Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square,
    London, UK
  4. Department of Genetics, Aziz Sancar Institute of Experimental Medicine, Istanbul
    University, Istanbul, Turkey
  5. UK Dementia Research Institute at UCL, London, UK
  6. Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology,
    the Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden
  7. Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden
  8. Hong Kong Center for Neurodegenerative Diseases, Clear Water Bay, Hong Kong, China
  9. Wisconsin Alzheimer’s Disease Research Center, University of Wisconsin School of
    Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA
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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.