Back to Publications​
Publication
medRxiv

Plasma and CSF proteomic signatures related to Alzheimer’s, α-synuclein, or vascular pathologies and clinical decline

Back to Publications​
  • February 4, 2026
  • Oskar Hansson, et al., Lund University
Topic/Product:
CNS Disease Panel 120, Inflammation Panel 250
Disease Area:
Alzheimer's Disease
Sample Type:
CSF, Plasma

Abstract

Older individuals frequently harbor multiple brain pathologies, including Alzheimer’s disease (AD) related amyloid-β (Aβ) and tau alongside α-synucleinopathy and vascular pathology. Proteomic profiling offers a strategy to better understand common as well as unique features of these different brain pathologies.

We analyzed cerebrospinal fluid (CSF) (n=1,658) and plasma (n=749) samples from participants in the BioFINDER cohorts using the automated NULISAseq CNS Disease panel of 125 proteins. Differentially abundant proteins (DAPs) related to AD pathology (based on Aβ– and tau-PET positivity), α-synuclein (based on synuclein amplification assay [SAA] positivity) and vascular pathology (based on white matter lesion [WML] load) were identified with linear models simultaneously including a binary measure for the three pathologies. In the BioFINDER-2 subcohorts, DAPs were further evaluated for associations with continuous baseline (n=1,137) and longitudinal (n=656) Aβ-PET, tau-PET, and WML measures in models accounting for all pathologies. Associations with AD-signature cortical atrophy (n=915) and cognitive decline by the MMSE (n=1054) were also examined.

We identified 84 CSF DAPs, with largely distinct protein signatures for each pathology (AD, n=66 DAPs; vascular pathology, n=55; α-synuclein pathology, n=16). 10 DAPs (e.g., FABP3, UCHL1, NPTXR, NPTX2) were altered across all three pathologies, reflecting general neurodegeneration. AD-associated DAPs included glial/inflammatory markers (CHIT1, CX3CL1, CD63) linked to Aβ pathology, and synaptic/neuronal injury markers (VSNL1, NRGN, NEFL) and metabolic enzymes (FABP3, MDH1) linked to tau pathology. Aβ-associated proteomic differences were most evident in CU individuals, while tau-associated differences predominated in MCI. More proteins, particularly neurodegeneration and synaptic markers, were associated with tau change than with Aβ change. Vascular pathology exhibited a distinct profile, enriched for inflammatory, angiogenic and extracellular matrix proteins (PGF, POSTN, TREM1, VCAM1). DDC was the main protein associated with α-synucleinopathy. Only a few proteins, including UCHL1, NPTX2, and NEFL, predicted cognitive decline and cortical atrophy after accounting for all brain pathologies.

In plasma, although fewer DAPs were identified (n=20), findings included established AD biomarkers. Only plasma VCAM1 and NEFL were associated with α-synuclein and vascular pathology.

NULISA identified stage-dependent, disease-specific CSF biomarker signatures with limited overlap, alongside shared neurodegenerative markers, supporting improved biological interpretation and more refined classification of neurodegenerative pathology.

Read the Pre-print

Authors & Affiliations

Orduña Dolado¹, Alexa Pichet Binette¹²³, Andréa L. Benedet⁴, Ilaria Pola⁴, Kübra Tan⁴, Wiebke Traichel⁴, Ines Hristovska¹, Angela Mammana⁹, Erik Stomrud¹⁵, Gemma Salvadó¹⁶, Shorena Janelidze¹, Sebastian Palmqvist¹⁵, Niklas Mattsson-Carlgren¹⁵⁷, Piero Parchi⁸⁹, Henrik Zetterberg⁴¹⁰¹¹¹²¹³¹⁴, Nicholas J Ashton⁴¹⁵¹⁶¹⁷¹⁸, and Oskar Hansson¹

¹ Clinical Memory Research Unit, Department of Clinical Sciences Malmö, Faculty of Medicine, Lund University, Lund, Sweden
² Department of Physiology and Pharmacology, Université de Montréal, Montréal, Quebec, Canada
³ Centre de Recherche de l’Institut Universitaire de Gériatrie de Montréal, Montréal, Quebec, Canada
⁴ Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Mölndal, Sweden
⁵ Memory Clinic, Skåne University Hospital, Malmö, Sweden
⁶ Barcelonaβeta Brain Research Center (BBRC), Pasqual Maragall Foundation, Barcelona, Spain
⁷ Wallenberg Center for Molecular Medicine, Lund University, Lund, Sweden
⁸ Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy
⁹ IRCCS Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy
¹⁰ Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Gothenburg, Sweden
¹¹ School of Medicine and Public Health, Wisconsin Alzheimer’s Institute, University of Wisconsin, Madison, WI, United States
¹² Department of Neurodegenerative Disease, Institute of Neurology, University College London, London, United Kingdom
¹³ UK Dementia Research Institute, University College London, London, United Kingdom
¹⁴ Department of Pathology and Laboratory Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA
¹⁵ Centre for Age-Related Medicine, Stavanger University Hospital, Stavanger, Norway
¹⁶ Institute of Psychiatry, Psychology and Neuroscience, Maurice Wohl Institute Clinical Neuroscience Institute, King’s College London, London, UK
¹⁷ NIHR Biomedical Research Centre for Mental Health and Biomedical Research Unit for Dementia at South London and Maudsley NHS Foundation, London, UK
¹⁸ Banner Alzheimer’s Institute and University of Arizona, Phoenix, AZ, USA

Linkedin

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.

Linkedin

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.