Cerebrospinal fluid proteomic profiling of individuals with mild cognitive impairment and suspected non-Alzheimer's disease pathophysiology

Aurore Delvenne; Johan Gobom; Betty Tijms; Isabelle Bos; Lianne M Reus; Valerija Dobricic; Mara Ten Kate; Frans Verhey; Inez Ramakers; Philip Scheltens; Charlotte E Teunissen; Rik Vandenberghe; Jolien Schaeverbeke; Silvy Gabel; Julius Popp; Gwendoline Peyratout; Pablo Martinez-Lage; Mikel Tainta; Magda Tsolaki; Yvonne Freund-Levi; Simon Lovestone; Johannes Streffer; Frederik Barkhof; Lars Bertram; Kaj Blennow; Henrik Zetterberg; Pieter Jelle Visser; Stephanie J B Vos

doi:10.1002/alz.12713

Cerebrospinal fluid proteomic profiling of individuals with mild cognitive impairment and suspected non-Alzheimer's disease pathophysiology

Alzheimers Dement. 2022 Jun 14. doi: 10.1002/alz.12713. Online ahead of print.

Authors

Aurore Delvenne¹, Johan Gobom^{2

3}, Betty Tijms⁴, Isabelle Bos^{1

4}, Lianne M Reus⁴, Valerija Dobricic⁵, Mara Ten Kate^{4

6}, Frans Verhey¹, Inez Ramakers¹, Philip Scheltens⁴, Charlotte E Teunissen⁷, Rik Vandenberghe^{8

9}, Jolien Schaeverbeke^{8

9}, Silvy Gabel^{8

9}, Julius Popp^{10

11}, Gwendoline Peyratout¹⁰, Pablo Martinez-Lage¹², Mikel Tainta¹², Magda Tsolaki¹³, Yvonne Freund-Levi^{14

15

16}, Simon Lovestone¹⁷, Johannes Streffer^{18

19}, Frederik Barkhof^{6

20}, Lars Bertram^{5

21}, Kaj Blennow^{2

3}, Henrik Zetterberg^{2

3

22

23}, Pieter Jelle Visser^{1

4

24}, Stephanie J B Vos¹

Affiliations

¹ Department of Psychiatry and Neuropsychology, Alzheimer Centrum Limburg, School for Mental Health and Neuroscience, Maastricht University, Maastricht, the Netherlands.
² Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden.
³ Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden.
⁴ Alzheimer Center Amsterdam, Department of Neurology, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC, the Netherlands.
⁵ Lübeck Interdisciplinary Platform for Genome Analytics, University of Lübeck, Lübeck, Germany.
⁶ Department of Radiology and Nuclear Medicine, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC, Amsterdam, the Netherlands.
⁷ Neurochemistry Laboratory, Department of Clinical Chemistry, Amsterdam University Medical Centers (AUMC), Amsterdam Neuroscience, the Netherlands.
⁸ Neurology Service, University Hospitals Leuven, Leuven, Belgium.
⁹ Laboratory for Cognitive Neurology, Department of Neurosciences, KU Leuven, Leuven, Belgium.
¹⁰ Old Age Psychiatry, University Hospital Lausanne, Lausanne, Switzerland.
¹¹ Department of Geriatric Psychiatry, Psychiatry University Hospital Zürich, Zürich, Switzerland.
¹² Fundación CITA-Alzhéimer Fundazioa, San Sebastian, Spain.
¹³ 1st Department of Neurology, AHEPA University Hospital, Medical School, Faculty of Health Sciences, Aristotle University of Thessaloniki, Makedonia, Thessaloniki, Greece.
¹⁴ Department of Neurobiology, Caring Sciences and Society (NVS), Division of Clinical Geriatrics, Karolinska Institutet, Stockholm, Sweden.
¹⁵ Department of Psychiatry in Region Örebro County and School of Medical Sciences, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
¹⁶ Department of Old Age Psychiatry, Psychology & Neuroscience, King's College, London, UK.
¹⁷ University of Oxford, Oxford, United Kingdom (currently at Johnson and Johnson Medical Ltd.), London, UK.
¹⁸ Institute Born-Bunge, Reference Center for Biological Markers of Dementia (BIODEM), Institute Born-Bunge, University of Antwerp, Belgium.
¹⁹ UCB Biopharma SPRL, Brain-l'Alleud, Belgium.
²⁰ Institutes of Neurology & Healthcare Engineering, UCL London, London, UK.
²¹ Center for Lifespan Changes in Brain and Cognition, Department of Psychology, University of Oslo, Oslo, Norway.
²² Department of Neurodegenerative Disease, UCL Institute of Neurology, London, UK.
²³ UK Dementia Research Institute at UCL, London, UK.
²⁴ Department of Neurobiology, Care Sciences and Society, Division of Neurogeriatrics, Karolinska Institutet, Stockholm, Sweden.

PMID: 35698882
DOI: 10.1002/alz.12713

Abstract

Background: Suspected non-Alzheimer's disease pathophysiology (SNAP) is a biomarker concept that encompasses individuals with neuronal injury but without amyloidosis. We aim to investigate the pathophysiology of SNAP, defined as abnormal tau without amyloidosis, in individuals with mild cognitive impairment (MCI) by cerebrospinal fluid (CSF) proteomics.

Methods: Individuals were classified based on CSF amyloid beta (Aβ)1-42 (A) and phosphorylated tau (T), as cognitively normal A-T- (CN), MCI A-T+ (MCI-SNAP), and MCI A+T+ (MCI-AD). Proteomics analyses, Gene Ontology (GO), brain cell expression, and gene expression analyses in brain regions of interest were performed.

Results: A total of 96 proteins were decreased in MCI-SNAP compared to CN and MCI-AD. These proteins were enriched for extracellular matrix (ECM), hemostasis, immune system, protein processing/degradation, lipids, and synapse. Fifty-one percent were enriched for expression in the choroid plexus.

Conclusion: The pathophysiology of MCI-SNAP (A-T+) is distinct from that of MCI-AD. Our findings highlight the need for a different treatment in MCI-SNAP compared to MCI-AD.

Keywords: Alzheimer's disease; biomarkers; cerebrospinal fluid; mild cognitive impairment; pathophysiology; proteomics; suspected non-Alzheimer's disease pathophysiology; tau.

Abstract

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