Cerebrospinal fluid proteome alterations related to depressive symptoms in cognitive decline and Alzheimer's disease
Year: 2025
Type: article
Study design: Observational Study
Abstract: BACKGROUND: Depressive symptoms are common in cognitive decline and Alzheimer's disease (AD), but their underlying pathology remains poorly understood. We aimed to investigate the pathophysiology of depressive symptoms in the context of AD. METHODS: Individuals with normal cognition (NC), mild cognitive impairment (MCI), or mild AD dementia from two independent, large cohorts were included. Untargeted mass spectrometry-based cerebrospinal fluid (CSF) proteomics, regression analyses, and pathway-enrichment analyses were applied. RESULTS: A total of 688 individuals (223 NC, 190 MCI, and 275 AD dementia) were included. The levels of 57 out of 946 robustly quantified CSF proteins were associated with depressive symptoms consistently across both cohorts. These proteins were enriched for cell adhesion/inflammation, synaptic signaling, and neurogenesis. In amyloid-positive subjects, cholesterol metabolism and transport were additionally associated with depressive symptoms. CONCLUSION: The identified proteome alterations may reflect shared biological mechanisms involved in both AD and depression in older people. HIGHLIGHTS: This is the first study to investigate cerebrospinal fluid proteome alterations associated with depressive symptoms in the context of cognitive decline and Alzheimer's disease (AD). Dysregulated proteins in patients with higher depression scores were related to pathways linked to cell adhesion/inflammation, synaptic signaling, and neurogenesis, as well as cholesterol metabolism in amyloid-positive individuals. The identified proteome alterations may represent shared biological mechanisms involved in both AD and depression in older people.
Source: Alzheimer s & Dementia
DOI: 10.1002/alz.71054
Authors: Miriam Rabl, Willem L. Hartog, Wiesje M. van der Flier, Yolande A. L. Pijnenburg, Charlotte E. Teunissen, Magda Tsolaki, Yvonne Freund‐Levi, Rik Vandenberghe, Lutz Froelich, Johannes Streffer, Simon Lovestone, Lars Bertram, Henrik Zetterberg, Johan Gobom, Stephanie J. B. Vos, Pieter Jelle Visser, Betty M. Tijms, Julius Popp
Institutions: University of Zurich, University Hospital Zurich, Psychiatrische Universitätsklinik Zürich, Amsterdam University Medical Centers, Vrije Universiteit Amsterdam, Amsterdam UMC Location Vrije Universiteit Amsterdam, Amsterdam Neuroscience, Amsterdam Public Health, Alzheimer Nederland, Aristotle University of Thessaloniki, Greek Association of Alzheimer's Disease and Related Disorders, Örebro University, Karolinska Institutet, Stockholm South General Hospital, Örebro University Hospital, Universitair Ziekenhuis Leuven, KU Leuven, Central Institute of Mental Health, Medizinische Fakultät Mannheim, Lundbeck (Denmark), Janssen (Belgium), University of Antwerp, University of Oxford, Johnson & Johnson (United Kingdom), University of Lübeck, University of Wisconsin–Madison, Sahlgrenska University Hospital, UK Dementia Research Institute, UCL Queen Square Institute of Neurology, University College London, University of Gothenburg, Maastricht University, Centre Hospitalier Universitaire Vaudois
Language: English
Subfield: Psychiatry and Mental health
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $4,200
Funders: National Science Foundation, Eli Lilly and Company, Biogen, Stiftelsen för Gamla Tjänarinnor, EU Joint Programme – Neurodegenerative Disease Research, European Federation of Pharmaceutical Industries and Associations, Noaber Foundation, Roche Nederland, European Commission, Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung, ZonMw, Nederlandse Organisatie voor Wetenschappelijk Onderzoek, Eisai, Vetenskapsrådet, Universität Zürich, Hersenstichting, Alzheimerfonden, Stiftung Synapsis - Alzheimer Forschung Schweiz AFS, Innovatiefonds Zorgverzekeraars, Stichting Dioraphte, Alzheimer Nederland, Amsterdam Neuroscience, Bentham-Moxon Trust, GIESKES-STRIJBIS FONDS, Avid Radiopharmaceuticals, HORIZON EUROPE Framework Programme
Awards: G1389459409, G1456642880, G1521734507, G1613806636, G1802301745, An integrative multi-omics approach to investigate cerebral and systemic biological pathway alterations with clinical relevance in early Alzheimer’s disease, G2075818824, G2501976640, Fluid biomarkers for neurodegenerative dementias, G3914690605, Macrophage migration inhibitory factor and neuroinflammation in early Alzheimer’s Disease, G4260843567, REAL-WORLD IMPLEMENTATION, DEPLOYMENT AND VALIDATION OF EARLY DETECTION TOOLS AND LIFESTYLE ENHANCEMENT, G5040492720, Fluid biomarkers for neurodegenerative dementias, G5616778589, CASCADE: CAuSe or Consequence in Alzheimer DiseasE?, G6158734006, G6382720711, G663896020, G696262100, PRECISION MEDICINE PLATFORM IN NEURODEGENERATIVE DISEASE, European Medical Information Framework, G861818073, G880118091, G8906644882
OpenAlex ID: W7117298752