Cerebrospinal fluid markers link to synaptic plasticity responses and Alzheimer’s disease genetic pathways
Year: 2025
Type: article
Study design: Observational Study
Abstract: BACKGROUND: Synapse loss is linked to cognitive symptoms in Alzheimer's Disease (AD) and Cerebrospinal fluid (CSF) synaptic biomarkers may clarify disease heterogeneity and disease mechanisms for progression beyond amyloid (Aβ) and tau pathologies, potentially revealing new drug targets. METHODS: We used a mass-spectrometry panel of 17 synaptic biomarkers including neuronal pentraxins (NPTXs) linked to glutamatergic signaling, and 14-3-3 proteins linked to tau-pathology and synaptic plasticity. Synapse markers were evaluated in two independent cohorts: Dementia Disease Initiation (DDI) (n = 346) and Amsterdam Dementia Cohort (n = 397), both with cognitive assessments up to 10 years. We used linear regression to compare synapse marker differences between CSF-determined Aβ + cognitively normal (CN) and Mild Cognitive Impairment (MCI) groups, with or without CSF tau pathology (Tau+/-), relative to CN Aβ-/Tau- controls; and associations between synapse markers and medial temporal lobe (MTL) MRI volumetrics in the DDI cohort and with verbal memory in both cohorts. A funneling procedure identified proteins related to Aβ/Tau pathology and memory impairment in both cohorts, which were used to evaluate relations to Aβ/Tau biological progression in the DDI cohort and memory decline in both cohorts. Finally, we explored genetic pathways associated with these synaptic proteins. RESULTS: In both cohorts, most markers were elevated in Aβ+/Tau + cases compared to controls, particularly 14-3-3ζ/δ. Several proteins were reduced in Aβ+/Tau- cases, especially NPTX-2, while 14-3-3ζ/δ remained elevated. However, the increase in e.g. 14-3-3ζ/δ and reduction in e.g. NPTX2 were more pronounced in patients with MCI than CN cases regardless of tau-pathology, corresponding to verbal memory impairment and MTL atrophy. Elevated baseline 14-3-3ζ/δ and rab GDP Dissociation Inhibitor Alpha (GDI-1) associated with future progression from Aβ+/Tau- to Aβ+/Tau+. Significant associations (all p < 0.001) were found between 14-3-3 protein genes (YWHAZ, YWHAE) and pathways linked to AD, including the p38 MAPK, IGF, PIK3/AKT and between GDI1 and p38 MAPK upstream pathway (p < 0.05) all connected to synaptic plasticity. Correspondingly, a robust 14-3-3ζ/δ association with future memory decline was observed in both cohorts. CONCLUSIONS: Reduced markers for excitatory signaling in Aβ+/Tau- and increased synaptic plasticity markers in Aβ+/Tau + cases suggest differential but linked processes underlying disease progression and resilience in the groups.
Source: Molecular Neurodegeneration
Authors: Bjørn-Eivind Kirsebom, Johanna Nilsson, Ellen Vromen, Peter Mikael Arnesen, Atle Bjørnerud, Ann Brinkmalm, Geir Bråthen, Gøril Rolfseng Grøntvedt, Jonas Jarholm, Kaja Nordengen, Lene Pålhaugen, Per Selnes, Nikias Siafarikas, Ragnhild Eide Skogseth, Sandra Tecelão, Knut Waterloo, Panpan You, Henrik Zetterberg, Dag Aarsland, Betty Tijms, Pieter Jelle Visser, Kaj Blennow, Tormod Fladby
Institutions: University Hospital of North Norway, Akershus University Hospital, UiT The Arctic University of Norway, University of Gothenburg, Amsterdam Neuroscience, Amsterdam UMC Location Vrije Universiteit Amsterdam, Oslo University Hospital, Sahlgrenska University Hospital, Norwegian University of Science and Technology, St Olav's University Hospital, Haraldsplass Diakonale Sykehus, University of Bergen, University of Wisconsin–Madison, UK Dementia Research Institute, UCL Queen Square Institute of Neurology, University College London, King's College London, Stavanger University Hospital, University of Science and Technology of China, Sorbonne Université, Institut des Sciences Moléculaires, Pitié-Salpêtrière Hospital, Institut du Cerveau, University of Oslo
Language: English
Subfield: Psychiatry and Mental health
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,090
Funders: Alzheimer's Association, Alzheimer's Drug Discovery Foundation, Familjen Erling-Perssons Stiftelse, Universitetet i Tromsø, Cure Alzheimer's Fund, Stiftelsen för Gamla Tjänarinnor, EU Joint Programme – Neurodegenerative Disease Research, National Institute for Health and Care Research, University College London, European Commission, Hjärnfonden, Vetenskapsrådet, UK Dementia Research Institute, HORIZON EUROPE Framework Programme
Awards: G1057200632, G1088883541, G1253720191, The Alzheimer’s Association quality control (QC) program for CSF and plasma biomarkers - Continuation, G150733400, G1551449788, G1588116593, G1771944843, G1833008592, G201353144, G2057385626, G237833635, G2543812357, G2799940023, The Alzheimer biomarker toolbox – use in pathogenic studies, diagnostics and theragnostics, G2841269746, G2879339865, G292763017, G3241251457, G3903502641, G4181470480, G4234328627, G4260843567, G432431387, G434337789, G4377393254, G5040492720, G506008078, G516766298, G6158734006, G6289970089, Multi-omics Interdisciplinary Research Integration to Address DEmentia diagnosis, G6745400708, G691317373
OpenAlex ID: W4415106459