. 2025 Oct 13;20(1):107.

doi: 10.1186/s13024-025-00899-w.

Cerebrospinal fluid markers link to synaptic plasticity responses and Alzheimer's disease genetic pathways

Bjørn-Eivind Kirsebom^{1

2

3}, Johanna Nilsson⁴, Ellen Vromen^{5

6}, Peter Mikael Arnesen⁷, Atle Bjørnerud⁸, Ann Brinkmalm^{4

9}, Geir Bråthen^{10

11}, Gøril Rolfseng Grøntvedt^{10

11}, Jonas Jarholm⁷, Kaja Nordengen^{7

12}, Lene Pålhaugen⁷, Per Selnes⁷, Nikias Siafarikas¹³, Ragnhild Eide Skogseth^{14

15}, Sandra Tecelão⁷, Knut Waterloo^{16

17}, Panpan You⁷, Henrik Zetterberg^{4

9

18

19

20

21}, Dag Aarsland^{22

23}, Betty Tijms^{5

6}, Pieter Jelle Visser^{5

6}, Kaj Blennow^#^{4

9

24

25}, Tormod Fladby^#^{7

26}

Affiliations

¹ Department of Neurology, University Hospital of North Norway, Tromsø, 9038, Norway. bjorneivind.kirsebom@gmail.com.
² Department of Psychology, Faculty of Health Sciences, UiT, The Arctic University of Norway, Tromsø, Norway. bjorneivind.kirsebom@gmail.com.
³ Department of Neurology, Akershus University Hospital, Lørenskog, Norway. bjorneivind.kirsebom@gmail.com.
⁴ Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
⁵ Alzheimer Center Amsterdam, Neurology, Vrije Universiteit Amsterdam, Amsterdam UMC Location VUmc, Amsterdam, The Netherlands.
⁶ Amsterdam Neuroscience, Neurodegeneration, Amsterdam, The Netherlands.
⁷ Department of Neurology, Akershus University Hospital, Lørenskog, Norway.
⁸ Division of Radiology and Nuclear Medicine, Oslo University Hospital, Oslo, Norway.
⁹ Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden.
¹⁰ Department of Neurology and Clinical Neurophysiology, University Hospital of Trondheim, Trondheim, Norway.
¹¹ Department of Neuromedicine and Movement Science, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Trondheim, Norway.
¹² Department of Neurology, Oslo University Hospital, Oslo, Norway.
¹³ Department of Geriatric Psychiatry, Akershus University Hospital, Lørenskog, Norway.
¹⁴ Department of Geriatric Medicine, Neuro-SysMed, Haraldsplass Deaconess Hospital, Bergen, Norway.
¹⁵ Institute of Clinical Science, Department of Medicine, University of Bergen, Bergen, Norway.
¹⁶ Department of Neurology, University Hospital of North Norway, Tromsø, 9038, Norway.
¹⁷ Department of Psychology, Faculty of Health Sciences, UiT, The Arctic University of Norway, Tromsø, Norway.
¹⁸ Department of Neurodegenerative Disease, University College London Institute of Neurology, London, UK.
¹⁹ UK Dementia Research Institute at University College London, London, UK.
²⁰ Hong Kong Centre for Neurodegenerative Diseases, Hong Kong, China.
²¹ Wisconsin Alzheimer's Disease Research Center, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA.
²² King's College London, Institute of Psychiatry, Psychology and Neuroscience, London, UK.
²³ Centre for Age-Related Medicine, Stavanger University Hospital, Stavanger, Norway.
²⁴ Paris Brain Institute, ICM, Pitié-Salpêtrière Hospital, Sorbonne University, Paris, France.
²⁵ Neurodegenerative Disorder Research Center, Division of Life Sciences and Medicine, and Department of Neurology, Institute on Aging and Brain Disorders, University of Science and Technology of China and First Affiliated Hospital of USTC, Hefei, P.R. China.
²⁶ Institute of Clinical Medicine, Campus Ahus, University of Oslo, Lørenskog, Norway.

^# Contributed equally.

PMID: 41084010
PMCID: PMC12519626
DOI: 10.1186/s13024-025-00899-w

Cerebrospinal fluid markers link to synaptic plasticity responses and Alzheimer's disease genetic pathways

Bjørn-Eivind Kirsebom et al. Mol Neurodegener. 2025.

. 2025 Oct 13;20(1):107.

doi: 10.1186/s13024-025-00899-w.

Authors

Affiliations

¹ Department of Neurology, University Hospital of North Norway, Tromsø, 9038, Norway. bjorneivind.kirsebom@gmail.com.
² Department of Psychology, Faculty of Health Sciences, UiT, The Arctic University of Norway, Tromsø, Norway. bjorneivind.kirsebom@gmail.com.
³ Department of Neurology, Akershus University Hospital, Lørenskog, Norway. bjorneivind.kirsebom@gmail.com.
⁴ Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
⁵ Alzheimer Center Amsterdam, Neurology, Vrije Universiteit Amsterdam, Amsterdam UMC Location VUmc, Amsterdam, The Netherlands.
⁶ Amsterdam Neuroscience, Neurodegeneration, Amsterdam, The Netherlands.
⁷ Department of Neurology, Akershus University Hospital, Lørenskog, Norway.
⁸ Division of Radiology and Nuclear Medicine, Oslo University Hospital, Oslo, Norway.
⁹ Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden.
¹⁰ Department of Neurology and Clinical Neurophysiology, University Hospital of Trondheim, Trondheim, Norway.
¹¹ Department of Neuromedicine and Movement Science, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Trondheim, Norway.
¹² Department of Neurology, Oslo University Hospital, Oslo, Norway.
¹³ Department of Geriatric Psychiatry, Akershus University Hospital, Lørenskog, Norway.
¹⁴ Department of Geriatric Medicine, Neuro-SysMed, Haraldsplass Deaconess Hospital, Bergen, Norway.
¹⁵ Institute of Clinical Science, Department of Medicine, University of Bergen, Bergen, Norway.
¹⁶ Department of Neurology, University Hospital of North Norway, Tromsø, 9038, Norway.
¹⁷ Department of Psychology, Faculty of Health Sciences, UiT, The Arctic University of Norway, Tromsø, Norway.
¹⁸ Department of Neurodegenerative Disease, University College London Institute of Neurology, London, UK.
¹⁹ UK Dementia Research Institute at University College London, London, UK.
²⁰ Hong Kong Centre for Neurodegenerative Diseases, Hong Kong, China.
²¹ Wisconsin Alzheimer's Disease Research Center, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA.
²² King's College London, Institute of Psychiatry, Psychology and Neuroscience, London, UK.
²³ Centre for Age-Related Medicine, Stavanger University Hospital, Stavanger, Norway.
²⁴ Paris Brain Institute, ICM, Pitié-Salpêtrière Hospital, Sorbonne University, Paris, France.
²⁵ Neurodegenerative Disorder Research Center, Division of Life Sciences and Medicine, and Department of Neurology, Institute on Aging and Brain Disorders, University of Science and Technology of China and First Affiliated Hospital of USTC, Hefei, P.R. China.
²⁶ Institute of Clinical Medicine, Campus Ahus, University of Oslo, Lørenskog, Norway.

^# Contributed equally.

PMID: 41084010
PMCID: PMC12519626
DOI: 10.1186/s13024-025-00899-w

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.

Keywords: Alzheimer’s disease; Cognition; Memory; Neurodegeneration; Synaptic loss.

PubMed Disclaimer

Conflict of interest statement

Declarations. Ethics approval and consent to participate: The DDI study was approved by the Regional Committees for Medical and Health Research Ethics in Norway and conducted in line with the guidelines provided by the Helsinki declaration, and the Norwegian Health and Research act. All participants volunteered and gave written informed consent before participating in the study. All patients in the ADC study gave written informed consent, was in line with the guidelines provided by the Helsinki declaration, was approved by the ethics committee of the Amsterdam UMC (location VUmc), the Biobank Research Ethics Committee of the Amsterdam UMC (location VUmc). Consent for publication: All authors have reviewed and approved the contents of this manuscript and have provided their consent for publication. Competing interests: BEK has served as a consultant for Biogen and on an advisory board for Eisai and Eli Lilly. TF has served as a consultant and at the advisory boards for Biogen, Novo Nordisk, Eli Lilly, Roche and Eisai. KB has served as a consultant and at advisory boards for Abbvie, AC Immune, ALZPath, AriBio, Beckman-Coulter, BioArctic, Biogen, Eisai, Lilly, Moleac Pte. Ltd, Neurimmune, Novartis, Ono Pharma, Prothena, Quanterix, Roche Diagnostics, Sanofi and Siemens Healthineers; has served at data monitoring committees for Julius Clinical and Novartis; has given lectures, produced educational materials and participated in educational programs for AC Immune, Biogen, Celdara Medical, Eisai and Roche Diagnostics; and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program, outside the work presented in this paper. HZ has served at scientific advisory boards and/or as a consultant for Abbvie, Acumen, Alector, Alzinova, ALZpath, Amylyx, Annexon, Apellis, Artery Therapeutics, AZTherapies, Cognito Therapeutics, CogRx, Denali, Eisai, LabCorp, Merry Life, Nervgen, Novo Nordisk, Optoceutics, Passage Bio, Pinteon Therapeutics, Prothena, Quanterix, Red Abbey Labs, reMYND, Roche, Samumed, Siemens Healthineers, Triplet Therapeutics, and Wave, has given lectures sponsored by Alzecure, BioArctic, Biogen, Cellectricon, Fujirebio, Lilly, Novo Nordisk, Roche, and WebMD, and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program (outside submitted work). PS has served as a consultant for Roche. RES has served on an advisory board for Eisai and as local PI on GSK 219867. DA has received research support and/or honoraria from, Astra-Zeneca, H. Lundbeck, Novartis Pharmaceuticals, Biogen, and GE Health, and served as paid consultant for H. Lundbeck, Eisai, Heptares, Mentis Cura and Cognetivity. All other authors declare that they have no competing interests.

Figures

**Fig. 1**
Between-group comparisons of synapse markers compared to controls. Between-group comparisons of synaptic marker concentrations relative to controls. Comparisons were made within Aβ+/Tau and Aβ+/Tau + groups, separately for cognitively normal (CN), mild cognitive impairment (MCI), and combined (CN + MCI) cases. The top row shows results from the Dementia Disease Initiation (DDI) cohort, the middle row from the Amsterdam Dementia Cohort (ADC), and the bottom row presents pooled estimates from meta-analyses across cohorts.The grey vertical bar in each plot is the reference group (CN Aβ-/Tau- controls). The top row are results from the Dementia Disease Initiation (DDI) cohort. The bottom row are results from the Amsterdam Dementia Cohort (ADC). P-values are listed as *, **, *** and n.s. corresponding to p < 0.05, < 0.01, < 0.001 and non-significant respectively. Horizontal bars show the 95% confidence intervals for each marker. All models included age and sex as covariates. Multiple comparisons were adjusted with False Discovery Rate

**Fig. 2**
Associations between synapse markers and cross-sectional verbal memory performance. Associations between synaptic markers and cross-sectional verbal memory performance. Results are shown separately for the Dementia Disease Initiation (DDI) cohort (top row; CERAD verbal memory recall) and the Amsterdam Dementia Cohort (ADC; middle row; Rey Auditory Verbal Learning Test, RAVLT), with pooled meta-analytic estimates presented in the bottom row. The grey vertical bar in each plot is standardized beta (β) = 0. P-values are listed as *, **, *** and n.s. corresponding to p < 0.05, < 0.01, < 0.001 and non-significant respectively. Horizontal bars show the 95% confidence intervals for each marker. All models included age, sex and education as covariates. Multiple comparisons were adjusted with False Discovery Rate

**Fig. 3**
Associations between synapse markers and MRI regions of interest in Aβ/Tau groups. Associations between MRI medial temporal lobe regions of interest and synapse markers in the Aβ+/Tau- and Aβ+/Tau + and CN Aβ-/Tau- control groups. The grey vertical bar in each plot is standardized beta (β) = 0. All results are from the Dementia Disease Initiation (DDI) cohort. The top row: entorhinal cortex, middle row: anterior hippocampus, bottom row: posterior hippocampus. P-values are listed as *, **, *** and n.s. corresponding to p < 0.05, < 0.01, < 0.001 and non-significant respectively. All models included age, sex and intracranial volume as covariates. Multiple comparisons were adjusted with False Discovery Rate

**Fig. 4**
Within-pathology group comparisons of synaptic marker concentrations between cognitively normal and mild cognitive impairment cases. Analyses are restricted to synaptic proteins selected through our funneling approach. Comparisons were conducted separately within the Aβ+/Tau − and Aβ+/Tau + groups. The top row shows results from the Dementia Disease Initiation (DDI) cohort, the middle row from the Amsterdam Dementia Cohort (ADC), and the bottom row presents pooled effect estimates from meta-analyses across cohorts. The vertical grey line represents the cognitively normal (CN) reference group within each pathology group. P-values are listed as *, **, *** and n.s. corresponding to p < 0.05, < 0.01, < 0.001 and non-significant respectively. Horizontal bars show the 95% confidence intervals for each marker. All models included age and sex as covariates. No adjustment for multiple comparisons were performed

**Fig. 5**
Associations between baseline CSF 14-3-3ζ/δ and future memory decline. Shows the longitudinal associations between baseline 14-3-3ζ/δ and future memory decline in (A) the Dementia Disease Initiation cohort (DDI, Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) memory recall) and (B) the Amsterdam Dementia Cohort (ADC, Rey Auditory Verbal Learning Test (RAVLT) memory recall). Ribbons fitted to each regression line shows the 95% confidence interval for the estimates. The models included age at baseline, sex and education as covariates

**Fig. 6**
Comparison of baseline synapse markers with pathological Aβ and/or Tau progression. Comparison of baseline synapse marker concentrations in Dementia Disease Initiation (DDI) cases progressing from Aβ-/Tau- to Aβ+/Tau- (A) and from Aβ+/Tau- to Aβ+/Tau+ (B) as compared to stable cognitively normal (CN) and Aβ-/Tau- controls (vertical grey bar in each plot). P-values are listed as *,**,*** and n.s. corresponding to p < 0.05, < 0.01, < 0.001 and non-significant respectively. Horizontal bars show the 95% confidence intervals for each marker. All models included adjustment for individual years of observation. No adjustment for multiple comparisons were performed

See this image and copyright information in PMC

References

1. Brookmeyer R, Johnson E, Ziegler-Graham K, Arrighi M. Forecasting the global burden of Alzheimer´s disease. Alzheimer´s Dement. 2007;3(3):186–91. - PubMed
1. Sims JR, Zimmer JA, Evans CD, Lu M, Ardayfio P, Sparks J, et al. Donanemab in early symptomatic Alzheimer disease: the TRAILBLAZER-ALZ 2 randomized clinical trial. JAMA. 2023;330(6):512–27. - PMC - PubMed
1. van Dyck CH, Swanson CJ, Aisen P, Bateman RJ, Chen C, Gee M, et al. Lecanemab in early Alzheimer’s disease. N Engl J Med. 2023;388(1):9–21. - PubMed
1. Mistridis P, Krumm S, Monsch AU, Berres M, Taylor KI. The 12 years preceding mild cognitive impairment due to Alzheimer’s disease: the Temporal emergence of cognitive decline. J Alzheimer’s Disease: JAD. 2015;48(4):1095–107. - PMC - PubMed
1. Jarholm JA, Bjornerud A, Dalaker TO, Akhavi MS, Kirsebom BE, Palhaugen L, et al. Medial Temporal lobe atrophy in predementia Alzheimer’s disease: A longitudinal Multi-Site study comparing staging and A/T/N in a clinical research cohort. J Alzheimers Dis. 2023;94(1):259–79. - PMC - PubMed

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

Substances

Actions
Actions
Actions
Actions

LinkOut - more resources

Full Text Sources
- BioMed Central
- PubMed Central
Medical
- MedlinePlus Health Information
Research Materials
- NCI CPTC Antibody Characterization Program

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

Cerebrospinal fluid markers link to synaptic plasticity responses and Alzheimer's disease genetic pathways

Affiliations

Cerebrospinal fluid markers link to synaptic plasticity responses and Alzheimer's disease genetic pathways

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

MeSH terms

Substances

LinkOut - more resources

Full Text Sources

Medical

Research Materials