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. 2025 Mar 3;17(1):56.
doi: 10.1186/s13195-025-01703-z.

Synaptic protein CSF levels relate to memory scores in individuals without dementia

Kirsten E J Wesenhagen #  1 , Diederick M de Leeuw #  2 , Jori Tomassen  1 , Johan Gobom  3   4 , Isabelle Bos  1   5 , Stephanie J B Vos  6 , Pablo Martinez-Lage  7 , Mikel Tainta  8 , Julius Popp  9   10 , Gwendoline Peyratout  10 , Magda Tsolaki  11 , Rik Vandenberghe  12   13 , Yvonne Freund-Levi  14   15 , Frans Verhey  16 , Simon Lovestone  17   18 , Johannes Streffer  19   20 , Valerija Dobricic  21 , Kaj Blennow  4   22 , Philip Scheltens  1 , August B Smit  23 , Lars Bertram  21   24 , Charlotte E Teunissen  25 , Henrik Zetterberg  3   4   26   27   28 , Betty M Tijms  1 , Pieter Jelle Visser  1   14   16 ; Alzheimer’s Disease Neuroimaging Initiative
Affiliations

Synaptic protein CSF levels relate to memory scores in individuals without dementia

Kirsten E J Wesenhagen et al. Alzheimers Res Ther. .

Abstract

Background: We investigated how cerebrospinal fluid levels of synaptic proteins associate with memory function in normal cognition (CN) and mild cognitive impairment (MCI), and investigated the effect of amyloid positivity on these associations.

Methods: We included 242 CN (105(43%) abnormal amyloid), and 278 MCI individuals (183(66%) abnormal amyloid) from the European Medical Information Framework for Alzheimer's Disease Multimodal Biomarker Discovery (EMIF-AD MBD) and the Alzheimer's Disease Neuroimaging Initiative (ADNI). For 181 (EMIF-AD MBD) and 36 (ADNI) proteins with a synaptic annotation in SynGO, associations with word learning recall were analysed with linear models.

Results: Subsets of synaptic proteins showed lower levels with worse recall in preclinical AD (EMIF-AD MBD: 7, ADNI: 5 proteins, none overlapping), prodromal AD (EMIF-AD MBD only, 27 proteins) and non-AD MCI (EMIF-AD MBD: 1, ADNI: 7 proteins). The majority of these associations were specific to these clinical groups.

Conclusions: Synaptic disturbance-related memory impairment occurred very early in AD, indicating it may be relevant to develop therapies targeting the synapse early in the disease.

Keywords: Cerebrospinal fluid proteomics; Early Alzheimer’s disease; Memory performance; Synaptic proteins.

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Conflict of interest statement

Declarations. Ethics approval and consent to participate: For both ADNI and EMIF-AD MBD, Local institutional review boards approved the procedures for this study and written informed consent was obtained in accordance with the Declaration of Helsinki. Supplementary Table 4 contains a full overview of Ethical Committee/IRB names of each center. Consent for publication: Not applicable. Competing interests: KB has served as a consultant, at advisory boards, or at data monitoring committees for Abcam, Axon, BioArctic, Biogen, JOMDD/Shimadzu. Julius Clinical, Lilly, MagQu, Novartis, Pharmatrophix, Prothena, Roche Diagnostics, and Siemens Healthineers, 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, Alector, Annexon, Artery Therapeutics, AZTherapies, CogRx, Denali, Eisai, Nervgen, Pinteon Therapeutics, Red Abbey Labs, Passage Bio, Roche, Samumed, Siemens Healthineers, Triplet Therapeutics, and Wave, has given lectures in symposia sponsored by Cellectricon, Fujirebio, Alzecure, Biogen, and Roche, and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program. PS has acquired grants for the institution from GE Healthcare and Piramal and received consultancy/speaker fees paid to the institution from Novartis, Probiodrug, Biogen, Roche, and EIP Pharma, LLC in the past 2 years. CT received grants from the European Commission, the Dutch Research Council (ZonMW), Association of Frontotemporal Dementia/Alzheimer’s Drug Discovery Foundation, The Weston Brain Institute, Alzheimer Netherlands. Prof. dr. Teunissen has functioned in advisory boards of Roche, received non-financial support in the form of research consumables from ADxNeurosciences and Euroimmun, performed contract research or received grants from Probiodrug, Biogen, Esai, Toyama, Janssen Prevention Center, Boehringer, AxonNeurosciences, EIP farma, PeopleBio, Roche. The other authors report no conflict of interest.

Figures

Fig. 1
Fig. 1
Characterization of synaptic proteomic dataset. A Schematic overview of study design. B Overlap of ADNI proteomics and EMIF-AD MBD proteomics with SynGO annotation used to select synaptic proteins. C SynGO locations and processes for which synaptic proteins were included in the datasets. One protein can have multiple annotations for different locations and processes. The SynGO annotation uses a hierarchical organisation, and we show here the first and second level of subprocesses, with proteins in lower subprocesses categorized with the respective second level subprocess
Fig. 2
Fig. 2
Differences in synaptic proteins depending on diagnostic group. a Mean protein levels are shown for top proteins depending on amyloid and cognitive subgroups, b boxplots of protein levels between diagnostic groups for neurogranin (NRGN) and neurofilament light (NEFL). The box of the boxplot indicates 25th percentile, median and 75th percentile, whiskers indicate 1.5 × interquartile range. See Supplementary Table 2 for mean differences between groups and full synaptic annotation for all proteins. Synaptic category ‘Other’ refers to other synaptic locations and functions as detailed in Fig. 1c. *, ** and *** indicate significant difference between diagnostic group and controls (a), or between indicated diagnostic groups (b): *, p-value < 0.05, **, p-value < 0.01; ***, p-value < 0.001, n.s.: not significant
Fig. 3
Fig. 3
Synaptic proteins associated with memory independent of diagnostic group. Top proteins associated with memory across all diagnostic groups are shown. Associations were considered significant when proteins did not show an interaction with diagnostic group (interaction p-value ≥ 0.1) and had an association with memory function (*, p-value < 0.05; **, p-value < 0.01), ***, p-value < 0.001). Associations of all analysed synaptic proteins are provided in Supplementary Table 1
Fig. 4
Fig. 4
Memory-associated synaptic proteins stratified for amyloid and cognitive status. Associations between synaptic protein levels and delayed and immediate recall on word learning tests are shown stratified for diagnostic groups based on amyloid and cognitive status in EMIF-AD MBD and ADNI. Proteins which were related to memory function depending on diagnostic group in at least one cohort are shown. Associations were considered significant when proteins showed an interaction with diagnostic group on memory scores (p-value < 0.1) and showed an effect on memory function in diagnostic group-stratified analyses (p-value < 0.05). *, **, ***: significant effect of protein level on memory function in diagnostic group-stratified analyses (*, p-value < 0.05, **, p-value < 0.01; ***, p-value < 0.001). Synaptic category ‘Other’ refers to other synaptic locations and functions as detailed in Fig. 1c. Associations of all analysed synaptic proteins are provided in Supplementary Table 1
Fig. 5
Fig. 5
Associations of synaptic composite scores with immediate and delayed memory scores. Synaptic composites contain proteins associated with delayed recall (left) or immediate recall (right). CN A-, controls; CN A + , preclinical AD, MCI A-, non-AD MCI, MCI A + , prodromal AD
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