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

the Alzheimer’s Disease Neuroimaging Initiative

doi:10.1186/s13195-025-01703-z

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

the Alzheimer’s Disease Neuroimaging Initiative

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.

Originalsprache	Englisch
Aufsatznummer	56
Zeitschrift	Alzheimer's Research and Therapy
Jahrgang	17
Ausgabenummer	1
DOIs	https://doi.org/10.1186/s13195-025-01703-z
Publikationsstatus	Veröffentlicht - 12.2025

Fördermittel

YVF is funded by “Hjärnfonden” (FO2018-0315) grants from the Petrus and Augusta Hedlunds Foundation, the Gun och Bertil Stohnes Foundation, the Loo and Hans Osterman Foundation, the Demensförbundet, Brain Foundation “Särfond 31 Forskning Senil demens,” Region Örebro län, “Stiftelsen for Gamla Tjänarinnor,” and Demensfonden, Stockholm Sweden. This work has been supported by ZonMW Memorabel grant programme #733050824 (KW, BMT and PJV) and by the Innovative Medicines Initiative Joint Undertaking under EMIF-AD MBD grant agreement #115372. KB is supported by the Swedish Research Council (#2017–00915), the Alzheimer Drug Discovery Foundation (ADDF), USA (#RDAPB-201809–2016615), the Swedish Alzheimer Foundation (#AF-742881), Hjärnfonden, Sweden (#FO2017-0243), the Swedish state under the agreement between the Swedish government and the County Councils, the ALF-agreement (#ALFGBG-715986), the European Union Joint Program for Neurodegenerative Disorders (JPND2019-466–236), the National Institute of Health (NIH), USA, (grant #1R01AG068398-01), and the Alzheimer’s Association 2021 Zenith Award (ZEN-21–848495). HZ is a Wallenberg Scholar supported by grants from the Swedish Research Council (#2018–02532), the European Research Council (#681712), Swedish State Support for Clinical Research (#ALFGBG-720931), the Alzheimer Drug Discovery Foundation (ADDF), USA (#201809–2016862), the AD Strategic Fund and the Alzheimer's Association (#ADSF-21–831376-C, #ADSF-21–831381-C and #ADSF-21–831377-C), the Olav Thon Foundation, the Erling-Persson Family Foundation, Stiftelsen för Gamla Tjänarinnor, Hjärnfonden, Sweden (#FO2019-0228), the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No 860197 (MIRIADE), European Union Joint Program for Neurodegenerative Disorders (JPND2021-00694), and the UK Dementia Research Institute at UCL. JG is supported by grants from Alzheimerfonden (AF-930934) and Stiftelsen för Gamla Tjänarinnor. 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. Data was used for this project of which collection and sharing was funded by the Alzheimer's Disease Neuroimaging Initiative (ADNI) (National Institutes of Health Grant U01 AG024904) and DOD ADNI (Department of Defense award number W81XWH-12–2-0012). ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the following: AbbVie, Alzheimer’s Association; Alzheimer’s Drug Discovery Foundation; Araclon Biotech; BioClinica, Inc.; Biogen; Bristol-Myers Squibb Company; CereSpir, Inc.; Cogstate; Eisai Inc.; Elan Pharmaceuticals, Inc.; Eli Lilly and Company; EuroImmun; F. Hoffmann-La Roche Ltd and its affiliated company Genentech, Inc.; Fujirebio; GE Healthcare; IXICO Ltd.; Janssen Alzheimer Immunotherapy Research & Development, LLC.; Johnson & Johnson Pharmaceutical Research & Development LLC.; Lumosity; Lundbeck; Merck & Co., Inc.; Meso Scale Diagnostics, LLC.; NeuroRx Research; Neurotrack Technologies; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Piramal Imaging; Servier; Takeda Pharmaceutical Company; and Transition Therapeutics. The Canadian Institutes of Health Research is providing funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the National Institutes of Health ( www.fnih.org ). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer’s Therapeutic Research Institute at the University of Southern California. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of Southern California.

Träger	Trägernummer
Petrus och Augusta Hedlunds Stiftelse
Familjen Erling-Perssons Stiftelse
Nederlandse Organisatie voor Wetenschappelijk Onderzoek
National Institute of Biomedical Imaging and Bioengineering
UK Dementia Research Institute
Horizon 2020 Framework Programme
European Commission
Gun och Bertil Stohnes Foundation
Olav Thon Stiftelsen
Stiftelsen för Gamla Tjänarinnor, Hjärnfonden, Sweden	#FO2019-0228
Association of Frontotemporal Dementia
Swedish government
Weston Brain Institute
Alzheimer's Disease Neuroimaging Initiative
DOD ADNI
Loo och Hans Ostermans Stiftelse för Medicinsk Forskning
AD Strategic Fund
National Institute on Aging
Innovative Medicines Initiative	115372
Alzheimer's Association	-21–831376-C, -21–831377-C, ZEN-21–848495, 2018–02532, -21–831381-C
National Institutes of Health	1R01AG068398-01, U01 AG024904
European Union Joint Program for Neurodegenerative Disorders	JPND2019-466–236
Alzheimerfonden	AF-930934, -0243, -742881
County Councils	-715986
ZonMw	733050824
Swedish State Support for Clinical Research	-720931, 201809–2016862
U.S. Department of Defense	W81XWH-12–2-0012
H2020 Marie Skłodowska-Curie Actions	JPND2021-00694, 860197
European Research Council	681712
Vetenskapsrådet	2017–00915
Alzheimer's Drug Discovery Foundation	-201809–2016615

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Strategische Forschungsbereiche und Zentren

Querschnittsbereich: Medizinische Genetik

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10.1186/s13195-025-01703-z

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@article{a3866b420fab42e3a39c43cf047a0b81,

title = "Synaptic protein CSF levels relate to memory scores in individuals without dementia",

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{\textquoteright}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.",

author = "\{the Alzheimer{\textquoteright}s Disease Neuroimaging Initiative\} and Wesenhagen, \{Kirsten E.J.\} and \{de Leeuw\}, \{Diederick M.\} and Jori Tomassen and Johan Gobom and Isabelle Bos and Vos, \{Stephanie J.B.\} and Pablo Martinez-Lage and Mikel Tainta and Julius Popp and Gwendoline Peyratout and Magda Tsolaki and Rik Vandenberghe and Yvonne Freund-Levi and Frans Verhey and Simon Lovestone and Johannes Streffer and Valerija Dobricic and Kaj Blennow and Philip Scheltens and Smit, \{August B.\} and Lars Bertram and Teunissen, \{Charlotte E.\} and Henrik Zetterberg and Tijms, \{Betty M.\} and Visser, \{Pieter Jelle\}",

note = "Publisher Copyright: {\textcopyright} The Author(s) 2025.",

year = "2025",

month = dec,

doi = "10.1186/s13195-025-01703-z",

language = "English",

volume = "17",

journal = "Alzheimer's Research and Therapy",

issn = "1758-9193",

publisher = "BioMed Central Ltd",

number = "1",

}

TY - JOUR

T1 - Synaptic protein CSF levels relate to memory scores in individuals without dementia

AU - the Alzheimer’s Disease Neuroimaging Initiative

AU - Wesenhagen, Kirsten E.J.

AU - de Leeuw, Diederick M.

AU - Tomassen, Jori

AU - Gobom, Johan

AU - Bos, Isabelle

AU - Vos, Stephanie J.B.

AU - Martinez-Lage, Pablo

AU - Tainta, Mikel

AU - Popp, Julius

AU - Peyratout, Gwendoline

AU - Tsolaki, Magda

AU - Vandenberghe, Rik

AU - Freund-Levi, Yvonne

AU - Verhey, Frans

AU - Lovestone, Simon

AU - Streffer, Johannes

AU - Dobricic, Valerija

AU - Blennow, Kaj

AU - Scheltens, Philip

AU - Smit, August B.

AU - Bertram, Lars

AU - Teunissen, Charlotte E.

AU - Zetterberg, Henrik

AU - Tijms, Betty M.

AU - Visser, Pieter Jelle

PY - 2025/12

Y1 - 2025/12

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/86000274206

UR - https://www.mendeley.com/catalogue/e84361cf-407a-3b32-95ac-88e61971d809/

U2 - 10.1186/s13195-025-01703-z

DO - 10.1186/s13195-025-01703-z

M3 - Journal articles

C2 - 40033427

AN - SCOPUS:86000274206

SN - 1758-9193

VL - 17

JO - Alzheimer's Research and Therapy

JF - Alzheimer's Research and Therapy

IS - 1

M1 - 56

ER -

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

Abstract

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