Abstract
BACKGROUND: The apolipoprotein E (APOE) gene includes the strongest protective (ε2) and risk (ε4) variants for sporadic Alzheimer's disease (AD), but underlying mechanisms remain unclear. We studied APOE genotype effects on the cerebrospinal fluid (CSF) proteome. METHODS: Using untargeted tandem mass tag mass spectrometry, we analyzed CSF from 227 cognitively normal (CN) controls (A–T–), 165 CN A+, and 177 individuals with mild cognitive impairment (MCI A+) from two large cohorts. We compared protein levels across APOE genotypes using linear regression and characterized biological pathways. RESULTS: Five hundred forty-nine of 978 proteins (56%) differed between ε2/ε3 (n = 32 individuals) or ε4 carriers (n = 181 individuals) and ε3/ε3 controls. ε2/ε3 controls showed the most differences, with higher levels of 280 proteins enriched for neuronal plasticity. ε4 carrier controls showed increased proteins linked to blood–brain barrier dysfunction, and A+ ε4 carriers were related to glucose metabolism. DISCUSSION: Combining two cohorts enabled analysis of the rare APOE ε2 genotype, suggesting protective effects may occur through improved neuronal plasticity. Highlights: Apolipoprotein E (APOE) genotypes show distinct cerebrospinal fluid proteomic mechanisms in early Alzheimer's disease (AD). Combining cohorts enabled analysis of rare APOE ε2–associated protection in AD. The rare ε2 genotype may confer protection through improved neuronal plasticity. APOE ε4 carriers show increased blood–brain barrier dysfunction and glucose metabolism. These findings offer new insights into genotype-specific mechanisms in early AD.
| Originalsprache | Englisch |
|---|---|
| Aufsatznummer | e70738 |
| Zeitschrift | Alzheimer's and Dementia |
| Jahrgang | 21 |
| Ausgabenummer | 10 |
| ISSN | 1552-5260 |
| DOIs | |
| Publikationsstatus | Veröffentlicht - 10.2025 |
Fördermittel
Research of Alzheimer Center Amsterdam is part of the neurodegeneration research program of Amsterdam Neuroscience. Alzheimer Center Amsterdam is supported by Stichting Alzheimer Nederland and Stichting VUmc fonds. The chair of Wiesje van der Flier is supported by the Pasman stichting. Mass spectrometry‐based proteomic analyses were performed by the Proteomics Unit at the University of Bergen (PROBE). This facility is a member of the National Network of Advanced Proteomics Infrastructure (NAPI), which is funded by the Research Council of Norway INFRASTRUKTUR program (project number: 295910). The EMIF‐AD MBD study was conducted as part of the EMIF‐AD project, which has received support from the Innovative Medicines Initiative Joint Undertaking under EMIF grant agreement n° 115372, the resources of which are composed of financial contribution from the European Union's Seventh Framework Program (FP7/2007‐2013) and EFPIA companies’ in kind contribution. This work has been supported by the ZonMW Memorabel grant programme #733050824736 (B.M.T. and P.J.V.), and ZonMW VIDI #09150171910068 (B.M.T.), EPND #101034344 (P.J.V.), JPND PMI‐AD #733051111 (P.J.V.). The VD cohort was supported by grants from SNSF (320030_141179) and the Synapsis Foundation (2017‐PI01) to J.P. H.Z. is a Wallenberg Scholar supported by grants from the Swedish Research Council (#2022‐01018 and #2019‐02397), the European Union's Horizon Europe research and innovation programme under grant agreement No 101053962, Swedish State Support for Clinical Research (#ALFGBG‐71320), 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 Bluefield Project, the Olav Thon Foundation, the Erling‐Persson Family Foundation, Stiftelsen för Gamla Tjänarinnor, Hjärnfonden, Sweden (#FO2022‐0270), the European Union's Horizon 2020 research and innovation programme under the Marie Skłodowska‐Curie grant agreement No 860197 (MIRIADE), the European Union Joint Programme – Neurodegenerative Disease Research (JPND2021‐00694), the National Institute for Health and Care Research University College London Hospitals Biomedical Research Centre, and the UK Dementia Research Institute at UCL (UKDRI‐1003). J.M.S. is supported by a senior postdoctoral fellowship grant of Fonds voor wetenschappelijk onderzoek (FWO) (#12Y1623N) and Stichting Alzheimer Association grant (#SAO‐FRA 2021/0022). B.T., C.T., and W.F. are recipients of TAP‐dementia ( www.tap‐dementia.nl ), receiving funding from ZonMw (#10510032120003) in the context of Onderzoeksprogramma Dementie, part of the Dutch National Dementia Strategy. Y.F.L. is supported by The Brain Foundation (Hjärnfonden FO2018‐0315), Stohne's Foundation (Stohnes Stiftelse), Gamla Tjänarinnor Stiftelse, Stohnes Stiftelse, Särfond 31S Research Fund Region Örebro län Sweden, AFA 200386. S.L. is recipient of funding from ZonMW (#733050512), Health∼Holland, Topsector Life Sciences & Health (PPP‐allowance; #LSHM20106). Stichting Dioraphte, the Edwin Bouw Fonds, and Stichting VUmc fonds. W.F., S.L. and C.T. are recipients of ABOARD, which is a public–private partnership receiving funding from ZonMW (#73305095007) and Health∼Holland, Topsector Life Sciences & Health (PPP‐allowance; #LSHM20106). More than 30 partners participate in ABOARD ( www.aboard‐project.nl ). ABOARD also receives funding from de Hersenstichting, Edwin Bouw Fonds, and Gieskes‐Strijbisfonds. K.B. is supported by the Swedish Research Council (#2017‐00915 and #2022‐00732), the Swedish Alzheimer Foundation (#AF‐930351, #AF‐939721, and #AF‐968270), Hjärnfonden, Sweden (#FO2017‐0243 and #ALZ2022‐0006), the Swedish state under the agreement between the Swedish government and the County Councils, the ALF‐agreement (#ALFGBG‐715986 and #ALFGBG‐965240), the European Union Joint Program for Neurodegenerative Disorders (JPND2019‐466‐236), the Alzheimer's Association 2021 Zenith Award (ZEN‐21‐848495), and the Alzheimer's Association 2022‐2025 Grant (SG‐23‐1038904 QC). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. J.P. received consultation and speaker honoraria from Nestle Institute of Health Sciences, Innovation Campus, EPFL, Lausanne, Switzerland; Ono Pharma, Schwabe Pharma Switzerland; OM Pharma Switzerland; Roche Pharma; and Fujirebio Europe, all not related to this work. H.Z. has served on scientific advisory boards and/or as a consultant for AbbVie, Acumen, Alector, Alzinova, ALZPath, Annexon, Apellis, Artery Therapeutics, AZTherapies, Cognito Therapeutics, CogRx, Denali, Eisai, Nervgen, Novo Nordisk, Optoceutics, Passage Bio, Pinteon Therapeutics, Prothena, Red Abbey Labs, reMYND, Roche, Samumed, Siemens Healthineers, Triplet Therapeutics, and Wave; has given lectures in symposia sponsored by Alzecure, Biogen, Cellectricon, Fujirebio, Lilly, 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 (outside submitted work). C.E.T. is employed by Amsterdam UMC. She has grants or contracts for Research of the European Commission (Marie Curie International Training Network, grant agreement No 860197 (MIRIADE); Innovative Medicines Initiatives 3TR (Horizon 2020, grant no. 831434), EPND (IMI 2 Joint Undertaking [JU], grant No. 101034344) and JPND (bPRIDE), National MS Society (Progressive MS Alliance), Alzheimer Drug Discovery Foundation, Alzheimer Association, Health Holland, and the Dutch Research Council (ZonMW), including TAP‐dementia, a ZonMw‐funded project (#10510032120003) in the context of the Dutch National Dementia Strategy, Alzheimer Drug Discovery Foundation, the Selfridges Group Foundation, and Alzheimer Netherlands. She is the recipient of ABOARD, which is a public–private partnership receiving funding from ZonMW (#73305095007) and Health∼Holland, Topsector Life Sciences & Health (PPP‐allowance; #LSHM20106). She is also a contract researcher for ADx Neurosciences, AC‐Immune, Aribio, Axon Neurosciences, Beckman‐Coulter, BioConnect, Bioorchestra, Brainstorm Therapeutics, Celgene, Cognition Therapeutics, EIP Pharma, Eisai, Eli Lilly, Fujirebio, Grifols, Instant Nano Biosensors, Merck, Novo Nordisk, Olink, PeopleBio, Quanterix, Roche, Siemens, Toyama, Vivoryon, and the European Commission. She has received payment or honoraria from Roche, Novo Nordisk, and Grifols, where all payments were made to her institution. She also serves on editorial boards of Medidact Neurologie/Springer; and in . She is editor of . R.V.’s institution has clinical trial agreements (R.V. as PI) with Alector, AviadoBio, Biogen, Denali, J&J, and UCB. R.V.’s institution has consultancy agreements (R.V. as DSMB chair) with AC Immune and with Eli Lilly and Roche (R.V. as member of the advisory board). K.B. has served as a consultant and on advisory boards for Acumen, ALZPath, BioArctic, Biogen, Eisai, Lilly, Moleac Pte. Ltd, Novartis, Ono Pharma, Prothena, Roche Diagnostics, and Siemens Healthineers; has served on 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. P.S. is a full‐time employee of EQT Life Sciences (formerly LSP) and professor emeritus at Amsterdam University Medical Centers. He has received consultancy fees (paid to the university) from Alzheon, Brainstorm Cell, and Green Valley. Within his university affiliation, he was global PI of the phase 1b study of AC Immune, phase 2b study with FUJI‐film/Toyama, and the phase 2 study of UCB. He is past chair of the EU steering committee of the phase 2b program of Vivoryon and the phase 2b study of Novartis Cardiology and presently co‐chair of the phase 3 study with NOVO‐Nordisk. P.J.V. has received honoraria for a workshop on grant writing organized by Stiftung Synapsis, Alzheimer Forschung Schweiz AFS (payment to university), and is a member of the executive board of EADC. P.J.V. and B.M.T. have a patent on AD subtypes (PCT/NL2020/050216). The remaining authors report no conflicts of interest. Author disclosures are available in the supporting information . Neurology: Neuroimmunology & Neuroinflammation Alzheimer Research and Therapy Research of Alzheimer Center Amsterdam is part of the neurodegeneration research program of Amsterdam Neuroscience. Alzheimer Center Amsterdam is supported by Stichting Alzheimer Nederland and Stichting VUmc fonds. The chair of Wiesje van der Flier is supported by the Pasman stichting. Mass spectrometry-based proteomic analyses were performed by the Proteomics Unit at the University of Bergen (PROBE). This facility is a member of the National Network of Advanced Proteomics Infrastructure (NAPI), which is funded by the Research Council of Norway INFRASTRUKTUR program (project number: 295910). The EMIF-AD MBD study was conducted as part of the EMIF-AD project, which has received support from the Innovative Medicines Initiative Joint Undertaking under EMIF grant agreement n° 115372, the resources of which are composed of financial contribution from the European Union's Seventh Framework Program (FP7/2007-2013) and EFPIA companies’ in kind contribution. This work has been supported by the ZonMW Memorabel grant programme #733050824736 (B.M.T. and P.J.V.), and ZonMW VIDI #09150171910068 (B.M.T.), EPND #101034344 (P.J.V.), JPND PMI-AD #733051111 (P.J.V.). The VD cohort was supported by grants from SNSF (320030_141179) and the Synapsis Foundation (2017-PI01) to J.P. H.Z. is a Wallenberg Scholar supported by grants from the Swedish Research Council (#2022-01018 and #2019-02397), the European Union's Horizon Europe research and innovation programme under grant agreement No 101053962, Swedish State Support for Clinical Research (#ALFGBG-71320), 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 Bluefield Project, the Olav Thon Foundation, the Erling-Persson Family Foundation, Stiftelsen för Gamla Tjänarinnor, Hjärnfonden, Sweden (#FO2022-0270), the European Union's Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No 860197 (MIRIADE), the European Union Joint Programme – Neurodegenerative Disease Research (JPND2021-00694), the National Institute for Health and Care Research University College London Hospitals Biomedical Research Centre, and the UK Dementia Research Institute at UCL (UKDRI-1003). J.M.S. is supported by a senior postdoctoral fellowship grant of Fonds voor wetenschappelijk onderzoek (FWO) (#12Y1623N) and Stichting Alzheimer Association grant (#SAO-FRA 2021/0022). B.T., C.T., and W.F. are recipients of TAP-dementia (www.tap-dementia.nl), receiving funding from ZonMw (#10510032120003) in the context of Onderzoeksprogramma Dementie, part of the Dutch National Dementia Strategy. Y.F.L. is supported by The Brain Foundation (Hjärnfonden FO2018-0315), Stohne's Foundation (Stohnes Stiftelse), Gamla Tjänarinnor Stiftelse, Stohnes Stiftelse, Särfond 31S Research Fund Region Örebro län Sweden, AFA 200386. S.L. is recipient of funding from ZonMW (#733050512), Health∼Holland, Topsector Life Sciences & Health (PPP-allowance; #LSHM20106). Stichting Dioraphte, the Edwin Bouw Fonds, and Stichting VUmc fonds. W.F., S.L. and C.T. are recipients of ABOARD, which is a public–private partnership receiving funding from ZonMW (#73305095007) and Health∼Holland, Topsector Life Sciences & Health (PPP-allowance; #LSHM20106). More than 30 partners participate in ABOARD (www.aboard-project.nl). ABOARD also receives funding from de Hersenstichting, Edwin Bouw Fonds, and Gieskes-Strijbisfonds. K.B. is supported by the Swedish Research Council (#2017-00915 and #2022-00732), the Swedish Alzheimer Foundation (#AF-930351, #AF-939721, and #AF-968270), Hjärnfonden, Sweden (#FO2017-0243 and #ALZ2022-0006), the Swedish state under the agreement between the Swedish government and the County Councils, the ALF-agreement (#ALFGBG-715986 and #ALFGBG-965240), the European Union Joint Program for Neurodegenerative Disorders (JPND2019-466-236), the Alzheimer's Association 2021 Zenith Award (ZEN-21-848495), and the Alzheimer's Association 2022-2025 Grant (SG-23-1038904 QC). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
| Träger | Trägernummer |
|---|---|
| Alzheimer's Association | |
| Dutch National Dementia Strategy | |
| Alzheimer Association | |
| Health Holland | |
| Familjen Erling-Perssons Stiftelse | |
| EPND | |
| European Federation of Pharmaceutical Industries and Associations | |
| National Institute for Health and Care Research | |
| Horizon 2020 Framework Programme | |
| TAP-dementia | |
| Geestkracht Programme of the Dutch Health Research Council | |
| Olav Thon Stiftelsen | |
| Swedish government | |
| MS Trust and National MS Society | |
| Innovative Medicines Initiative | |
| AD Strategic Fund | |
| Gun och Bertil Stohnes Stiftelse | |
| Institut für Medizinische Informatik | 101034344 |
| Edwin Bouw Fonds | 2017‐00915, 2022‐00732 |
| Stichting Alzheimer Association | ‐FRA 2021/0022, #SAO-FRA 2021/0022 |
| ZonMw | 733050824736, 10510032120003, 09150171910068 |
| Alzheimerfonden | ‐968270, ‐930351, ‐939721, -0243, #ALZ2022‐0006 |
| Stiftung Synapsis - Alzheimer Forschung Schweiz AFS | 2017‐PI01 |
| Selfridges Group Foundation | 73305095007 |
| Fonds Wetenschappelijk Onderzoek | 12Y1623N |
| Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung | 320030_141179 |
| EU Joint Programme – Neurodegenerative Disease Research | 733051111, JPND2021‐00694 |
| Gamla Tjänarinnor Stiftelse | 733050512, AFA 200386 |
| Stiftelsen för Gamla Tjänarinnor, Hjärnfonden, Sweden | #FO2022‐0270 |
| Norges Forskningsråd | 295910 |
| European Commission | 101053962, 71320 |
| Alzheimer's Drug Discovery Foundation | 201809‐2016862 |
| H2020 Marie Skłodowska-Curie Actions | 860197 |
| Vetenskapsrådet | 2019‐02397, 2022‐01018 |
| UK Dementia Research Institute | UKDRI‐1003 |
| County Councils | 965240, 715986 |
| European Commission | 831434 |
| European Union Joint Program for Neurodegenerative Disorders | JPND2019‐466‐236, ZEN‐21‐848495, SG‐23‐1038904 QC |
| Brain and Behavior Research Foundation | FO2018-0315 |
| EMIF | 115372 |
| Seventh Framework Programme | FP7/2007-2013 |
UN SDGs
Dieser Output leistet einen Beitrag zu folgendem(n) Ziel(en) für nachhaltige Entwicklung
-
SDG 3 – Gesundheit und Wohlergehen
Strategische Forschungsbereiche und Zentren
- Querschnittsbereich: Medizinische Genetik
DFG-Fachsystematik
- 2.23-06 Molekulare und zelluläre Neurologie und Neuropathologie
Fingerprint
Untersuchen Sie die Forschungsthemen von „Cerebrospinal fluid proteomic associations of APOE genotypes reveal distinct protective and risk mechanisms for Alzheimer's disease“. Zusammen bilden sie einen einzigartigen Fingerprint.Zitieren
- APA
- Author
- BIBTEX
- Harvard
- Standard
- RIS
- Vancouver