Abstract
Background: Suspected non-Alzheimer's disease pathophysiology (SNAP) is a biomarker concept that encompasses individuals with neuronal injury but without amyloidosis. We aim to investigate the pathophysiology of SNAP, defined as abnormal tau without amyloidosis, in individuals with mild cognitive impairment (MCI) by cerebrospinal fluid (CSF) proteomics. Methods: Individuals were classified based on CSF amyloid beta (Aβ)1-42 (A) and phosphorylated tau (T), as cognitively normal A—T– (CN), MCI A–T+ (MCI-SNAP), and MCI A+T+ (MCI-AD). Proteomics analyses, Gene Ontology (GO), brain cell expression, and gene expression analyses in brain regions of interest were performed. Results: A total of 96 proteins were decreased in MCI-SNAP compared to CN and MCI-AD. These proteins were enriched for extracellular matrix (ECM), hemostasis, immune system, protein processing/degradation, lipids, and synapse. Fifty-one percent were enriched for expression in the choroid plexus. Conclusion: The pathophysiology of MCI-SNAP (A–T+) is distinct from that of MCI-AD. Our findings highlight the need for a different treatment in MCI-SNAP compared to MCI-AD.
| Original language | English |
|---|---|
| Journal | Alzheimer's and Dementia |
| Volume | 19 |
| Issue number | 3 |
| Pages (from-to) | 807-820 |
| Number of pages | 14 |
| ISSN | 1552-5260 |
| DOIs | |
| Publication status | Published - 03.2023 |
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In: Alzheimer's and Dementia, Vol. 19, No. 3, 03.2023, p. 807-820.
Research output: Journal Articles › Journal articles › Research › peer-review
TY - JOUR
T1 - Cerebrospinal fluid proteomic profiling of individuals with mild cognitive impairment and suspected non-Alzheimer's disease pathophysiology
AU - Delvenne, Aurore
AU - Gobom, Johan
AU - Tijms, Betty
AU - Bos, Isabelle
AU - Reus, Lianne M.
AU - Dobricic, Valerija
AU - Kate, Mara ten
AU - Verhey, Frans
AU - Ramakers, Inez
AU - Scheltens, Philip
AU - Teunissen, Charlotte E.
AU - Vandenberghe, Rik
AU - Schaeverbeke, Jolien
AU - Gabel, Silvy
AU - Popp, Julius
AU - Peyratout, Gwendoline
AU - Martinez-Lage, Pablo
AU - Tainta, Mikel
AU - Tsolaki, Magda
AU - Freund-Levi, Yvonne
AU - Lovestone, Simon
AU - Streffer, Johannes
AU - Barkhof, Frederik
AU - Bertram, Lars
AU - Blennow, Kaj
AU - Zetterberg, Henrik
AU - Visser, Pieter Jelle
AU - Vos, Stephanie J.B.
N1 - Funding Information: The present study was supported by the Memorabel program of ZonMw (the Netherlands Organization for Health Research and Development) grant number 733050502, Janssen Pharmaceutica N.V., and EMIF‐AD. J.G. has received in the past 36 months grants or contracts from Åhléns‐stiftelsen (150000 SEK), Gothenburg University Alzheimerfonden (500000 SEK), and Gothenburg University FoU VGR (50000 SEK). B.T. has received in the past 36 months grants or contracts from ZonMW VIDI (#09150171910068). B.T. has a patent on CSF proteomic subtypes in AD (#19165795.6 / #PCT/NL2020/050216; Applicant: Stichting Vumc). V.D. has received in the past 36 months a grant (SEQ1122) from DFG. F.V. has, in the past 36 months, other financial or non‐financial interests as a member of Dutch advisory board Biogen. I.R. has received in the past 36 months grants or contracts from EIT Health Institution and Janssen Institution. P.S. has received consultancy fees (paid to the institution) from AC Immune, Alkermes, Alnylam, Alzheon, Anavex, Biogen, Brainstorm Cell, Cortexyme, Denali, EIP, ImmunoBrain Checkpoint, GemVax, Genentech, Green Valley, Novartis, Novo Nordisk, PeopleBio, Renew LLC, Roche. He is PI of studies with AC Immune, CogRx, FUJI‐film/Toyama, IONIS, UCB, and Vivoryon. He is a part‐time employee of Life Sciences Partners Amsterdam. He serves on the board of Brain Research Center and New Amsterdam Pharma. P.S. has, in the past 36 months, held a leadership or fiduciary role in Trustee of the World Dementia Council. C.E.T. has received in the past 36 months grants or contracts from Weston brain institute, ZonMW, Alzheimer Nederland, and European Union and is part of the editorial board of , and . R.V. has received in the past 36 months clinical trial agreements with Roche, AbbVie, J&J, UCB, NovoNordisk. R.V.’s institution has received payment for consultancy agreement Cytox and for Data Safety Monitoring Board AC Immune and Novartis. J.S. has received in the past 36 months a personal grant of the Research Foundation Flanders (FWO)(12Y1620N). P.M. has received in the past 36 months grants or contracts from Carlos III Institute, Ministry of Health of Spain, for the EPAD and AMYPAD projects, and from the Department of Health, Government of the Basque Country. P.M. has received in the past 36 months consulting fees from Biogen, Esteve, Zambon, and Roche (to himself); payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Biogen, Roche, Zambon, Grifols, and Nutricia (to himself); and support for attending meetings and/or travel from Nutricia (to himself). S.L. has been on the Dementia Discovery Fund advisory board member on behalf of Janssen, has held stock options as part of renumeration from Janssen Medical Ltd, and has been an employee of Janssen Medical Ltd (UK). F.B. is a consultant to Biogen, Roche, Merck, Novartis, IXICO, and Combinostics; has participated on a Data Safety Monitoring Board or Advisory Board for Merck, Biogen, and NIA. L.B. has received in the past 36 months grants or contracts ERC (institution), DFG (institution), Cure Alzheimer Foundation (institution). K.B. 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), and the National Institute of Health (NIH), USA, (grant #1R01AG068398‐01). K.B. has served as a consultant or at advisory boards for Abcam (payment to himself), Axon (payment to himself), Biogen (payment to himself), JOMDD/Shimadzu (payment to himself), Lilly (payment to himself), MagQu (payment to himself), Prothena (payment to himself), Roche Diagnostics (payment to himself), and Siemens Healthineers (payment to himself). K.B. has served on data monitoring committees for Julius Clinical (payment to himself) and Novartis (payment to himself). K.B. is a co‐founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program. H.Z. 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), and the UK Dementia Research Institute at UCL (payments made to institution). H.Z. has served at scientific advisory boards for Alector, Eisai, Denali, Roche Diagnostics, Wave, Samumed, Siemens Healthineers, Pinteon Therapeutics, Nervgen, AZTherapies, and CogRx (payments made to HZ). H.Z. has given lectures in symposia sponsored by Cellectricon, Fujirebio, Alzecure, and Biogen (payments made to H.Z.). H.Z. is chair of the Alzheimer's Association Global Biomarker Standardization Consortium and the Alzheimer's Association Biofluid‐Based Biomarker Professional Interest Area. H.Z. is a co‐founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program (payments made to H.Z.). P.V. has received in the past 36 months research funding from IMI, Zon‐MW, and Biogen; has given a workshop on grant writing funded by Synapse (payments made to P.V.). P.V. has a patent on CSF proteomic subtypes in AD (#19165795.6 / #PCT/NL2020/050216; Applicant: Stichting Vumc). S.J.B.V. has received in the past 36 months grants or contracts from Alzheimer Nederland, institution Stichting van rinsum ponssen, and institution Zonmw. All other authors report no conflicts of interest. Author disclosures are available in the supporting information. Alzheimer Research and Therapy Neurology Funding Information: The present study was supported by the Memorabel program of ZonMw (the Netherlands Organization for Health Research and Development) grant number 733050502, Janssen Pharmaceutica N.V., and EMIF‐AD. The EMIF‐AD project has received support from the Innovative Medicines Initiative Joint Undertaking under EMIF grant agreement n° 115372, 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. The DESCRIPA study was funded by the European Commission within the 5th framework program (QLRT‐2001‐ 2455). The EDAR study was funded by the European Commission within the 5th framework program (contract # 37670). San Sebastian GAP study is partially funded by the Department of Health of the Basque Government (allocation 17.0.1.08.12.0000.2.454.01.41142.001.H), Provincial Government of Gipuzkoa (124/16), Kutxa Fundazioa, and by the Carlos III Institute of Health (PI15/00919, PN de I+D+I 2013‐2016). The Lausanne study was funded by a grant from the Swiss National Research Foundation (SNF 320030_141179). RV received funding from Stichting Alzheimer Onderzoek. YFL is supported by The Brain Foundation (Hjärnfonden FO2018‐0315), Stohne's Foundation (Stohnes Stiftelse), Gamla Tjänarinnor Stftelse, Stohnes Stiftelse, Särfond 31S Research Fund Region Örebro län Sweden, Familjen Kamprad s Stiftelse ref 20210034, AFA 200386. FB is supported by the NIHR biomedical reserach center at UCLH. Funding Information: The present study was supported by the Memorabel program of ZonMw (the Netherlands Organization for Health Research and Development) grant number 733050502, Janssen Pharmaceutica N.V., and EMIF-AD. The EMIF-AD project has received support from the Innovative Medicines Initiative Joint Undertaking under EMIF grant agreement n° 115372, 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. The DESCRIPA study was funded by the European Commission within the 5th framework program (QLRT-2001- 2455). The EDAR study was funded by the European Commission within the 5th framework program (contract # 37670). San Sebastian GAP study is partially funded by the Department of Health of the Basque Government (allocation 17.0.1.08.12.0000.2.454.01.41142.001.H), Provincial Government of Gipuzkoa (124/16), Kutxa Fundazioa, and by the Carlos III Institute of Health (PI15/00919, PN de I+D+I 2013-2016). The Lausanne study was funded by a grant from the Swiss National Research Foundation (SNF 320030_141179). RV received funding from Stichting Alzheimer Onderzoek. YFL is supported by The Brain Foundation (Hjärnfonden FO2018-0315), Stohne's Foundation (Stohnes Stiftelse), Gamla Tjänarinnor Stftelse, Stohnes Stiftelse, Särfond 31S Research Fund Region Örebro län Sweden, Familjen Kamprad s Stiftelse ref 20210034, AFA 200386. FB is supported by the NIHR biomedical reserach center at UCLH. Publisher Copyright: © 2022 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.
PY - 2023/3
Y1 - 2023/3
N2 - Background: Suspected non-Alzheimer's disease pathophysiology (SNAP) is a biomarker concept that encompasses individuals with neuronal injury but without amyloidosis. We aim to investigate the pathophysiology of SNAP, defined as abnormal tau without amyloidosis, in individuals with mild cognitive impairment (MCI) by cerebrospinal fluid (CSF) proteomics. Methods: Individuals were classified based on CSF amyloid beta (Aβ)1-42 (A) and phosphorylated tau (T), as cognitively normal A—T– (CN), MCI A–T+ (MCI-SNAP), and MCI A+T+ (MCI-AD). Proteomics analyses, Gene Ontology (GO), brain cell expression, and gene expression analyses in brain regions of interest were performed. Results: A total of 96 proteins were decreased in MCI-SNAP compared to CN and MCI-AD. These proteins were enriched for extracellular matrix (ECM), hemostasis, immune system, protein processing/degradation, lipids, and synapse. Fifty-one percent were enriched for expression in the choroid plexus. Conclusion: The pathophysiology of MCI-SNAP (A–T+) is distinct from that of MCI-AD. Our findings highlight the need for a different treatment in MCI-SNAP compared to MCI-AD.
AB - Background: Suspected non-Alzheimer's disease pathophysiology (SNAP) is a biomarker concept that encompasses individuals with neuronal injury but without amyloidosis. We aim to investigate the pathophysiology of SNAP, defined as abnormal tau without amyloidosis, in individuals with mild cognitive impairment (MCI) by cerebrospinal fluid (CSF) proteomics. Methods: Individuals were classified based on CSF amyloid beta (Aβ)1-42 (A) and phosphorylated tau (T), as cognitively normal A—T– (CN), MCI A–T+ (MCI-SNAP), and MCI A+T+ (MCI-AD). Proteomics analyses, Gene Ontology (GO), brain cell expression, and gene expression analyses in brain regions of interest were performed. Results: A total of 96 proteins were decreased in MCI-SNAP compared to CN and MCI-AD. These proteins were enriched for extracellular matrix (ECM), hemostasis, immune system, protein processing/degradation, lipids, and synapse. Fifty-one percent were enriched for expression in the choroid plexus. Conclusion: The pathophysiology of MCI-SNAP (A–T+) is distinct from that of MCI-AD. Our findings highlight the need for a different treatment in MCI-SNAP compared to MCI-AD.
UR - http://www.scopus.com/inward/record.url?scp=85131726329&partnerID=8YFLogxK
UR - https://www.mendeley.com/catalogue/ffa87a52-0a29-37d2-ab25-2fe6f4a86371/
U2 - 10.1002/alz.12713
DO - 10.1002/alz.12713
M3 - Journal articles
AN - SCOPUS:85131726329
SN - 1552-5260
VL - 19
SP - 807
EP - 820
JO - Alzheimer's and Dementia
JF - Alzheimer's and Dementia
IS - 3
ER -