CSF proteomic profiles of neurodegeneration biomarkers in Alzheimer's disease

Aurore Delvenne; Johan Gobom; Suzanne E. Schindler; Mara ten Kate; Lianne M. Reus; Valerija Dobricic; Betty M. Tijms; Tammie L.S. Benzinger; Carlos Cruchaga; Charlotte E. Teunissen; Inez Ramakers; Pablo Martinez-Lage; Mikel Tainta; Rik Vandenberghe; Jolien Schaeverbeke; Sebastiaan Engelborghs; Ellen De Roeck; Julius Popp; Gwendoline Peyratout; Magda Tsolaki; Yvonne Freund-Levi; Simon Lovestone; Johannes Streffer; Frederik Barkhof; Lars Bertram; Kaj Blennow; Henrik Zetterberg; Pieter Jelle Visser; Stephanie J.B. Vos

doi:10.1002/alz.14103

CSF proteomic profiles of neurodegeneration biomarkers in Alzheimer's disease

Aurore Delvenne^*, Johan Gobom, Suzanne E. Schindler, Mara ten Kate, Lianne M. Reus, Valerija Dobricic, Betty M. Tijms, Tammie L.S. Benzinger, Carlos Cruchaga, Charlotte E. Teunissen, Inez Ramakers, Pablo Martinez-Lage, Mikel Tainta, Rik Vandenberghe, Jolien Schaeverbeke, Sebastiaan Engelborghs, Ellen De Roeck, Julius Popp, Gwendoline Peyratout, Magda TsolakiYvonne Freund-Levi, Simon Lovestone, Johannes Streffer, Frederik Barkhof, Lars Bertram, Kaj Blennow, Henrik Zetterberg, Pieter Jelle Visser, Stephanie J.B. Vos

^*Korrespondierende/r Autor/-in für diese Arbeit

5 Zitate (Scopus)

Abstract

INTRODUCTION: We aimed to unravel the underlying pathophysiology of the neurodegeneration (N) markers neurogranin (Ng), neurofilament light (NfL), and hippocampal volume (HCV), in Alzheimer's disease (AD) using cerebrospinal fluid (CSF) proteomics. METHODS: Individuals without dementia were classified as A+ (CSF amyloid beta [Aβ]42), T+ (CSF phosphorylated tau181), and N+ or N− based on Ng, NfL, or HCV separately. CSF proteomics were generated and compared between groups using analysis of covariance. RESULTS: Only a few individuals were A+T+Ng−. A+T+Ng+ and A+T+NfL+ showed different proteomic profiles compared to A+T+Ng− and A+T+NfL−, respectively. Both Ng+ and NfL+ were associated with neuroplasticity, though in opposite directions. Compared to A+T+HCV−, A+T+HCV+ showed few proteomic changes, associated with oxidative stress. DISCUSSION: Different N markers are associated with distinct neurodegenerative processes and should not be equated. N markers may differentially complement disease staging beyond amyloid and tau. Our findings suggest that Ng may not be an optimal N marker, given its low incongruency with tau pathophysiology. Highlights: In Alzheimer's disease, neurogranin (Ng)+, neurofilament light (NfL)+, and hippocampal volume (HCV)+ showed differential protein expression in cerebrospinal fluid. Ng+ and NfL+ were associated with neuroplasticity, although in opposite directions. HCV+ showed few proteomic changes, related to oxidative stress. Neurodegeneration (N) markers may differentially refine disease staging beyond amyloid and tau. Ng might not be an optimal N marker, as it relates more closely to tau.

Originalsprache	Englisch
Zeitschrift	Alzheimer's and Dementia
Jahrgang	20
Ausgabenummer	9
Seiten (von - bis)	6205-6220
Seitenumfang	16
ISSN	1552-5260
DOIs	https://doi.org/10.1002/alz.14103
Publikationsstatus	Veröffentlicht - 09.2024

Fördermittel

A.D. received funding from Alzheimer Nederland (grant No. WE.15‐2022‐01). J.G. has nothing to disclose. S.E.S. has analyzed data provided by C2N Diagnostics to Washington University. She has served on scientific advisory boards for Eisai. M.K. has nothing to disclose. L.M.R. has nothing to disclose. V.D. has nothing to disclose. B.M.T. has nothing to disclose. T.L.S.B. has investigator‐initiated research funding from the NIH, the Alzheimer's Association, the Barnes‐Jewish Hospital Foundation, and Siemens. She participates as a site investigator in clinical trials sponsored by Avid Radiopharmaceuticals, Eli Lilly, Biogen, Eisai, Jaansen, and Roche. She serves as a consultant to Biogen, Lilly, Eisai, and Siemens. C.C. has nothing to disclose. C.E.T. has nothing to disclose. I.R. has nothing to disclose. P.M.L. has nothing to disclose. M.T. has nothing to disclose. R.V.’s institution has clinical trial agreements (R.V. as P.I.) with Alector, Biogen, Denali, EliLilly, J&J, UCB. R.V.’s institution has consultancy agreements (R.V. as DSMB member) with AC Immune. J.S. is a senior postdoctoral fellow (12Y1623N) of FWO. J.S. receives funding from Stichting Alzheimer Onderzoek (SAO‐FRA 2021/0022). S.E. has nothing to disclose. E.D.R. has nothing to disclose. J.P. served as a consultant and on advisory boards for the Nestlé Institute of Health Sciences, Ono Pharma, OM Pharma, Schwabe Pharma, Lilly, Roche, and Fujirebio Europe. All his disclosures are unrelated to the present work. The VD cohort was supported by grants from the Swiss National Research Foundation (SNF 320030_204886), Synapsis Foundation – Dementia Research Switzerland (Grant No. 2017‐PI01). G.P. has nothing to disclose. M.T. has nothing to disclose. Y.F.L. has nothing to disclose. S.L. has nothing to disclose. J.S. has nothing to disclose. F.B. is a steering committee or Data Safety Monitoring Board member for Biogen, Merck, Eisai, and Prothena; an advisory board member for Combinostics, Scottish Brain Sciences; a consultant for Roche, Celltrion, Rewind Therapeutics, Merck, Bracco. F.B. has research agreements with ADDI, Merck, Biogen, GE Healthcare, Roche. F.B. is co‐founder and shareholder of Queen Square Analytics LTD. L.B. has nothing to disclose. K.B. has served as a consultant and on advisory boards for AC Immune, Acumen, ALZPath, AriBio, 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. H.Z. has served on 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, Merry Life, 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, Novo Nordisk, 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). P.J.V. received funding from the European Commission, IMI 2 Joint Undertaking (JU), AMYPAD, grant No. 115952; European Commission, IMI 2 JU, RADAR‐AD, grant No. 806999; European Commission, IMI 2 JU, EPND, grant No. 101034344. The IMI JU receives support from the European Union's Horizon 2020 research and innovation programme and EFPIA. P.J.V. received also funding from Zon‐MW, Redefining Alzheimer's disease, grant No. 733050824736; and Biogen (Amyloid biomarker study group). Grants were paid to the university. S.J.B.V. received funding from ZonMW (SNAP VIMP grant No. 7330505021), Stichting Adriana van Rinsum‐Ponssen, and the EPND project, which received funding from the European Commision, IMI 2 Joint Undertaking (JU) under grant agreement No. 101034344. The IMI JU receives support from the European Union's Horizon 2020 research and innovation programme and EFPIA. Author disclosures are available in the supporting information . The present study was supported by the Memorabel program of ZonMw (the Netherlands Organization for Health Research and Development) grant No. 733050502 and 7330505021, an anonymous foundation, and EMIF‐AD. The EMIF‐AD project has received support from the Innovative Medicines Initiative Joint Undertaking under EMIF grant agreement No. 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). Collection of data from the Knight ADRC was supported by the National Institute on Aging grants K23AG053426, P30AG066444, P01AG003991, and P01AG026276. F.B. is supported by the NIHR Biomedical Research Centre at UCLH. H.Z. is a Wallenberg Scholar and a Distinguished Professor at the Swedish Research Council supported by grants from the Swedish Research Council (#2023‐00356; #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, #ADSF‐21‐831377‐C, and #ADSF‐24‐1284328‐C), the Bluefield Project, Cure Alzheimer's Fund, 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).

Träger	Trägernummer
Alzheimer's Association
Erling‐Persson Family Foundation
Seventh Framework Programme
Foundation for Barnes-Jewish Hospital
National Institute on Aging	K23AG053426, P01AG003991, P30AG066444, P01AG026276
Cure Alzheimer's Fund
Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
Siemens CT
Manchester Biomedical Research Centre
Netherlands Organization for Health Research and Development	733050502
European Union's Horizon 2020 research and innovation programme	860197
Schweizerischer Nationalfonds (SNF)	320030_141179, 320030_204886
EU Joint Programme – Neurodegenerative Disease Research	JPND2021‐00694
EPND	101034344
AMYPAD	IMI 2 JU, 806999, 115952
UK Dementia Research Institute	UKDRI‐1003
Redefining Alzheimer's disease	733050824736
Synapsis Foundation – Dementia Research Switzerland	2017‐PI01
European Union’s Horizon Europe research and innovation programme	101053962, 71320
EMIF	115372
Stiftelsen för Gamla Tjänarinnor, Hjärnfonden, Sweden	#FO2022‐0270
Stichting Alzheimer Onderzoek	SAO‐FRA 2021/0022
Alzheimer's Drug Discovery Foundation	201809‐2016862
SNAP VIMP	7330505021
Swedish Research Council	2019‐02397, 2023‐00356, 2022‐01018
European Commission within the 5th framework program	37670, QLRT‐2001‐2455

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SDG 3 – Gesundheit und Wohlergehen

Strategische Forschungsbereiche und Zentren

Querschnittsbereich: Medizinische Genetik

DFG-Fachsystematik

2.23-06 Molekulare und zelluläre Neurologie und Neuropathologie

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10.1002/alz.14103

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Delvenne, A., Gobom, J., Schindler, S. E., Kate, M. T., Reus, L. M., Dobricic, V., Tijms, B. M., Benzinger, T. L. S., Cruchaga, C., Teunissen, C. E., Ramakers, I., Martinez-Lage, P., Tainta, M., Vandenberghe, R., Schaeverbeke, J., Engelborghs, S., Roeck, E. D., Popp, J., Peyratout, G., ... Vos, S. J. B. (2024). CSF proteomic profiles of neurodegeneration biomarkers in Alzheimer's disease. Alzheimer's and Dementia, 20(9), 6205-6220. https://doi.org/10.1002/alz.14103

@article{c65791b895a8459b863150170cef3a13,

title = "CSF proteomic profiles of neurodegeneration biomarkers in Alzheimer's disease",

abstract = "INTRODUCTION: We aimed to unravel the underlying pathophysiology of the neurodegeneration (N) markers neurogranin (Ng), neurofilament light (NfL), and hippocampal volume (HCV), in Alzheimer's disease (AD) using cerebrospinal fluid (CSF) proteomics. METHODS: Individuals without dementia were classified as A+ (CSF amyloid beta [Aβ]42), T+ (CSF phosphorylated tau181), and N+ or N− based on Ng, NfL, or HCV separately. CSF proteomics were generated and compared between groups using analysis of covariance. RESULTS: Only a few individuals were A+T+Ng−. A+T+Ng+ and A+T+NfL+ showed different proteomic profiles compared to A+T+Ng− and A+T+NfL−, respectively. Both Ng+ and NfL+ were associated with neuroplasticity, though in opposite directions. Compared to A+T+HCV−, A+T+HCV+ showed few proteomic changes, associated with oxidative stress. DISCUSSION: Different N markers are associated with distinct neurodegenerative processes and should not be equated. N markers may differentially complement disease staging beyond amyloid and tau. Our findings suggest that Ng may not be an optimal N marker, given its low incongruency with tau pathophysiology. Highlights: In Alzheimer's disease, neurogranin (Ng)+, neurofilament light (NfL)+, and hippocampal volume (HCV)+ showed differential protein expression in cerebrospinal fluid. Ng+ and NfL+ were associated with neuroplasticity, although in opposite directions. HCV+ showed few proteomic changes, related to oxidative stress. Neurodegeneration (N) markers may differentially refine disease staging beyond amyloid and tau. Ng might not be an optimal N marker, as it relates more closely to tau.",

author = "Aurore Delvenne and Johan Gobom and Schindler, \{Suzanne E.\} and Kate, \{Mara ten\} and Reus, \{Lianne M.\} and Valerija Dobricic and Tijms, \{Betty M.\} and Benzinger, \{Tammie L.S.\} and Carlos Cruchaga and Teunissen, \{Charlotte E.\} and Inez Ramakers and Pablo Martinez-Lage and Mikel Tainta and Rik Vandenberghe and Jolien Schaeverbeke and Sebastiaan Engelborghs and Roeck, \{Ellen De\} and Julius Popp and Gwendoline Peyratout and Magda Tsolaki and Yvonne Freund-Levi and Simon Lovestone and Johannes Streffer and Frederik Barkhof and Lars Bertram and Kaj Blennow and Henrik Zetterberg and Visser, \{Pieter Jelle\} and Vos, \{Stephanie J.B.\}",

note = "Publisher Copyright: {\textcopyright} 2024 The Author(s). Alzheimer's \& Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.",

year = "2024",

month = sep,

doi = "10.1002/alz.14103",

language = "English",

volume = "20",

pages = "6205--6220",

journal = "Alzheimer's and Dementia",

issn = "1552-5260",

publisher = "John Wiley and Sons Inc",

number = "9",

}

Delvenne, A, Gobom, J, Schindler, SE, Kate, MT, Reus, LM, Dobricic, V, Tijms, BM, Benzinger, TLS, Cruchaga, C, Teunissen, CE, Ramakers, I, Martinez-Lage, P, Tainta, M, Vandenberghe, R, Schaeverbeke, J, Engelborghs, S, Roeck, ED, Popp, J, Peyratout, G, Tsolaki, M, Freund-Levi, Y, Lovestone, S, Streffer, J, Barkhof, F, Bertram, L, Blennow, K, Zetterberg, H, Visser, PJ & Vos, SJB 2024, 'CSF proteomic profiles of neurodegeneration biomarkers in Alzheimer's disease', Alzheimer's and Dementia, Jg. 20, Nr. 9, S. 6205-6220. https://doi.org/10.1002/alz.14103

TY - JOUR

T1 - CSF proteomic profiles of neurodegeneration biomarkers in Alzheimer's disease

AU - Delvenne, Aurore

AU - Gobom, Johan

AU - Schindler, Suzanne E.

AU - Kate, Mara ten

AU - Reus, Lianne M.

AU - Dobricic, Valerija

AU - Tijms, Betty M.

AU - Benzinger, Tammie L.S.

AU - Cruchaga, Carlos

AU - Teunissen, Charlotte E.

AU - Ramakers, Inez

AU - Martinez-Lage, Pablo

AU - Tainta, Mikel

AU - Vandenberghe, Rik

AU - Schaeverbeke, Jolien

AU - Engelborghs, Sebastiaan

AU - Roeck, Ellen De

AU - Popp, Julius

AU - Peyratout, Gwendoline

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.

PY - 2024/9

Y1 - 2024/9

N2 - INTRODUCTION: We aimed to unravel the underlying pathophysiology of the neurodegeneration (N) markers neurogranin (Ng), neurofilament light (NfL), and hippocampal volume (HCV), in Alzheimer's disease (AD) using cerebrospinal fluid (CSF) proteomics. METHODS: Individuals without dementia were classified as A+ (CSF amyloid beta [Aβ]42), T+ (CSF phosphorylated tau181), and N+ or N− based on Ng, NfL, or HCV separately. CSF proteomics were generated and compared between groups using analysis of covariance. RESULTS: Only a few individuals were A+T+Ng−. A+T+Ng+ and A+T+NfL+ showed different proteomic profiles compared to A+T+Ng− and A+T+NfL−, respectively. Both Ng+ and NfL+ were associated with neuroplasticity, though in opposite directions. Compared to A+T+HCV−, A+T+HCV+ showed few proteomic changes, associated with oxidative stress. DISCUSSION: Different N markers are associated with distinct neurodegenerative processes and should not be equated. N markers may differentially complement disease staging beyond amyloid and tau. Our findings suggest that Ng may not be an optimal N marker, given its low incongruency with tau pathophysiology. Highlights: In Alzheimer's disease, neurogranin (Ng)+, neurofilament light (NfL)+, and hippocampal volume (HCV)+ showed differential protein expression in cerebrospinal fluid. Ng+ and NfL+ were associated with neuroplasticity, although in opposite directions. HCV+ showed few proteomic changes, related to oxidative stress. Neurodegeneration (N) markers may differentially refine disease staging beyond amyloid and tau. Ng might not be an optimal N marker, as it relates more closely to tau.

AB - INTRODUCTION: We aimed to unravel the underlying pathophysiology of the neurodegeneration (N) markers neurogranin (Ng), neurofilament light (NfL), and hippocampal volume (HCV), in Alzheimer's disease (AD) using cerebrospinal fluid (CSF) proteomics. METHODS: Individuals without dementia were classified as A+ (CSF amyloid beta [Aβ]42), T+ (CSF phosphorylated tau181), and N+ or N− based on Ng, NfL, or HCV separately. CSF proteomics were generated and compared between groups using analysis of covariance. RESULTS: Only a few individuals were A+T+Ng−. A+T+Ng+ and A+T+NfL+ showed different proteomic profiles compared to A+T+Ng− and A+T+NfL−, respectively. Both Ng+ and NfL+ were associated with neuroplasticity, though in opposite directions. Compared to A+T+HCV−, A+T+HCV+ showed few proteomic changes, associated with oxidative stress. DISCUSSION: Different N markers are associated with distinct neurodegenerative processes and should not be equated. N markers may differentially complement disease staging beyond amyloid and tau. Our findings suggest that Ng may not be an optimal N marker, given its low incongruency with tau pathophysiology. Highlights: In Alzheimer's disease, neurogranin (Ng)+, neurofilament light (NfL)+, and hippocampal volume (HCV)+ showed differential protein expression in cerebrospinal fluid. Ng+ and NfL+ were associated with neuroplasticity, although in opposite directions. HCV+ showed few proteomic changes, related to oxidative stress. Neurodegeneration (N) markers may differentially refine disease staging beyond amyloid and tau. Ng might not be an optimal N marker, as it relates more closely to tau.

UR - https://www.scopus.com/pages/publications/85197672291

U2 - 10.1002/alz.14103

DO - 10.1002/alz.14103

M3 - Journal articles

C2 - 38970402

AN - SCOPUS:85197672291

SN - 1552-5260

VL - 20

SP - 6205

EP - 6220

JO - Alzheimer's and Dementia

JF - Alzheimer's and Dementia

IS - 9

ER -

CSF proteomic profiles of neurodegeneration biomarkers in Alzheimer's disease

Abstract

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