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. 2024 Sep;20(9):6205-6220.
doi: 10.1002/alz.14103. Epub 2024 Jul 6.

CSF proteomic profiles of neurodegeneration biomarkers in Alzheimer's disease

Aurore Delvenne  1 , Johan Gobom  2   3 , Suzanne E Schindler  4   5 , Mara Ten Kate  6   7 , Lianne M Reus  6 , Valerija Dobricic  8 , Betty M Tijms  6 , Tammie L S Benzinger  9 , Carlos Cruchaga  10 , Charlotte E Teunissen  11 , Inez Ramakers  1 , Pablo Martinez-Lage  12 , Mikel Tainta  12 , Rik Vandenberghe  13   14 , Jolien Schaeverbeke  13   14 , Sebastiaan Engelborghs  15   16 , Ellen De Roeck  15   17 , Julius Popp  18   19 , Gwendoline Peyratout  18 , Magda Tsolaki  20 , Yvonne Freund-Levi  21   22   23 , Simon Lovestone  24 , Johannes Streffer  15   25 , Frederik Barkhof  6   26 , Lars Bertram  8 , Kaj Blennow  2   3   27   28 , Henrik Zetterberg  2   3   29   30   31   32 , Pieter Jelle Visser  1   6   33 , Stephanie J B Vos  1
Affiliations

CSF proteomic profiles of neurodegeneration biomarkers in Alzheimer's disease

Aurore Delvenne et al. Alzheimers Dement. 2024 Sep.

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.

Keywords: Alzheimer's disease; biomarkers; cerebrospinal fluid; hippocampal volume; neurodegeneration markers; neurofilament light; neurogranin; pathophysiology; proteomics.

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Conflict of interest statement

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.

Figures

FIGURE 1
FIGURE 1
A, Stacked bar graph showing the numbers of N+ and N− participants within the A+T+ group for the three neurodegeneration markers (i.e., CSF neurogranin, CSF neurofilament light, and hippocampal volume). The number of individuals with normal cognition (NC; orange) and mild cognitive impairment (MCI; blue) is also shown. B, Stacked bar graph showing the numbers of N+ and N− participants within the A+T− group for the three neurodegeneration markers (i.e., CSF neurogranin, CSF neurofilament light, and hippocampal volume). The number of individuals with NC (yellow) and MCI (green) is also shown. A−, absence of amyloid pathology determined by CSF Aβ42 level above cut point; A+, presence of amyloid pathology determined by CSF Aβ42 level below cut point; T−, normal CSF p‐tau level below cut point; T+, abnormal CSF p‐tau level above cut point; N−, absence of neurodegeneration or neuronal injury determined by CSF neurogranin, CSF neurofilament light, or hippocampal volume; N+, presence of neurodegeneration or neuronal injury determined by CSF neurogranin, CSF neurofilament light, or hippocampal volume. Aβ, amyloid beta; CSF, cerebrospinal fluid; HCV, hippocampal volume; MCI, mild cognitive impairment; NC, normal cognition; NfL, neurofilament light; Ng, neurogranin; p‐tau, phosphorylated tau.
FIGURE 2
FIGURE 2
Cerebrospinal fluid (CSF) proteomics in A+T+ individuals without dementia by neurogranin status. A, Volcano plot displaying the log2 fold‐change against the −log10 statistical p‐value for the comparison of A+T+N+ versus A+T+N− (N = neurogranin). Significantly different proteins are red. The top 15 proteins are named. B, C, Selected biological processes Gene Ontology (GO) terms for decreased (B) and increased (C) proteins in the comparison of A+T+N+ versus A+T+N−.
FIGURE 3
FIGURE 3
CSF proteomics in A+T+ individuals without dementia by neurofilament light status. A, Volcano plot displaying the log2 fold‐change against the −log10 statistical p‐value for the comparison of A+T+N+ versus A+T+N− (N = neurofilament light). Significantly different proteins are red. The top 15 proteins are named. B, C, Selected biological processes Gene Ontology (GO) terms for decreased (B) and increased (C) proteins in the comparison A+T−N+ versus A+T−N−. CSF, cerebrospinal fluid; TGFβ, transforming growth factor beta.
FIGURE 4
FIGURE 4
Cerebrospinal fluid (CSF) proteomics in A+T+ individuals without dementia by hippocampal volume status. A, Volcano plot displaying the log2 fold‐change against the −log10 statistical p‐value for the comparison A+T+N+ versus A+T+N− (N = hippocampal volume). Significantly different proteins are red. The top 15 proteins are named. B, C, Selected biological processes Gene Ontology (GO) terms for decreased (B) and increased (C) proteins in the comparison of A+T−N+ versus A+T−N−.
FIGURE 5
FIGURE 5
Comparison of the proteomic profiles of the groups classified using distinct N markers. A, Heatmap representing the log2 fold‐change values of the proteins with significant level changes in each comparison using different neurodegeneration markers. B, Gene Ontology biological pathway enrichment analysis with a dot plot representing the top 10 biological pathways enriched for the different comparisons.
FIGURE 6
FIGURE 6
Association between the different neurodegeneration biomarkers. A, Correlation matrix for AD biomarkers using the Spearman rank correlation test in A+T+ individuals with no dementia (upper part of the graph) and in A+T− individuals with no dementia (lower part of the graph). The figure presents the p‐value and correlation coefficient (ρ). The color scale depicts the strength of the Spearman correlation coefficient in the significant correlations. B, Venn diagram depicting the distribution of the three neurodegeneration biomarkers in a subset of 128 A+T+ individuals and with availability of the three N markers. C, Venn diagram depicting the distribution of the three neurodegeneration biomarkers in a subset of 58 A+T− individuals and with availability of the three N markers. Aβ, amyloid beta; AD, Alzheimer's disease; HCV, hippocampal volume; NC, normal cognition; NfL, neurofilament light; Ng, neurogranin; p‐tau, phosphorylated tau; t‐tau, total tau.
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References

    1. Jack CR Jr, Bennett DA, Blennow K, et al. NIA‐AA Research Framework: toward a biological definition of Alzheimer's disease. Alzheimers Dement. 2018;14(4):535‐562. - PMC - PubMed
    1. Mielke MM, Syrjanen JA, Blennow K, et al. Comparison of variables associated with cerebrospinal fluid neurofilament, total‐tau, and neurogranin. Alzheimers Dement. 2019;15(11):1437‐1447. - PMC - PubMed
    1. Wang Z, Yang J, Zhu W, Tang Y, Jia J. The synaptic marker neurogranin as a disease state biomarker in Alzheimer's disease: a systematic review and meta‐analysis. Int J Neurosci. 2021:1‐9. - PubMed
    1. Nilsson J, Cousins KAQ, Gobom J, et al. Cerebrospinal fluid biomarker panel of synaptic dysfunction in Alzheimer's disease and other neurodegenerative disorders. Alzheimer Dement. 2023;19(5):1775‐1784. - PMC - PubMed
    1. Portelius E, Olsson B, Höglund K, et al. Cerebrospinal fluid neurogranin concentration in neurodegeneration: relation to clinical phenotypes and neuropathology. Acta Neuropathol. 2018;136(3):363‐376. - PMC - PubMed