Abstract
Development of disease-modifying therapies against Alzheimer’s disease (AD) requires biomarkers reflecting the diverse pathological pathways specific for AD. We measured 665 proteins in 797 cerebrospinal fluid (CSF) samples from patients with mild cognitive impairment with abnormal amyloid (MCI(Aβ+): n = 50), AD-dementia (n = 230), non-AD dementias (n = 322) and cognitively unimpaired controls (n = 195) using proximity ligation-based immunoassays. Here we identified >100 CSF proteins dysregulated in MCI(Aβ+) or AD compared to controls or non-AD dementias. Proteins dysregulated in MCI(Aβ+) were primarily related to protein catabolism, energy metabolism and oxidative stress, whereas those specifically dysregulated in AD dementia were related to cell remodeling, vascular function and immune system. Classification modeling unveiled biomarker panels discriminating clinical groups with high accuracies (area under the curve (AUC): 0.85–0.99), which were translated into custom multiplex assays and validated in external and independent cohorts (AUC: 0.8–0.99). Overall, this study provides novel pathophysiological leads delineating the multifactorial nature of AD and potential biomarker tools for diagnostic settings or clinical trials.
| Original language | English |
|---|---|
| Pages (from-to) | 1040-1053 |
| Number of pages | 22 |
| Journal | Nature aging |
| Volume | 2 |
| Issue number | 11 |
| DOIs | |
| Publication status | Published - 1 Nov 2022 |
Keywords
- NATIONAL INSTITUTE
- RESEARCH CRITERIA
- LEWY BODIES
- A-BETA
- DIAGNOSIS
- DEMENTIA
- TAU
- RECOMMENDATIONS
- MANAGEMENT
- DISCOVERY
Access to Document
Fingerprint
Dive into the research topics of 'CSF proteome profiling across the Alzheimer's disease spectrum reflects the multifactorial nature of the disease and identifies specific biomarker panels'. Together they form a unique fingerprint.Cite this
- APA
- Author
- BIBTEX
- Harvard
- Standard
- RIS
- Vancouver
}
In: Nature aging, Vol. 2, No. 11, 01.11.2022, p. 1040-1053.
Research output: Contribution to journal › Article › Academic › peer-review
TY - JOUR
T1 - CSF proteome profiling across the Alzheimer's disease spectrum reflects the multifactorial nature of the disease and identifies specific biomarker panels
AU - del Campo, M.
AU - Peeters, C.F.W.
AU - Johnson, E.C.B.
AU - Vermunt, L.
AU - Hok-A-Hin, Y.S.
AU - van Nee, M.
AU - Chen-Plotkin, A.
AU - Irwin, D.J.
AU - Hu, W.T.
AU - Lah, J.J.
AU - Seyfried, N.T.
AU - Dammer, E.B.
AU - Herradon, G.
AU - Meeter, L.H.
AU - van Swieten, J.
AU - Alcolea, D.
AU - Lleo, A.
AU - Levey, A.I.
AU - Lemstra, A.W.
AU - Pijnenburg, Y.A.L.
AU - Visser, P.J.
AU - Tijms, B.M.
AU - van der Flier, W.M.
AU - Teunissen, C.E.
N1 - Funding Information: This research is part of the neurodegeneration research program of Amsterdam Neuroscience. This study was supported by Alzheimer Nederland (WE.03-2018-05, M.d.C. and C.E.T.) and Selfridges Group Foundation (NR170065, M.d.C. and C.E.T.). M.d.C. and G.H. are supported by the attraction talent fellowship of Comunidad de Madrid (2018-T2/BMD-11885) and San Pablo CEU University. D.A. acknowledges support from Institute of Health Carlos III (PI18/00435, INT19/00016) and the Department of Health Generalitat de Catalunya PERIS program (SLT006/17/125). Collection of patients samples and data from Penn University (A.C.-P. and D.J.I.) was supported by different funding sources, including National Institute on Aging NINDS R01-NS109260-01A1, P01-AG066597, P30-AG072979 (formerly P30-AG10124) and U19-AG062418-03 (formerly NINDSP50-NS053488-09). Alzheimer Center Amsterdam is supported by Stichting Alzheimer Nederland and Stichting VUmc fonds. The chair (W.M.v.d.F.) is supported by the Pasman stichting. The clinical database structure was developed with funding from Stichting Dioraphte. Research programs of W.M.v.d.F. have been funded by ZonMW, NWO, EU-FP7, EU-JPND, Alzheimer Nederland, Hersenstichting CardioVascular Onderzoek Nederland, Health~Holland, Topsector Life Sciences & Health, stichting Dioraphte, Gieskes-Strijbisfonds, stichting Equilibrio, Edwin Bouw fonds, Pasman stichting, stichting Alzheimer & Neuropsychiatrie Foundation, Philips, Biogen MA, Novartis-NL, Life-MI, AVID, Roche BV, Fujifilm and Combinostics. W.M.v.d.F. holds the Pasman chair. W.M.v.d.F. is a recipient of ABOARD, which is a public-private partnership receiving funding from ZonMW (73305095007) and Health~Holland, Topsector Life Sciences & Health (PPP-allowance; #LSHM20106). All funding is paid to her institution. Research of C.E.T. is supported by the European Commission (Marie Curie International Training Network, grant agreement No. 860197 (MIRIADE)), Innovative Medicines Initiatives 3TR (Horizon 2020, grant 831434), EPND (IMI 2 Joint Undertaking (JU) under grant agreement 101034344) and JPND (bPRIDE), National MS Society (Progressive MS alliance) and Health Holland, the Dutch Research Council (ZonMW), Alzheimer Drug Discovery Foundation, The Selfridges Group Foundation, Alzheimer Netherlands and Alzheimer Association. C.E.T. is a recipient of ABOARD, which is a public-private partnership receiving funding from ZonMW (3305095007) and Health~Holland, Topsector Life Sciences & Health (PPP allowance; LSHM20106). ABOARD also receives funding from Edwin Bouw Fonds and Gieskes-Strijbisfonds. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. Funding Information: This research is part of the neurodegeneration research program of Amsterdam Neuroscience. This study was supported by Alzheimer Nederland (WE.03-2018-05, M.d.C. and C.E.T.) and Selfridges Group Foundation (NR170065, M.d.C. and C.E.T.). M.d.C. and G.H. are supported by the attraction talent fellowship of Comunidad de Madrid (2018-T2/BMD-11885) and San Pablo CEU University. D.A. acknowledges support from Institute of Health Carlos III (PI18/00435, INT19/00016) and the Department of Health Generalitat de Catalunya PERIS program (SLT006/17/125). Collection of patients samples and data from Penn University (A.C.-P. and D.J.I.) was supported by different funding sources, including National Institute on Aging NINDS R01-NS109260-01A1, P01-AG066597, P30-AG072979 (formerly P30-AG10124) and U19-AG062418-03 (formerly NINDSP50-NS053488-09). Alzheimer Center Amsterdam is supported by Stichting Alzheimer Nederland and Stichting VUmc fonds. The chair (W.M.v.d.F.) is supported by the Pasman stichting. The clinical database structure was developed with funding from Stichting Dioraphte. Research programs of W.M.v.d.F. have been funded by ZonMW, NWO, EU-FP7, EU-JPND, Alzheimer Nederland, Hersenstichting CardioVascular Onderzoek Nederland, Health~Holland, Topsector Life Sciences & Health, stichting Dioraphte, Gieskes-Strijbisfonds, stichting Equilibrio, Edwin Bouw fonds, Pasman stichting, stichting Alzheimer & Neuropsychiatrie Foundation, Philips, Biogen MA, Novartis-NL, Life-MI, AVID, Roche BV, Fujifilm and Combinostics. W.M.v.d.F. holds the Pasman chair. W.M.v.d.F. is a recipient of ABOARD, which is a public-private partnership receiving funding from ZonMW (73305095007) and Health~Holland, Topsector Life Sciences & Health (PPP-allowance; #LSHM20106). All funding is paid to her institution. Research of C.E.T. is supported by the European Commission (Marie Curie International Training Network, grant agreement No. 860197 (MIRIADE)), Innovative Medicines Initiatives 3TR (Horizon 2020, grant 831434), EPND (IMI 2 Joint Undertaking (JU) under grant agreement 101034344) and JPND (bPRIDE), National MS Society (Progressive MS alliance) and Health Holland, the Dutch Research Council (ZonMW), Alzheimer Drug Discovery Foundation, The Selfridges Group Foundation, Alzheimer Netherlands and Alzheimer Association. C.E.T. is a recipient of ABOARD, which is a public-private partnership receiving funding from ZonMW (3305095007) and Health~Holland, Topsector Life Sciences & Health (PPP allowance; LSHM20106). ABOARD also receives funding from Edwin Bouw Fonds and Gieskes-Strijbisfonds. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. Funding Information: M.d.C. has been an invited speaker at Eisai. L.V. received a grant for the CORAL consortium by Olink. B.M.T. and P.J.V. are inventors on a patent (WO2020197399A1; owned by Stichting VUmc). D.J.I. is a Scientific Advisory Board Member for Denali Therapeutics. D.A. participated in advisory boards from Fujirebio-Europe and Roche Diagnostics and received speaker honoraria from Fujirebio-Europe, Roche Diagnostics, Nutricia, Krka Farmacéutica S.L., Zambon S.A.U. and Esteve Pharmaceuticals S.A. D.A. declares a filed patent application (WO2019175379 A1 Markers of synaptopathy in neurodegenerative disease). W.M.v.d.F. has performed contract research for Biogen MA and Boehringer Ingelheim. W.M.v.d.F. has been an invited speaker at Boehringer Ingelheim, Biogen MA, Danone, Eisai, WebMD Neurology (Medscape) and Springer Healthcare. W.M.v.d.F. is consultant to Oxford Health Policy Forum CIC, Roche and Biogen MA. W.M.v.d.F. participated in advisory boards of Biogen MA and Roche. All funding is paid to her institution. W.M.v.d.F. is member of the steering committee of PAVE and Think Brain Health. W.M.v.d.F. was associate editor of Alzheimer’s Research & Therapy in 2020/2021. W.M.v.d.F. is associate editor at Brain. C.E.T. has a collaboration contract with ADx Neurosciences, Quanterix and Eli Lilly and performed contract research or received grants from AC-Immune, Axon Neurosciences, Bioconnect, Bioorchestra, Brainstorm Therapeutics, Celgene, EIP Pharma, Eisai, Grifols, Novo Nordisk, PeopleBio, Roche, Toyama and Vivoryon. She serves on editorial boards of Medidact Neurologie/Springer, Alzheimer’s Research & Therapy and Neurology: Neuroimmunology & Neuroinflammation and is editor of a Neuromethods book (Springer). She had speaker contracts for Roche, Grifols and Novo Nordisk. The other authors declare no competing interests. Publisher Copyright: © 2022, The Author(s), under exclusive licence to Springer Nature America, Inc.
PY - 2022/11/1
Y1 - 2022/11/1
N2 - Development of disease-modifying therapies against Alzheimer’s disease (AD) requires biomarkers reflecting the diverse pathological pathways specific for AD. We measured 665 proteins in 797 cerebrospinal fluid (CSF) samples from patients with mild cognitive impairment with abnormal amyloid (MCI(Aβ+): n = 50), AD-dementia (n = 230), non-AD dementias (n = 322) and cognitively unimpaired controls (n = 195) using proximity ligation-based immunoassays. Here we identified >100 CSF proteins dysregulated in MCI(Aβ+) or AD compared to controls or non-AD dementias. Proteins dysregulated in MCI(Aβ+) were primarily related to protein catabolism, energy metabolism and oxidative stress, whereas those specifically dysregulated in AD dementia were related to cell remodeling, vascular function and immune system. Classification modeling unveiled biomarker panels discriminating clinical groups with high accuracies (area under the curve (AUC): 0.85–0.99), which were translated into custom multiplex assays and validated in external and independent cohorts (AUC: 0.8–0.99). Overall, this study provides novel pathophysiological leads delineating the multifactorial nature of AD and potential biomarker tools for diagnostic settings or clinical trials.
AB - Development of disease-modifying therapies against Alzheimer’s disease (AD) requires biomarkers reflecting the diverse pathological pathways specific for AD. We measured 665 proteins in 797 cerebrospinal fluid (CSF) samples from patients with mild cognitive impairment with abnormal amyloid (MCI(Aβ+): n = 50), AD-dementia (n = 230), non-AD dementias (n = 322) and cognitively unimpaired controls (n = 195) using proximity ligation-based immunoassays. Here we identified >100 CSF proteins dysregulated in MCI(Aβ+) or AD compared to controls or non-AD dementias. Proteins dysregulated in MCI(Aβ+) were primarily related to protein catabolism, energy metabolism and oxidative stress, whereas those specifically dysregulated in AD dementia were related to cell remodeling, vascular function and immune system. Classification modeling unveiled biomarker panels discriminating clinical groups with high accuracies (area under the curve (AUC): 0.85–0.99), which were translated into custom multiplex assays and validated in external and independent cohorts (AUC: 0.8–0.99). Overall, this study provides novel pathophysiological leads delineating the multifactorial nature of AD and potential biomarker tools for diagnostic settings or clinical trials.
KW - NATIONAL INSTITUTE
KW - RESEARCH CRITERIA
KW - LEWY BODIES
KW - A-BETA
KW - DIAGNOSIS
KW - DEMENTIA
KW - TAU
KW - RECOMMENDATIONS
KW - MANAGEMENT
KW - DISCOVERY
U2 - 10.1038/s43587-022-00300-1
DO - 10.1038/s43587-022-00300-1
M3 - Article
C2 - 37118088
SN - 2662-8465
VL - 2
SP - 1040
EP - 1053
JO - Nature aging
JF - Nature aging
IS - 11
ER -