Abstract
Introduction: Our objective was determining the optimal combinations of cerebrospinal fluid (CSF) biomarkers for predicting disease progression in Alzheimer's disease (AD) and other neurodegenerative diseases. Methods: We included 1,983 participants from three different cohorts with longitudinal cognitive and clinical data, and baseline CSF levels of Aβ42, Aβ40, phosphorylated tau at threonine-181 (p-tau), neurofilament light (NfL), neurogranin, α-synuclein, soluble triggering receptor expressed on myeloid cells 2 (sTREM2), glial fibrillary acidic protein (GFAP), YKL-40, S100b, and interleukin 6 (IL-6) (Elecsys NeuroToolKit). Results: Change of modified Preclinical Alzheimer's Cognitive Composite (mPACC) in cognitively unimpaired (CU) was best predicted by p-tau/Aβ42 alone (R 2 ≥ 0.31) or together with NfL (R 2 = 0.25), while p-tau/Aβ42 (R 2 ≥ 0.19) was sufficient to accurately predict change of the Mini-Mental State Examination (MMSE) in mild cognitive impairment (MCI) patients. P-tau/Aβ42 (AUC ≥ 0.87) and p-tau/Aβ42 together with NfL (AUC ≥ 0.75) were the best predictors of conversion to AD and all-cause dementia, respectively. Discussion: P-tau/Aβ42 is sufficient for predicting progression in AD, with very high accuracy. Adding NfL improves the prediction of all-cause dementia conversion and cognitive decline.
Original language | English |
---|---|
Pages (from-to) | 2943-2955 |
Number of pages | 13 |
Journal | Alzheimer's and Dementia |
Volume | 19 |
Issue number | 7 |
Early online date | 2023 |
DOIs | |
Publication status | Published - Jul 2023 |
Keywords
- BioFINDER
- WADRC
- WRAP
- amyloid-β
- cognitive decline
- conversion to dementia
- glial activation
- inflammation
- neurodegeneration
- tau ratio
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In: Alzheimer's and Dementia, Vol. 19, No. 7, 07.2023, p. 2943-2955.
Research output: Contribution to journal › Article › Academic › peer-review
TY - JOUR
T1 - Optimal combinations of CSF biomarkers for predicting cognitive decline and clinical conversion in cognitively unimpaired participants and mild cognitive impairment patients
T2 - A multi-cohort study
AU - Salvad?, Gemma
AU - Larsson, Victoria
AU - Cody, Karly A.
AU - Cullen, Nicholas C.
AU - Jonaitis, Erin M.
AU - Stomrud, Erik
AU - Kollmorgen, Gwendlyn
AU - Wild, Norbert
AU - Palmqvist, Sebastian
AU - Janelidze, Shorena
AU - Mattsson-Carlgren, Niklas
AU - Zetterberg, Henrik
AU - Blennow, Kaj
AU - Johnson, Sterling C.
AU - Ossenkoppele, Rik
AU - Hansson, Oskar
N1 - Funding Information: O.H. has acquired research support (for the institution) from ADx, AVID Radiopharmaceuticals, Biogen, Eli Lilly, Eisai, Fujirebio, GE Healthcare, Pfizer, and Roche. In the past 2 years, he has received consultancy/speaker fees from Amylyx, Alzpath, BioArctic, Biogen, Cerveau, Fujirebio, Genentech, Novartis, Roche, and Siemens. G.K. and N.W. are employees of Roche Diagnostics. SP has served on scientific advisory boards and/or given lectures in symposia sponsored by Biogen, Eli Lilly, Geras Solutions, and Roche. H.Z. has served at scientific advisory boards and/or as a consultant for Abbvie, Alector, Annexon, Artery Therapeutics, AZTherapies, CogRx, Denali, Eisai, Nervgen, Novo Nordisk, Pinteon Therapeutics, Red Abbey Labs, Passage Bio, Roche, Samumed, Siemens Healthineers, Triplet Therapeutics, and Wave, has given lectures in symposia sponsored by Cellectricon, Fujirebio, Alzecure, Biogen, 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). K.B. has served as a consultant, at advisory boards, or at data monitoring committees for Abcam, Axon, Biogen, JOMDD/Shimadzu. Julius Clinical, Lilly, MagQu, Novartis, Prothena, Roche Diagnostics, and Siemens Healthineers, and is a co‐founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program. S.C.J. previously served on an advisory board for Roche Diagnostics, and receives research funding from NIH and from Cerveau Technologies. COBAS, COBAS E and ELECSYS are trademarks of Roche. The Elecsys β‐Amyloid (1‐42) CSF assay, the Elecsys Phospo‐Tau (181P) CSF assay, and the Elecsys Total‐Tau CSF assay are not approved for clinical use in the United States. The NeuroToolKit robust prototype assays are for investigational purposes and are not approved for clinical use. G.S.B., V.L., K.A.C., N.C.C., E.M.J., E.S., S.J., N.M.C., and R.O. have nothing to disclose. Author disclosures are available in the supporting information . Funding Information: Work at the authors’ research center was supported by the Swedish Research Council (2016-00906), the Knut and Alice Wallenberg foundation (2017-0383), the Marianne and Marcus Wallenberg foundation (2015.0125), the Strategic Research Area MultiPark (Multidisciplinary Research in Parkinson's disease) at Lund University, the Swedish Alzheimer Foundation (AF-939932), the Swedish Brain Foundation (FO2021-0293), The Parkinson foundation of Sweden (1280/20), the Konung Gustaf V:s och Drottning Victorias Frimurarestiftelse, the Skåne University Hospital Foundation (2020-O000028), Regionalt Forskningsstöd (2020-0314) and the Swedish federal government under the ALF agreement (2018-Projekt0279). SP is supported by Swedish Research Council (2018-02052), the Swedish Brain Foundation (FO2020-0271) and the Swedish Alzheimer Foundation (AF-940046). HZ is a Wallenberg Scholar supported by grants from the Swedish Research Council (#2018-02532), the European Research Council (#681712 and #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 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), the European Union Joint Programme – Neurodegenerative Disease Research (JPND2021-00694), and the UK Dementia Research Institute at UCL (UKDRI-1003). KB 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), and European Union Joint Program for Neurodegenerative Disorders (JPND2019-466-236). The University of Wisconsin authors (KAC, EMJ, SCJ) and data were supported by NIH (R01AG027161, RO1AG021155, P30AG062715), and the University of Wisconsin Institute for Clinical and Translational Research NCATS (TL1TR002375). The funding sources had no role in the design and conduct of the study; in the collection, analysis, interpretation of the data; or in the preparation, review, or approval of the manuscript. Funding Information: Work at the authors’ research center was supported by the Swedish Research Council (2016‐00906), the Knut and Alice Wallenberg foundation (2017‐0383), the Marianne and Marcus Wallenberg foundation (2015.0125), the Strategic Research Area MultiPark (Multidisciplinary Research in Parkinson's disease) at Lund University, the Swedish Alzheimer Foundation (AF‐939932), the Swedish Brain Foundation (FO2021‐0293), The Parkinson foundation of Sweden (1280/20), the Konung Gustaf V:s och Drottning Victorias Frimurarestiftelse, the Skåne University Hospital Foundation (2020‐O000028), Regionalt Forskningsstöd (2020‐0314) and the Swedish federal government under the ALF agreement (2018‐Projekt0279). SP is supported by Swedish Research Council (2018‐02052), the Swedish Brain Foundation (FO2020‐0271) and the Swedish Alzheimer Foundation (AF‐940046). HZ is a Wallenberg Scholar supported by grants from the Swedish Research Council (#2018‐02532), the European Research Council (#681712 and #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 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), the European Union Joint Programme – Neurodegenerative Disease Research (JPND2021‐00694), and the UK Dementia Research Institute at UCL (UKDRI‐1003). KB 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), and European Union Joint Program for Neurodegenerative Disorders (JPND2019‐466‐236). The University of Wisconsin authors (KAC, EMJ, SCJ) and data were supported by NIH (R01AG027161, RO1AG021155, P30AG062715), and the University of Wisconsin Institute for Clinical and Translational Research NCATS (TL1TR002375). Publisher Copyright: © 2023 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.
PY - 2023/7
Y1 - 2023/7
N2 - Introduction: Our objective was determining the optimal combinations of cerebrospinal fluid (CSF) biomarkers for predicting disease progression in Alzheimer's disease (AD) and other neurodegenerative diseases. Methods: We included 1,983 participants from three different cohorts with longitudinal cognitive and clinical data, and baseline CSF levels of Aβ42, Aβ40, phosphorylated tau at threonine-181 (p-tau), neurofilament light (NfL), neurogranin, α-synuclein, soluble triggering receptor expressed on myeloid cells 2 (sTREM2), glial fibrillary acidic protein (GFAP), YKL-40, S100b, and interleukin 6 (IL-6) (Elecsys NeuroToolKit). Results: Change of modified Preclinical Alzheimer's Cognitive Composite (mPACC) in cognitively unimpaired (CU) was best predicted by p-tau/Aβ42 alone (R 2 ≥ 0.31) or together with NfL (R 2 = 0.25), while p-tau/Aβ42 (R 2 ≥ 0.19) was sufficient to accurately predict change of the Mini-Mental State Examination (MMSE) in mild cognitive impairment (MCI) patients. P-tau/Aβ42 (AUC ≥ 0.87) and p-tau/Aβ42 together with NfL (AUC ≥ 0.75) were the best predictors of conversion to AD and all-cause dementia, respectively. Discussion: P-tau/Aβ42 is sufficient for predicting progression in AD, with very high accuracy. Adding NfL improves the prediction of all-cause dementia conversion and cognitive decline.
AB - Introduction: Our objective was determining the optimal combinations of cerebrospinal fluid (CSF) biomarkers for predicting disease progression in Alzheimer's disease (AD) and other neurodegenerative diseases. Methods: We included 1,983 participants from three different cohorts with longitudinal cognitive and clinical data, and baseline CSF levels of Aβ42, Aβ40, phosphorylated tau at threonine-181 (p-tau), neurofilament light (NfL), neurogranin, α-synuclein, soluble triggering receptor expressed on myeloid cells 2 (sTREM2), glial fibrillary acidic protein (GFAP), YKL-40, S100b, and interleukin 6 (IL-6) (Elecsys NeuroToolKit). Results: Change of modified Preclinical Alzheimer's Cognitive Composite (mPACC) in cognitively unimpaired (CU) was best predicted by p-tau/Aβ42 alone (R 2 ≥ 0.31) or together with NfL (R 2 = 0.25), while p-tau/Aβ42 (R 2 ≥ 0.19) was sufficient to accurately predict change of the Mini-Mental State Examination (MMSE) in mild cognitive impairment (MCI) patients. P-tau/Aβ42 (AUC ≥ 0.87) and p-tau/Aβ42 together with NfL (AUC ≥ 0.75) were the best predictors of conversion to AD and all-cause dementia, respectively. Discussion: P-tau/Aβ42 is sufficient for predicting progression in AD, with very high accuracy. Adding NfL improves the prediction of all-cause dementia conversion and cognitive decline.
KW - BioFINDER
KW - WADRC
KW - WRAP
KW - amyloid-β
KW - cognitive decline
KW - conversion to dementia
KW - glial activation
KW - inflammation
KW - neurodegeneration
KW - tau ratio
UR - http://www.scopus.com/inward/record.url?scp=85146317403&partnerID=8YFLogxK
U2 - https://doi.org/10.1002/alz.12907
DO - https://doi.org/10.1002/alz.12907
M3 - Article
C2 - 36648169
SN - 1552-5260
VL - 19
SP - 2943
EP - 2955
JO - Alzheimer's and Dementia
JF - Alzheimer's and Dementia
IS - 7
ER -