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Plasma biomarkers for prediction of Alzheimer’s disease neuropathologic change

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Abstract

While plasma biomarkers for Alzheimer’s disease (AD) are increasingly being evaluated for clinical diagnosis and prognosis, few population-based autopsy studies have evaluated their utility in the context of predicting neuropathological changes. Our goal was to investigate the utility of clinically available plasma markers in predicting Braak staging, neuritic plaque score, Thal phase, and overall AD neuropathological change (ADNC).We utilized a population-based prospective study of 350 participants with autopsy and antemortem plasma biomarker testing using clinically available antibody assay (Quanterix) consisting of Aβ42/40 ratio, p-tau181, GFAP, and NfL. We utilized a variable selection procedure in cross-validated (CV) logistic regression models to identify the best set of plasma predictors along with demographic variables, and a subset of neuropsychological tests comprising the Mayo Clinic Preclinical Alzheimer Cognitive Composite (Mayo-PACC). ADNC was best predicted with plasma GFAP, NfL, p-tau181 biomarkers along with APOE ε4 carrier status and Mayo-PACC cognitive score (CV AUC = 0.798). Braak staging was best predicted using plasma GFAP, p-tau181, and cognitive scores (CV AUC = 0.774). Neuritic plaque score was best predicted using plasma Aβ42/40 ratio, p-tau181, GFAP, and NfL biomarkers (CV AUC = 0.770). Thal phase was best predicted using GFAP, NfL, p-tau181, APOE ε4 carrier status and Mayo-PACC cognitive score (CV AUC = 0.754). We found that GFAP and p-tau provided non-overlapping information on both neuritic plaque and Braak stage scores whereas Aβ42/40 and NfL were mainly useful for prediction of neuritic plaque scores. Separating participants by cognitive status improved predictive performance, particularly when plasma biomarkers were included. Plasma biomarkers can differentially inform about overall ADNC pathology, Braak staging, and neuritic plaque score when combined with demographics and cognitive variables and have significant utility for earlier detection of AD.

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Acknowledgements

We thank all the study participants and staff in the Mayo Clinic Study of Aging, Mayo Alzheimer’s Disease Research Center, and Aging Dementia Imaging Research laboratory at the Mayo Clinic for making this study possible. This work was supported by grants from National Institutes of Health (NIH) (U01 AG006786, R01 AG034676, RF1 AG069052). Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH.

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Authors and Affiliations

  1. Department of Neurology, Mayo Clinic, 200 First Street SW, Rochester, MN, 55902, USA

    Camilo Bermudez, Jonathan Graff-Radford, Ronald C. Petersen & David S. Knopman

  2. Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN, USA

    Jeremy A. Syrjanen & Walter K. Kremers

  3. Department of Psychiatry and Psychology, Mayo Clinic, Rochester, MN, USA

    Nikki H. Stricker

  4. Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA

    Alicia Algeciras-Schimnich, Aivi T. Nguyen & R. Ross Reichard

  5. Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA

    Naomi Kouri, Dennis W. Dickson & Melissa E. Murray

  6. Department of Radiology, Mayo Clinic, Rochester, MN, USA

    Clifford R. Jack Jr & Prashanthi Vemuri

  7. Department of Epidemiology and Prevention, Wake Forest University School of Medicine, Winston-Salem, NC, USA

    Michelle M. Mielke

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  1. Camilo Bermudez
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  2. Jonathan Graff-Radford
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Contributions

CB, JGR, JAS, WK, and PV contributed to the conception and design of the study; CB, JGR, JAS, NS, AAS, NK, WK, RCP, CRJ, DSK, DWD, ATN, RRR, MRM, MMM, PV contributed to the acquisition and analysis of data; CB, JGR, JAS, WK, PV contributed to drafting the text or preparing the figures.

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Correspondence to Camilo Bermudez.

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Bermudez, C., Graff-Radford, J., Syrjanen, J.A. et al. Plasma biomarkers for prediction of Alzheimer’s disease neuropathologic change. Acta Neuropathol 146, 13–29 (2023). https://doi.org/10.1007/s00401-023-02594-w

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