1. CSF proteome profiling across the Alzheimer’s disease spectrum reflects the multifactorial nature of the disease and identifies specific biomarker panels
- Author
-
Marta del Campo, Carel F. W. Peeters, Erik C. B. Johnson, Lisa Vermunt, Yanaika S. Hok-A-Hin, Mirrelijn van Nee, Alice Chen-Plotkin, David J. Irwin, William T. Hu, James J. Lah, Nicholas T. Seyfried, Eric B. Dammer, Gonzalo Herradon, Lieke H. Meeter, John van Swieten, Daniel Alcolea, Alberto Lleó, Allan I. Levey, Afina W. Lemstra, Yolande A. L. Pijnenburg, Pieter J. Visser, Betty M. Tijms, Wiesje M. van der Flier, Charlotte E. Teunissen, RS: MHeNs - R1 - Cognitive Neuropsychiatry and Clinical Neuroscience, Psychology 6, Laboratory Medicine, Amsterdam Neuroscience - Neurodegeneration, Amsterdam Neuroscience - Cellular & Molecular Mechanisms, Neurology, Amsterdam Neuroscience - Brain Imaging, Amsterdam Neuroscience - Neuroinfection & -inflammation, APH - Methodology, and APH - Personalized Medicine
- Subjects
NATIONAL INSTITUTE ,Aging ,DEMENTIA ,Neuroscience (miscellaneous) ,DIAGNOSIS ,Wiskundige en Statistische Methoden - Biometris ,LEWY BODIES ,RECOMMENDATIONS ,RESEARCH CRITERIA ,DISCOVERY ,MANAGEMENT ,Life Science ,TAU ,Geriatrics and Gerontology ,Mathematical and Statistical Methods - Biometris ,A-BETA - 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(A beta+): 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(A beta+) or AD compared to controls or non-AD dementias. Proteins dysregulated in MCI(A beta+) 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.This study identifies CSF proteins specifically dysregulated along the AD continuum that reflect the multifactorial nature of disease progression. Some of these CSF proteins were used to build biomarker panels with high diagnostic accuracies.
- Published
- 2022
- Full Text
- View/download PDF