Meta-analysis of published cerebrospinal fluid proteomics data identifies and validates metabolic enzyme panel as Alzheimer's disease biomarkers

Patrick W van Zalm; Saima Ahmed; Benoit Fatou; Rudy Schreiber; Omar Barnaby; Adam Boxer; Henrik Zetterberg; Judith A Steen; Hanno Steen

doi:10.1016/j.xcrm.2023.101005

Meta-analysis of published cerebrospinal fluid proteomics data identifies and validates metabolic enzyme panel as Alzheimer's disease biomarkers

Cell Rep Med. 2023 Apr 18;4(4):101005. doi: 10.1016/j.xcrm.2023.101005.

Authors

Patrick W van Zalm¹, Saima Ahmed², Benoit Fatou², Rudy Schreiber³, Omar Barnaby², Adam Boxer⁴, Henrik Zetterberg⁵, Judith A Steen⁶, Hanno Steen⁷

Affiliations

¹ Department of Pathology, Boston Children's Hospital, and Department of Pathology, Harvard Medical School, Boston, MA, USA; Department of Neuropsychology and Psychopharmacology, EURON, Faculty of Psychology and Neuroscience, Maastricht University, Maastricht, the Netherlands.
² Department of Pathology, Boston Children's Hospital, and Department of Pathology, Harvard Medical School, Boston, MA, USA.
³ Department of Neuropsychology and Psychopharmacology, EURON, Faculty of Psychology and Neuroscience, Maastricht University, Maastricht, the Netherlands.
⁴ Memory and Aging Center, Department of Neurology, Weill Institute for Neuroscience, University of California, San Francisco, CA, USA.
⁵ Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, the Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden; Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden; UK Dementia Research Institute at UCL, London, UK; Department of Neurodegenerative Disease, UCL Institute of Neurology, London, UK.
⁶ F.M. Kirby Neurobiology Center, Boston Children's Hospital, and Department of Neurology, Harvard Medical School, Boston, MA, USA; Neuroiology Program, Boston Children's Hospital, Boston, MA, USA.
⁷ Department of Pathology, Boston Children's Hospital, and Department of Pathology, Harvard Medical School, Boston, MA, USA; Neuroiology Program, Boston Children's Hospital, Boston, MA, USA. Electronic address: hanno.steen@childrens.harvard.edu.

Abstract

To develop therapies for Alzheimer's disease, we need accurate in vivo diagnostics. Multiple proteomic studies mapping biomarker candidates in cerebrospinal fluid (CSF) resulted in little overlap. To overcome this shortcoming, we apply the rarely used concept of proteomics meta-analysis to identify an effective biomarker panel. We combine ten independent datasets for biomarker identification: seven datasets from 150 patients/controls for discovery, one dataset with 20 patients/controls for down-selection, and two datasets with 494 patients/controls for validation. The discovery results in 21 biomarker candidates and down-selection in three, to be validated in the two additional large-scale proteomics datasets with 228 diseased and 266 control samples. This resulting 3-protein biomarker panel differentiates Alzheimer's disease (AD) from controls in the two validation cohorts with areas under the receiver operating characteristic curve (AUROCs) of 0.83 and 0.87, respectively. This study highlights the value of systematically re-analyzing previously published proteomics data and the need for more stringent data deposition.

Keywords: ALDOA; LDHB; PKM; biomarkers; glycolysis; logistic regression; meta-analysis; metabolism.

Publication types

Meta-Analysis
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Alzheimer Disease* / diagnosis
Biomarkers / cerebrospinal fluid
Humans
Proteomics / methods
ROC Curve

Substances

Biomarkers

Abstract

Publication types

MeSH terms

Substances

Grants and funding