Integrated proteomics reveals brain-based cerebrospinal fluid biomarkers in asymptomatic and symptomatic Alzheimer's disease

Lenora Higginbotham, Lingyan Ping, Eric B. Dammer, Duc M. Duong, Maotian Zhou, Marla Gearing, Cheyenne Hurst, Jonathan D. Glass, Stewart A. Factor, Erik C.B. Johnson, Ihab Hajjar, James J. Lah, Allan I. Levey, Nicholas T. Seyfried

Research output: Contribution to journalArticlepeer-review

54 Scopus citations

Abstract

Alzheimer's disease (AD) lacks protein biomarkers reflective of its diverse underlying pathophysiology, hindering diagnostic and therapeutic advancements. Here, we used integrative proteomics to identify cerebrospinal fluid (CSF) biomarkers representing a wide spectrum of AD pathophysiology. Multiplex mass spectrometry identified ~3500 and ~12,000 proteins in AD CSF and brain, respectively. Network analysis of the brain proteome resolved 44 biologically diverse modules, 15 of which overlapped with the CSF proteome. CSF AD markers in these overlapping modules were collapsed into five protein panels representing distinct pathophysiological processes. Synaptic and metabolic panels were decreased in AD brain but increased in CSF, while glial-enriched myelination and immunity panels were increased in brain and CSF. The consistency and disease specificity of panel changes were confirmed in >500 additional CSF samples. These panels also identified biological subpopulations within asymptomatic AD. Overall, these results are a promising step toward a network-based biomarker tool for AD clinical applications.

Original languageEnglish (US)
Article numbereaaz9360
JournalScience Advances
Volume6
Issue number43
DOIs
StatePublished - Oct 21 2020
Externally publishedYes

ASJC Scopus subject areas

  • General

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