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

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.

Pathophysiological subtypes of Alzheimer’s disease based on cerebrospinal fluid proteomics

“…These factors have previously been identified as key regulators in a sporadic Alzheimer’s disease iPSC model ( Meyer et al , 2019 ), in which neurons also showed increase excitability, and increased tau phosphorylation and amyloid-β 1–40 concentrations, which is in line with our observations and interpretation of subtype 1. Finally, proteins increased in subtype 1 also showed enrichment for glucose metabolism, which has been reported in two recent proteomic studies in tissue and in CSF that also observed clusters of proteins associated with glucose metabolism to be involved in Alzheimer’s disease, as well as clusters of synaptic proteins ( Higginbotham et al ., 2019; Johnson et al , 2020 ). In those studies, and our results, glucose metabolism pathways mostly included proteins that were specific for neurons and/or astrocytes.…”

Proteomic Profiling of Extracellular Vesicles Derived from Cerebrospinal Fluid of Alzheimer’s Disease Patients: A Pilot Study

“…NPEPPS digests soluble tau purified from non-pathological human brain but not the tau purified from AD brain [ 72 ], suggesting its role in the clearance of normal tau in a posttranslational modification-sensitive manner. CSF NPEPPS is investigated as a biomarker candidate in AD patients [ 73 ]. Thus, the combination of HSPA1A and NPEPPS in CSF EVs may serve as a potential biomarker in monitoring the conversion of MCI to AD.…”

Dysregulated gene-associated biomarkers for Alzheimer’s disease and aging

“…However, there are same bioinformatics analysis researches that reported many biomarkers for AD based on the peripheral blood mononuclear cell (PBMC) expression datasets [ 46 , 47 ]. Meanwhile, the currently published relevant papers were most associated with large-scale transcriptome or proteomics analysis in the brain tissues and cerebrospinal fluid samples [ 48 , 49 , 50 ]. The purpose of this study is to select potential biomarkers from GSE database and validate the expression of these DEGs in peripheral human AD samples and both peripheral/central nervous AD and aging mice samples, which could be served as both the early diagnosis biomarkers and potential targeted genes for pathological researches of AD or aging-related neurodegenerative disorders.…”