Proteome profiling in cerebrospinal fluid reveals novel biomarkers of Alzheimer's disease

Abstract

Neurodegenerative diseases are a growing burden, and there is an urgent need for better biomarkers for diagnosis, prognosis, and treatment efficacy. Structural and functional brain alterations are reflected in the protein composition of cerebrospinal fluid (CSF). Alzheimer's disease (AD) patients have higher CSF levels of tau, but we lack knowledge of systems-wide changes of CSF protein levels that accompany AD. Here, we present a highly reproducible mass spectrometry (MS)based proteomics workflow for the in-depth analysis of CSF from minimal sample amounts. From three independent studies (197 individuals), we characterize differences in proteins by AD status (> 1,000 proteins, CV < 20%). Proteins with previous links to neurodegeneration such as tau, SOD1, and PARK7 differed most strongly by AD status, providing strong positive controls for our approach. CSF proteome changes in Alzheimer's disease prove to be widespread and often correlated with tau concentrations. Our unbiased screen also reveals a consistent glycolytic signature across our cohorts and a recent study. Machine learning suggests clinical utility of this proteomic signature.

Urinary proteome profiling for stratifying patients with familial Parkinson’s disease

“…Additionally, instead of focusing on a single biomarker and/or a subset of molecular entities, our shotgun proteomic approach provides a multiparameter global map of the disease state. We previously showed that this strategy can yield powerful, data-driven descriptors of a disease [33,35,54], and we now confirm, for the first time, that this also works for urinary proteome analysis in the context of a complex neurodegenerative disease, such as PD.…”

“…We also identified several apolipoproteinsthe major proteinaceous constituent of lipoproteins -to be significantly upregulated in PD patients in the Columbia cohort. They have been linked to neurodegenerative disorders including Alzheimer disease, including in our recent proteomic study of CSF [54]. APOE variants were shown to exhibit neuroprotective activity (reviewed in [65]).…”

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

“…Data-independent acquisition (DIA) and other MS-based strategies may also prove useful for target validation. Bader et al ( 64 ) recently demonstrated significant overlap between the AD biomarkers identified in our CSF discovery dataset and an independent DIA-MS dataset composed of nearly 200 CSF samples across three different European cohorts. These recent studies support the translational potential of our panels into reliable MS-based assays.…”

An Integrative Multi-omics Approach Reveals New Central Nervous System Pathway Alterations in Alzheimer’s Disease

“…Tau, and P-Tau levels. This apoptosis inhibitor, one of the most abundant proteins in the brain, was previously found to exhibit altered levels in AD and modulate AD risk (29,30). We also identi ed associations of neuro lament medium polypeptide with Tau levels and of reelin with Aβ 1−42 and Tau levels.…”