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Proteomics identifies CSF biomarker panels reflective of pathological networks in the Alzheimer's disease brain
Author(s) -
Higginbotham Lenora A,
Ping Lingyan,
Dammer Eric B,
Duong Duc,
Zhou Maotian,
Gearing Marla,
Johnson Erik CB,
Hajjar Ihab,
Lah James J,
Levey Allan I,
Seyfried Nicholas T
Publication year - 2020
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1002/alz.042227
Subject(s) - cerebrospinal fluid , proteomics , proteome , biomarker , neuropathology , pathology , quantitative proteomics , alzheimer's disease , biomarker discovery , biology , neuroscience , disease , medicine , bioinformatics , biochemistry , gene
Background The repeated failures of amyloid‐targeting therapies have underscored the need for additional biomarkers of Alzheimer’s disease (AD) that reflect its complex multi‐network dysfunction. Using a network‐based proteomic approach, we previously defined a wide range of protein system alterations in the AD brain. In this study, we integrated these brain networks with proteomic analysis of cerebrospinal fluid (CSF), resulting in the identification of CSF biomarker panels reflective of diverse pathophysiology within the AD brain. Methods Using quantitative liquid chromatography coupled to tandem mass spectrometry (LC‐MS/MS), we comparatively analyzed the CSF proteomes of 40 samples (20 controls, 20 AD). Differential expression analysis resolved CSF proteins significantly altered in AD. These CSF biomarkers were mapped to proteomic networks derived from 48 postmortem brain tissues comprising control, asymptomatic AD (AsymAD), AD, and other neurodegenerative diseases. Validation was performed in an independent CSF cohort of 96 control, AsymAD, and AD samples using high‐throughput proteomic methods. Results We identified >3,500 proteins across the initial 40 CSF samples and >12,000 proteins across the 48 postmortem brain tissues. Co‐expression network analysis of the brain tissues yielded 44 protein modules, nearly half of which correlated significantly to AD neuropathology. Fifteen modules robustly overlapped with proteins quantified in the CSF, including 271 CSF markers highly altered in AD. These 15 overlapping modules were collapsed into five panels of brain‐linked fluid markers representing a variety of cortical functions. Neuron‐enriched synaptic and metabolic panels demonstrated decreased levels in the AD brain but increased levels in diseased CSF. Conversely, glial‐enriched myelination and immunity panels were highly increased in both the brain and CSF. Validation of these findings in an independent CSF cohort of control, AsymAD, and AD samples remarkably demonstrated panel alterations in the early, asymptomatic stages of disease. In fact, several panel markers appeared to stratify subpopulations within this preclinical cohort. Conclusion These brain‐linked CSF biomarker panels represent a promising step toward a comprehensive physiological tool that could enhance the therapeutic management of AD.