Abstract

Alzheimer’s disease (AD) is currently defined by the aggregation of amyloid-β (Aβ) and tau proteins in the brain. Although biofluid biomarkers are available to measure Aβ and tau pathology, few markers are available to measure the complex pathophysiology that is associated with these two cardinal neuropathologies. Here, we characterized the proteomic landscape of cerebrospinal fluid (CSF) changes associated with Aβ and tau pathology in 300 individuals using two different proteomic technologies—tandem mass tag mass spectrometry and SomaScan. Integration of both data types allowed for generation of a robust protein coexpression network consisting of 34 modules derived from 5242 protein measurements, including disease-relevant modules associated with autophagy, ubiquitination, endocytosis, and glycolysis. Three modules strongly associated with the apolipoprotein E ε4 ( APOE ε4) AD risk genotype mapped to oxidant detoxification, mitogen-associated protein kinase signaling, neddylation, and mitochondrial biology and overlapped with a previously described lipoprotein module in serum. Alterations of all three modules in blood were associated with dementia more than 20 years before diagnosis. Analysis of CSF samples from an AD phase 2 clinical trial of atomoxetine (ATX) demonstrated that abnormal elevations in the glycolysis CSF module—the network module most strongly correlated to cognitive function—were reduced by ATX treatment. Clustering of individuals based on their CSF proteomic profiles revealed heterogeneity of pathological changes not fully reflected by Aβ and tau.