The neuropathological changes of Alzheimer’s disease (AD) begin two decades or more before signs of cognitive impairment. Currently, our understanding of the pathological events and the molecular transition from this asymptomatic phase of AD (AsymAD) to clinically evident dementia is limited. To define changes associated with asymptomatic and symptomatic stages of AD our group employed a systems level mass spectrometry based proteomic analyses of 129 human postmortem brain tissues. Network analysis revealed 16 modules of co-expressed proteins, 10 of which correlated with AD phenotypes (i.e., neuropathology and cognitive status). A subset of modules also overlapped with RNA co-expression networks generated from previously published AD microarray data. These included modules associated with neurons and astroglial cell types, showing altered expression, even in the asymptomatic phase of AD. Overlap of RNA and protein networks was otherwise modest, with many modules specific to the proteome, including those linked to microtubule function and RNA/DNA binding. Proteomic modules were validated in a second independent cohort, demonstrating some module expression changes unique to AD and several observed in other neurodegenerative diseases. Notably, we also found that AD genetic risk loci were concentrated in glial-related modules in the proteome and transcriptome consistent with their causal role in AD. These findings support the utility of multi-network driven approaches (RNA and protein) to reveal disease-specific pathways involved in the etiology, initiation, and progression of AD.
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