Publication
Large-scale deep multi-layer analysis of Alzheimer's disease brain reveals strong proteomic disease-related changes not observed at the RNA level.
Johnson Erik C B, Carter E Kathleen, Dammer Eric B, Duong Duc M, Gerasimov Ekaterina S, Liu Yue, Liu Jiaqi, Betarbet Ranjita, Ping Lingyan, Yin Luming, Serrano Geidy E, Beach Thomas G, Peng Junmin, De Jager Philip L, Haroutunian Vahram, Zhang Bin, Gaiteri Chris, Bennett David A, Gearing Marla, Wingo Thomas S, Wingo Aliza P, Lah James J, Levey Allan I, Seyfried Nicholas T
# Alzheimer's Disease Proteomics Study
This study examined protein networks in over 1,000 brain tissue samples to identify disease-related changes in Alzheimer's disease (AD). Large-scale proteomic analysis revealed multiple protein co-expression modules associated with AD that were consistently observed across different brain cohorts and regions. Notably, nearly half of these altered protein modules—including two AD-associated modules linked to MAPK signaling/metabolism and the matrisome—were not detected in corresponding RNA networks from the same tissues, demonstrating that AD is fundamentally a proteopathic disorder with protein-level changes not reflected in transcriptional patterns.
The MAPK/metabolism module showed strong association with cognitive decline rates, whereas the matrisome module was influenced by APOE ε4 status but not independently predictive of cognitive outcomes. These findings suggest that protein-level disruptions provide critical insights into AD biology beyond what RNA analysis alone can reveal. The study identifies disease-associated proteomic modules as promising sources for new therapeutic targets and biomarkers in Alzheimer's disease.
Abstract
The biological processes that are disrupted in the Alzheimer's disease (AD) brain remain incompletely understood. In this study, we analyzed the proteomes of more than 1,000 brain tissues to reveal new AD-related protein co-expression modules that were highly preserved across cohorts and brain regions. Nearly half of the protein co-expression modules, including modules significantly altered in AD, were not observed in RNA networks from the same cohorts and brain regions, highlighting the proteopathic nature of AD. Two such AD-associated modules unique to the proteomic network included a module related to MAPK signaling and metabolism and a module related to the matrisome. The matrisome module was influenced by the APOE ε4 allele but was not related to the rate of cognitive decline after adjustment for neuropathology. By contrast, the MAPK/metabolism module was strongly associated with the rate of cognitive decline. Disease-associated modules unique to the proteome are sources of promising therapeutic targets and biomarkers for AD.