The Amyloid Plaque Proteomes of Alzheimer’s Disease and Mild Cognitive Impairment

Amyloid plaques contain numerous proteins in addition to amyloid beta in Alzheimer’s disease (AD). Previous localized proteomics identified plaque-associated proteins in late-onset AD, early-onset AD, rapidly progressive AD, preclinical AD, and AD in Down syndrome, although most studies had smaller cohorts and focused primarily on severe pathology. The amyloid plaque proteome in mild cognitive impairment (MCI) has not been evaluated. We evaluated plaque proteomes in MCI and AD with comparisons to neighboring non-plaque tissue and control non-plaque tissue from ROSMAP (151 cases (n = 240 samples); control (n = 62), MCI (n = 36), AD (n = 53)). Tissue was microdissected from autopsy paraffin embedded temporal cortex and evaluated by label-free quantitative proteomics. We identified differentially abundant proteins with robust differences at a false discovery rate (FDR) < 5% and fold-change > 1.5 for 135 proteins in MCI and 156 in AD plaque tissue compared to neighboring non-plaque tissue, which included proteins described previously as well as novel proteins. Gene ontology (GO) term associations included increased inflammatory response and lysosome proteins in both MCI and AD, and decreased myelin proteins particularly in AD. Of plaque proteins altered in at least one disease group, many changed in the same fold-change direction (p < 0.0001, R ²  = 0.53) and there were 100 shared proteins in MCI and AD. In non-plaque tissue, there were 277 differentially abundant proteins in MCI and 177 in AD; associated with structural constituent of chromatin in MCI and negative regulation of DNA recombination and autolysosome in AD, with decreased proteins associated with actin-myosin filament in AD. Weighted gene correlation network analysis (WGCNA) identified proteins associated with pathology and demographics. We have conducted the most extensive proteomics of microdissected plaque proteomes in both MCI and AD. Our results provide insights into MCI and AD molecular mechanisms, novel biomarkers, and potential novel therapeutic targets.