Proteomic analysis in Alzheimer's disease with psychosis reveals a shared AD proteomic landscape and a separate molecular signature of postsynaptic density disruption

Background and Hypothesis: Alzheimer's disease with psychosis (AD+P) is a subgroup of AD patients with more rapid cognitive deterioration. While our previous study showed that AD+P is associated with loss of prefrontal cortex postsynaptic density (PSD) proteins, identifying proteins in the broader cellular environment that influence PSD loss addresses a critical knowledge gap about synaptic dysfunction mechanisms in early disease stages. Study Design: We conducted a proteomic analysis comparing prefrontal grey matter cortex tissue homogenates from elderly normal controls (n=18), individuals with AD+P (n=61), and individuals with AD-P (n=48). Study Results: AD+P showed the most pronounced alterations relative to controls (178 proteins with q<0.05), although alterations in AD-P and AD+P relative to controls were highly similar (R2=0.965, p<0.001). Weighted-gene correlation network analysis (WGCNA) identified four modules significantly associated with disease status comparing AD subjects to controls, but none differed significantly between AD+P and AD-P. We identified 15 proteins significantly correlated with PSD yield across all samples, including ENPP6, linked to AD+P by GWAS. Additionally, PSD yield-associated proteins showed minimal overlap with altered AD proteins (1 of 137). Proteins negatively correlated with PSD yield were enriched for presynaptic endocytosis, whereas the one WGCNA module significantly correlated with PSD yield was enriched for inflammatory terms. Conclusions: Our findings suggest a model in which AD+P arises from the combination of quantitative alterations within a shared AD proteome profile and a superimposed set of protein alterations correlated with PSD yield that confer distinct mechanisms of synaptic vulnerability and psychosis risk.