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

In prefrontal grey matter cortex tissue, Alzheimer’s disease with psychosis shows 178 proteins altered versus controls (q<0.05), with AD+P and AD-P sharing a highly similar proteomic landscape (R2=0.965, p<0.001).

• Why it matters: This addresses how synaptic dysfunction mechanisms in early disease stages relate to broader cellular protein changes, beyond prior evidence of prefrontal cortex postsynaptic density loss in AD+P.
• What they did: Proteomic analysis compared prefrontal grey matter cortex homogenates from normal controls (n=18), AD+P (n=61), and AD-P (n=48), and used WGCNA to test module associations with disease status and PSD yield correlations.
• The result: Fifteen proteins correlated with PSD yield across all samples, with ENPP6 linked to AD+P by GWAS, while PSD yield-associated proteins overlapped minimally with altered AD proteins (1 of 137), implying distinct synaptic vulnerability mechanisms.