Proteomic Analysis in Alzheimer's Disease with Psychosis Reveals Separate Molecular Signatures for Core AD Proteinopathy and Postsynaptic Density Disruption

Ku, T. S.-H.; Mullet, S. J.; Sui, Z.; Zeng, L.; Ding, Y.; Yocum, A. K.; MacDonald, M. L.; Gelhaus, S. L.; Kofler, J. K.; Sweet, R. A.

doi:10.1101/2025.11.26.690872

bioRxiv · 10.1101/2025.11.26.690872

Proteomic Analysis in Alzheimer's Disease with Psychosis Reveals Separate Molecular Signatures for Core AD Proteinopathy and Postsynaptic Density Disruption

Ku, T. S.-H.·Mullet, S. J.·Sui, Z.·Zeng, L.·Ding, Y.·Yocum, A. K.·MacDonald, M. L.·Gelhaus, S. L.·Kofler, J. K.·Sweet, R. A.

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Abstract

Background and Hypothesis: Alzheimers 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), all with Braak stages 3-5. 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 (R{superscript 2}=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). WGCNA revealed one module significantly correlated with PSD yield across all samples, 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 are largely independent of the shared AD proteome, conferring distinct mechanisms of synaptic vulnerability and psychosis risk.

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Ku, T. S.-H., Mullet, S. J., Sui, Z., Zeng, L., Ding, Y., Yocum, A. K., MacDonald, M. L., Gelhaus, S. L., Kofler, J. K., Sweet, R. A.. 2025-12-01. Proteomic Analysis in Alzheimer's Disease with Psychosis Reveals Separate Molecular Signatures for Core AD Proteinopathy and Postsynaptic Density Disruption. https://doi.org/10.1101/2025.11.26.690872

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