A Reproducible MCI-Centered Ubiquitin–Proteasome Transcriptional Signature

Research overview

The ubiquitin-proteasome system (UPS) is central to cellular proteostasis, yet it remains unclear whether UPS-related transcriptional changes vary systematically across cognitive diagnostic groups. We tested whether peripheral blood expression of UPS genes exhibits a reproducible non-monotonic pattern across cognitively healthy controls, mild cognitive impairment (MCI), and Alzheimer’s disease (AD).

Three public blood transcriptomic datasets (GSE63060, GSE63061, and GSE140829) were analyzed. Age- and sex-adjusted linear regression models were used to calculate a standardized MCI-centered contrast for each gene, representing MCI expression relative to the control-AD midpoint. Among non-monotonic genes, pathway-level effects were summarized by the median absolute standardized contrast and compared with expression-matched non-UPS genes using 100,000-iteration Monte Carlo null distributions.

UPS genes showed significantly larger MCI-centered deviations than matched non-UPS genes in all three datasets, including the independently generated GSE140829 cohort (UPS/null ratios 1.1007-1.1425; UPS-null differences 0.0194-0.0286; p=0.0005-0.0211). The effect was driven primarily by MCI-centered reductions ("valleys") rather than increases ("peaks"): valley UPS/null ratios ranged from 1.1118 to 1.2021, with significance in GSE63061 and GSE140829 and concordant direction in GSE63060. Signed UPS deviations were also strongly concordant across datasets (pairwise r=0.61-0.71).

To assess pathway specificity, 876 size-filtered Gene Ontology Biological Process gene sets were analyzed using the same framework. After false discovery rate correction, only three comparator pathways remained significant in all three datasets; two overlapped extensively with UPS. By median cross-dataset effect, UPS ranked in the 95.7th percentile for observed/null ratio and the 95.0th percentile for absolute effect difference.

These findings identify a reproducible, MCI-centered peripheral UPS transcriptional signature that is unusually strong relative to the broader GO landscape and motivates longitudinal investigation of proteostasis-related transcription in cognitive impairment.