Abstract
BACKGROUND: Nociceptin (N/OFQ) and its receptor OPRL1 play crucial roles in emotional processing, reward-related behaviors, learning, and neurotransmitter regulation, but their involvement in Alzheimer's disease (AD) pathology remains poorly understood. This study investigated possible relationships between prepronociceptin ( PNOC ) and OPRL1 expression and psychiatric symptoms in AD, utilizing Natural Language Processing (NLP) to assess Research Domain Criteria (RDoC) domains. METHODS: Post-mortem brain tissue from the dorsal anterior cingulate gyrus (BA32) was analyzed in 61 donors across different Braak and Braak (B&B) stages. RNA expression of PNOC and OPRL1 was quantified and correlated with RDoC scores derived from medical records using NLP. Sex-stratified analyses, circadian rhythmicity analysis, and cell-type specific expression patterns were examined. RESULTS: Both genes showed significant downregulation in AD cases ( PNOC : p = 0.024; OPRL1 : p < 0.001), with notable sex differences. Men displayed higher post-mortem PNOC (Cohen's d = -0.482) and OPRL1 (Cohen's d = -0.237) expression compared to women. In adjusted models controlling for B&B stage and post-mortem interval, PNOC expression significantly correlated with dimensional scores of positive valence (β = -0.38, p = 0.035) and arousal regulatory systems (β = -0.43, p = 0.015) derived from a text classification algorithm applied to medical records. OPRL1 showed disrupted circadian rhythmicity in AD cases (p = 0.151 vs. p = 0.020 in controls). CONCLUSIONS: These findings suggest distinct roles for PNOC and OPRL1 in AD pathology, with PNOC primarily associated with psychiatric symptoms and OPRL1 showing disrupted circadian regulation. Sex-specific expression patterns further indicate the need for personalized therapeutic approaches targeting the nociceptin system.