INTRODUCTION: Neuropsychiatric symptoms are common in people with Alzheimers disease (AD) across all severity stages. Their heterogeneous presentation and variable temporal association with cognitive decline suggest shared and distinct biological mechanisms. We hypothesized that specific patterns of gene expression associate with distinct NIMH Research Domain Criteria (RDoC) domains in AD. METHODS: Post-mortem bulk RNAseq on the insula and anterior cingulate cortex from 60 brain donors representing the spectrum of canonical AD neuropathology combined with natural language processing approaches based on the RDoC Clinical Domains. RESULTS: Distinct sets of >100 genes (pFDR<0.05) were specifically associated with at least one clinical domain (Cognitive, Social, Negative, Positive, Arousal). In addition, dysregulation of immune response pathways was shared across domains and brain regions. DISCUSSION: Our findings provide evidence for distinct transcriptional profiles associated with RDoC domains suggesting that each dimension is characterized by specific sets of genes providing insight into the underlying mechanisms.

The authors have declared no competing interest.

This work was supported by P50MH115874, R01MH120991, German Research Foundation 413501650, P50NM119467, Alzheimers Association AACSFD-23-1149842, Eric Dorris Memorial Fellowship, Rappaport Mental Health Research Award, R01HD102974, and R01AG070704.

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All tissue samples and medical records were obtained from the Harvard Brain Tissue Resource Center (HBTRC; operating under the Mass General Brigham/McLean Institutional Review Board (IRB)).

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RNAseq data is available through the GEO accession number GSE261050. The code of the analyses is available at the Klengel Lab GitHub page under https://github.com/klengellab/RDoC_RNAseq.