Cellular and Regional Vulnerability Shapes the Molecular Landscape of Psychosis in Alzheimer’s Disease

Approximately 40% of Alzheimer’s disease (AD) patients develop psychosis, yet the molecular and cellular processes that govern the manifestation of psychotic symptoms in dementia remain poorly understood. To define the neurobiological correlates that distinguish AD patients with psychosis (AD+P) from AD patients that never exhibited psychotic symptoms (AD-P), we performed single-nucleus transcriptome and epigenome profiling from prefrontal cortex and hippocampus of 48 postmortem brains from AD subjects segmented by psychiatric diagnosis. Our snRNA-seq profiling uncovered differentially expressed genes (DEGs) across multiple cell types, including transcriptional signatures of enhanced synaptic transmission in upper-layer pyramidal neurons of the AD+P cortex. Cell fraction analysis and histology both indicate greater loss of upper-layer pyramidal neurons in AD+P in comparison to AD-P cortex. Integrating our snRNA-seq data with functional screens in stem-cell derived brain organoids, we defined how genetic perturbations modify input-output network connectivity in vitro in a model of cortico-cortical communication. We find that differential vulnerability of pyramidal neurons in AD+P is associated with CDK5/p35-associated neurotoxicity and IL6-mediated glial inflammatory expression changes. This neuronal response is associated with microglial exhaustion and astrocytic inflammation signatures triggered by layer-specific neuropathological changes in the brains of AD+P patients. Lastly, we elucidate common and distinct transcriptional signatures between psychosis in AD and several other psychiatric conditions, and found significant enrichment of schizophrenia genetics with AD+P that is most convergent in upper-layer pyramidal neurons. Our work provides novel insight into the pathophysiological role of hyperexcitable circuits in the etiology of neuropsychiatric symptoms of AD.