Compensatory Plasticity Defines a Vulnerable Neuronal State in Alzheimer’s Disease with Psychosis

Approximately 40 percent of Alzheimer’s disease patients develop psychosis (AD+P), yet the molecular and cellular basis of these symptoms remains poorly understood. Here we profiled single-nucleus transcriptomes and epigenomes from 48 postmortem Alzheimer’s brains stratified by psychiatric diagnosis. Across cell types, AD+P was distinguished by transcriptional programs in upper-layer cortical pyramidal neurons consistent with re-engagement of developmental and structural plasticity pathways. These neurons exhibited greater loss in AD+P cortex, indicating that such programs emerge in a context of heightened vulnerability. Integrating these findings with functional perturbation screens in stem-cell-derived brain organoids, we found that activation of these programs alters cortico-cortical network connectivity and can exacerbate network dysfunction. Our data suggest that compensatory neuronal plasticity, shaped by glial inflammatory responses, may paradoxically contribute to circuit instability and selective vulnerability underlying neuropsychiatric symptoms in dementia.