Basic Science and Pathogenesis

Area of Science:

• Neuroscience
• Genetics
• Pathology

Background:

• Approximately 40% of Alzheimer's disease (AD) patients experience psychotic symptoms.
• The underlying neural mechanisms of neuropsychiatric symptoms in dementia are not well understood.

Purpose of the Study:

• To identify neurobiological differences between AD patients with psychosis (AD+P) and those without (AD-P).
• To investigate the role of specific neuronal populations and genetic alterations in AD-related psychosis.

Main Methods:

• Single-nucleus transcriptome and epigenome profiling of prefrontal cortex and hippocampus from 48 subjects.
• In situ RNA hybridization and functional screens using stem-cell derived brain organoids.

Main Results:

• Differentially expressed genes (DEGs) were identified across multiple cell types in AD+P patients.
• A specific population of supragranular excitatory neurons in AD+P cortex showed enhanced synaptic transmission signatures.
• These neurons reactivated developmental programs to remodel network connectivity, potentially exacerbating pathology.

Conclusions:

• Selective vulnerability of supragranular excitatory neurons may be linked to glial inflammatory programs.
• Compensatory neuronal mechanisms in AD+P might worsen network dysfunction and pathology.
• The study identifies novel genetic targets for potential antipsychotic treatments in AD.