A major research effort supported by the National Institutes of Health (NIH) has expanded understanding of the molecular and cellular mechanisms underlying Alzheimer’s disease and other neurodegenerative and neuropsychiatric disorders.

The research, conducted through the PsychAD programme, represents the largest comparative investigation of human brain disorders at single-cell resolution. It aims to provide a foundation for precision medicine approaches to diagnose and treat Alzheimer’s and related disorders.

Researchers established a single-cell atlas of biological pathways across brain disorders using more than 6.3 million nuclei from brain tissue specimens from 1,494 donors. The atlas focuses on the human dorsolateral prefrontal cortex, a brain region involved in memory and complex cognitive functions.

The study included Alzheimer’s disease, Parkinson’s disease, Lewy body disease, vascular dementia, schizophrenia and bipolar disorder, along with neurotypical controls. Researchers identified shared and disease-specific molecular processes across different cell types and defined trajectories associated with Alzheimer’s disease progression and neuropsychiatric symptoms.

Alzheimer’s and related dementias are frequently accompanied by neuropsychiatric symptoms including depression, agitation, aggression, psychosis, insomnia and irritability. The PsychAD programme was established to improve understanding of the molecular processes underlying these symptoms.

The research also includes a single-nucleustranscriptome-wide association study, a single-cell atlas of the human prefrontal cortex across the lifespan, and an atlas of cell-type-specific gene regulation across the human prefrontal cortex.

Researchers also developed an AI framework to identify cell states associated with Alzheimer’s disease pathology, cognitive decline, resilience and neuropsychiatric symptoms, along with new personalised medicine tools and methods.

All data and methods have been made available to the global research community to support research on brain ageing, neurodegeneration and psychiatric disorders.

The PsychAD Consortium at Mount Sinai is a cross-disciplinary, multi-institutional effort focused on understanding the molecular and cellular mechanisms of Alzheimer’s and related neurodegenerative and neuropsychiatric disorders. The research was published in nine manuscripts in Nature and multiple Nature portfolio journals.