A major research effort supported by the National Institutes of Health has produced the largest comparative investigation of human brain disorders at single-cell resolution, expanding understanding of the molecular drivers behind Alzheimer's disease and other neurodegenerative and neuropsychiatric disorders.
The work, conducted through NIH's PsychAD program, established a single-cell atlas of biological pathways across brain disorders. The atlas of the human dorsolateral prefrontal cortex — a part of the brain key for memory and other complex cognitive functions — uses over 6.3 million nuclei from brain tissue specimens from 1,494 donors with common and complex brain disorders, including Alzheimer's, Parkinson's disease, Lewy body disease, vascular dementia, schizophrenia, and bipolar disorder, as well as from neurotypical controls.
"This is the most comprehensive, population-scale, molecular mapping of Alzheimer's and related neurodegenerative and neuropsychiatric disorders to date," said Dr. Richard Hodes, director of NIH's National Institute on Aging, which supported the research. "These insights provide a foundation that will help identify precision targets for managing, treating, and reducing the neuropsychiatric symptoms of Alzheimer's and related dementias, while also adding to our knowledge of the molecular processes happening in different conditions."
Alzheimer's and related dementias are frequently accompanied by neuropsychiatric symptoms such as depression, agitation, aggression, psychosis, insomnia, and irritability. According to NIH, these symptoms affect quality of life for patients and caregivers, accelerate the disease process, and are difficult to treat. NIH established the PsychAD program to better understand the molecular processes underlying these symptoms.
Researchers identified shared and disease-specific molecular processes across different cell types and defined trajectories associated with Alzheimer's disease progression and the presence of neuropsychiatric symptoms.
"These highly complex brain disorders impose an enormous public health burden, yet we still have a limited understanding of the molecular mechanisms that drive symptoms, progression, and resilience," said Panos Roussos, M.D., Ph.D., professor in the Department of Genetics and Genomics Sciences and the Department of Psychiatry at the Icahn School of Medicine at Mount Sinai, and senior author of the studies. "By mapping shared and distinct cellular programs across Alzheimer's disease, related dementias, and psychiatric disorders, PsychAD creates a framework for moving beyond traditional diagnostic boundaries toward precision approaches for target discovery, biomarker development, and therapeutic prioritization."
The studies also include a single-nucleus transcriptome-wide association study of human brain disorders; a single-cell atlas of the human prefrontal cortex over the lifespan; an atlas of cell-type-specific gene regulation across the human prefrontal cortex; an AI framework to identify cell states associated with Alzheimer's pathology, cognitive decline, resilience, and neuropsychiatric symptoms; and new personalized medicine tools and methods.
All data and methods have been made available to the global research community to accelerate precision medicine research on brain aging, neurodegeneration, and psychiatric disorders. The PsychAD Consortium at Mount Sinai is a cross-disciplinary, multi-institutional effort using open science practices. The research was published in nine manuscripts in Nature and multiple Nature portfolio journals.