A major NIH-funded research effort has produced comprehensive molecular maps of Alzheimer's disease and related brain disorders at single-cell resolution, providing new insights into the conditions' underlying mechanisms, the National Institutes of Health said.
The work represents the largest comparative investigation of human brain disorders at this level of detail. Researchers created a single-cell atlas of the human dorsolateral prefrontal cortex—a brain region key for memory and complex cognitive functions—using more than 6.3 million nuclei from brain tissue specimens from 1,494 donors. The donors had Alzheimer's disease, Parkinson's disease, Lewy body disease, vascular dementia, schizophrenia, and bipolar disorder, as well as neurotypical controls.
Alzheimer's and related dementias are frequently accompanied by neuropsychiatric symptoms such as depression, agitation, aggression, psychosis, insomnia, and irritability. These symptoms accelerate disease progression and are difficult to treat. The NIH established the PsychAD program to increase understanding of the molecular processes underlying these symptoms and develop better prevention and treatment approaches.
The 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. The research was published in nine manuscripts in Nature and multiple Nature portfolio journals.
The atlas serves as a reference for distinguishing normal aging from disease-associated brain changes. Researchers also developed an AI framework to identify cell states associated with Alzheimer's pathology, cognitive decline, resilience, and neuropsychiatric symptoms. 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.