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Scientists analyzed single cells located in the prefrontal cortex (orange), a brain region that helps regulate emotions and decision-making.
Many brain diseases involve changes in the prefrontal cortex. This brain region, located behind the forehead, helps regulate attention, emotions and decision-making. Understanding what drives brain changes at the cellular and molecular level remains challenging. This is largely due to the complexity of the processes involved.
The NIH-funded PsychAD Consortium was established to understand the mechanisms behind behavioral and psychological symptoms in Alzheimer’s disease and other brain diseases. To this end, scientists from several institutions constructed a single-cell atlas of gene activity in the prefrontal cortex. They analyzed gene activity in more than 6 million cells from almost 1,500 people. The results were published on September 23, 2026, in a series of eight papers, including three in Nature, three in Nature Communications, and one each in Nature Genetics and Nature Medicine.
The team analyzed cells in brain tissue from deceased donors, across the human lifespan. Donors comprised neurotypical people and those with eight brain diseases. Alzheimer’s disease, diffuse Lewy body disease, vascular dementia, Parkinson’s disease, tauopathy, frontotemporal dementia, schizophrenia, and bipolar disorder were all included.
The researchers found gene activity changes common to all the diseases studied. These mostly involved genes related to basic cellular functions. Other gene activity changes were specific to certain diseases. Alzheimer’s disease, diffuse Lewy body disease, vascular dementia and Parkinson’s disease were the most similar in their associated gene activity changes.
The researchers also examined changes linked with Alzheimer’s disease progression. Those with more severe disease had fewer neurons and more immune and vascular cells than those with less severe disease. Certain psychiatric symptoms of Alzheimer's disease were linked with more deep-layer excitatory neurons. This supports previous findings connecting these neurons with psychiatric symptoms.
In another paper in the series, the research team mapped how gene activity changes throughout the lifespan in healthy brains. They identified a period of rapid remodeling from birth to around age 24. This was followed by a period of relative stability in midlife. After age 65, gene activity began to change again in some cell types. The findings could help distinguish disease-related changes from normal aging.
Other papers in the series demonstrated further uses for the PsychAD atlas. Researchers connected genetic risk for brain diseases to specific cell types, genes, and biological pathways. They developed a computational framework to identify cell states associated with Alzheimer’s disease, cognitive decline, resilience, and psychiatric symptoms. And they introduced tools and methods for identifying differences among patients with Alzheimer’s disease.
The effort represents one of the largest single-cell analyses of the human brain performed to date. It also sheds light on potential targets for further study and therapeutic intervention.
“But it is only the beginning,” says Dr. Panos Roussos of the Icahn School of Medicine at Mount Sinai and senior author of the papers. “Our goal is to build a resource representing approximately 10,000 individuals. By harmonizing these data, we will gain a much deeper understanding of the molecular and genetic architecture underlying brain disorders.”
—by Brian Doctrow, Ph.D.