Scientists map gene activity in brain’s prefrontal cortex shedding light on Alzheimer’s, schizophrenia

A detailed mapping of genetic activity within the prefrontal cortex has offered new clarity on normal brain maturation as well as major conditions such as Alzheimer’s disease, Parkinson’s disease and schizophrenia.

Across nine separate studies, scientists examined age-related shifts across individual brain cell types to better decipher the molecular processes driving severe brain disorders, marking progress toward potential new therapies.

Located directly behind the forehead, the prefrontal cortex forms the outer layer’s frontal region, playing a key role in decision-making, emotional regulation, planning and behavior adaptation.

Highly vulnerable to age-related decline, its functionality is frequently impaired across various neurodegenerative and psychiatric conditions.

Researchers evaluated gene activity in the nuclei of more than 6.3 million brain cells, including neurons, immune cells, blood vessel structures and support cells that sustain neurological function.

The post-mortem samples came from 1,494 donors spanning from infancy to 108 years of age, representing diverse genetic ancestries.

The tissue donors comprised individuals without any diagnosed brain conditions alongside those affected by schizophrenia, bipolar disorder, vascular dementia, Lewy body dementia, Parkinson’s and Alzheimer’s.

The study revealed both universal molecular trends shared across multiple conditions and specific signatures tied to individual disorders.

“Together, these studies help explain where disease-related changes occur and which biological processes deserve closer investigation,” said Dr. Panos Roussos, director of the Center for Disease Neurogenomics at the Icahn School of Medicine at Mount Sinai in New York City and a leader of the research published on Wednesday in Nature and other journals.

“A useful treatment needs to influence the right biological process in the right cells. This map helps narrow that search. It can identify vulnerable cell populations, reveal processes associated with preserved brain function and help researchers decide which potential treatment targets to test,” Roussos said.

The project was executed through the PsychAD research consortium and supported by the National Institute on Aging, a branch of the U.S. government’s National Institutes of Health.

Strong similarities

Particularly strong overlaps in gene activity linked to nerve-cell maturation, cellular communication and blood-vessel biology were identified across vascular dementia, Lewy body disease, Parkinson’s and Alzheimer’s. Investigators also uncovered shared pathways in microglia, the brain’s resident immune cells, between Alzheimer’s and Parkinson’s.

Comparing brain tissue across various donor ages revealed pronounced molecular shifts during early development through adulthood, followed by relative stability across midlife, and a resurgence of cellular changes later in life, particularly within support and immune cells.

“This provides a reference for distinguishing typical aging from disease-associated changes,” Roussos said.

Data indicated that around age 24, a transitional phase occurs after which most cellular populations in this region stabilize.

“It does not mean the brain suddenly finishes developing on someone’s 24th birthday, or that decline begins at that age. Other aspects of brain biology continue to change throughout life,” Roussos said.

The team also identified cellular signatures tied to variations in cognitive ability and depression linked to Alzheimer’s. Notably, individuals who maintained cognitive health despite substantial Alzheimer’s pathology exhibited differences in energy-related cellular processes.

“These provide clues to possible protective mechanisms that need further testing,” Roussos said.

Inherited genetic risk

Researchers connected inherited genetic risks of disorders to specific genes and cell types, mapping genetic influences across the activity of over 14,000 genes.

By examining brain tissue from individuals who died at various times of day, the team reconstructed 24-hour cycles of gene activity. Younger and middle-aged adults displayed synchronized daily clock gene patterns in neurons, whereas these patterns proved weaker and less synchronized in older adults.

“This suggests that aging changes how daily biological rhythms are organized within the brain. Whether restoring those rhythms could improve brain health is an important question for future research,” Roussos said.

Additionally, the scientists generated individual molecular profiles for donors with Alzheimer’s, uncovering variations in gene regulation and projected cell-type interactions among patients.

“This helps explain biological variation among people with the same diagnosis, and provides a foundation for investigating more individualized treatment strategies,” Roussos said.