Scientists have created a detailed map of gene activity in the brain’s prefrontal cortex, providing new insights into normal brain development, ageing and major neurological and psychiatric disorders, including Alzheimer’s disease, Parkinson’s disease and schizophrenia. The research examined gene activity in more than 6.3 million brain cells from 1,494 deceased donors, ranging from infancy to 108 years of age. The findings, published in Nature and other journals, could help researchers identify vulnerable cell types and biological processes involved in brain disorders and guide the search for potential treatments.
Mapping Gene Activity in the Prefrontal Cortex
The prefrontal cortex forms the front portion of the brain’s outer layer, behind the forehead. It plays a key role in planning, decision-making, emotional regulation and adapting behaviour. However, this region is also vulnerable to ageing and disease. To better understand these changes, researchers studied gene activity in individual brain-cell nuclei, including neurons, immune cells, blood-vessel-associated cells and supporting cells. The study included donors without diagnosed brain disorders as well as people diagnosed with Alzheimer’s disease, Parkinson’s disease, Lewy body dementia, vascular dementia, schizophrenia and bipolar disorder. As a result, researchers identified both shared and disease-specific patterns of gene activity.
Linking Brain Cells to Disease
The researchers found particularly strong similarities in gene activity among Alzheimer’s disease, Lewy body disease, vascular dementia and Parkinson’s disease. These similarities involved biological processes related to nerve-cell development, neuronal communication and blood-vessel function. In addition, Alzheimer’s and Parkinson’s disease showed several shared molecular pathways in microglia, the brain’s resident immune cells. According to the researchers, these findings can help identify where disease-related changes occur and which biological processes require further investigation. Importantly, potential treatments may need to target specific biological processes within specific cell types. The new gene activity map could therefore help researchers identify vulnerable cell populations and investigate potential therapeutic targets.
Brain Development and Ageing
The study also revealed major changes in gene activity during brain development. Researchers observed extensive molecular changes from infancy through early adulthood, followed by greater stability during much of adulthood. However, these changes increased again later in life, particularly in immune and supporting cells. The researchers identified approximately age 24 as a transition point after which gene activity in most cell types in the prefrontal cortex became more stable. However, the researchers stressed that this does not mean brain development ends at age 24. Similarly, it does not indicate that brain decline begins at that age. Different aspects of brain biology continue to change throughout life.
Identifying Protective Brain Mechanisms
The researchers also identified cellular patterns associated with cognitive differences and depression in people with Alzheimer’s disease. For example, some individuals maintained relatively strong cognitive function despite having substantial Alzheimer’s-related brain pathology. These individuals showed differences in energy-related processes within brain cells. These findings could provide clues about biological mechanisms that may help protect brain function. However, researchers say these potential protective mechanisms require further investigation.
Mapping Inherited Genetic Risk
Beyond disease-related changes, the researchers linked inherited genetic risk to specific genes and brain-cell types. The studies mapped genetic influences on the activity of more than 14,000 genes, helping researchers understand how genetic risk may affect particular cell populations and biological pathways. This detailed information could help connect genetic risk factors with the molecular changes that contribute to neurological and psychiatric disorders.
Brain Gene Activity Changes with the Body Clock
The research also examined how gene activity changes throughout the day. Using brain samples from people who died at different times, researchers reconstructed daily patterns of gene activity. In younger and middle-aged adults, clock-related genes showed coordinated activity in neurons. However, these patterns became weaker and less synchronized in older adults. The findings suggest that ageing may alter how daily biological rhythms are organised within the brain. Researchers say future studies will need to determine whether restoring these rhythms could contribute to better brain health.
Toward More Personalised Brain Disorder Treatments
The researchers also developed molecular profiles of individual donors with Alzheimer’s disease. These profiles revealed differences in gene regulation and predicted interactions between different types of brain cells. Consequently, the findings highlight why people with the same diagnosis can experience different biological changes. As reported by reuters.com, by combining information on genes, cell types, ageing and disease, the new brain gene activity map provides a detailed reference for future research. It could ultimately help scientists distinguish normal ageing from disease-related changes and identify more targeted approaches to treating brain disorders.