Gene activity in brain reveals clues to Alzheimer’s, Parkinson’s and schizophrenia

WASHINGTON: Scientists have created a detailed map of gene activity within a crucial part of the brain called the prefrontal cortex, gaining insight into normal development and major brain disorders such as Alzheimer's disease, Parkinson's disease and schizophrenia. In nine separate studies, the researchers examined changes in individual types of brain cells that occur over time and made progress toward deciphering molecular processes that underlie some of the most devastating brain disorders, a step toward possible new treatments. The prefrontal cortex is the front part of the brain's outer layer, located behind the forehead. It helps a person plan, make decisions, regulate emotions and adapt behavior. It also is sensitive to age-related decline, and its functions are affected in many psychiatric and neurodegenerative disorders. Gene activity was examined in the nuclei of more than 6.3 million brain cells - neurons, immune cells, cells associated with blood vessels and support cells that help maintain brain function - from 1,494 deceased donors, ranging in age from infancy to 108 years old, and with various genetic ancestries. The donors included people with no diagnosed brain disorder as well as people diagnosed with conditions such as Alzheimer's, Parkinson's, Lewy body dementia, vascular dementia, schizophrenia and bipolar disorder. The research identified patterns shared across some of the diseases as well as some specific 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 work was conducted as part of the PsychAD research consortium, with support from the National Institute on Aging, part of the US government's National Institutes of Health. Strong similarities Alzheimer's, Lewy body disease, vascular dementia and Parkinson's showed particularly strong similarities in gene activity involved in nerve-cell development, neuronal communication and blood-vessel biology. The researchers also identified pathways shared in Alzheimer's and Parkinson's in microglia, the brain's resident immune cells. Comparing brain samples from donors of different ages, the researchers found extensive molecular changes during development until adulthood, relative stability through much of adulthood and then renewed changes later in life, particularly in immune and support cells. "This provides a reference for distinguishing typical aging from disease-associated changes," Roussos said. The researchers identified approximately age 24 as a transition point after which the bulk of most cell types in this region become more stable. "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 researchers found cellular patterns associated with differences in cognition and with depression accompanying Alzheimer's. For instance, people who retained cognitive function despite experiencing substantial Alzheimer's pathology showed differences in energy-related processes in brain cells. "These provide clues to possible protective mechanisms that need further testing," Roussos said. Inherited genetic risk The researchers connected inherited genetic risk of disorders to particular genes and cell types, and mapped genetic influences on the activity of more than 14,000 genes. They also reconstructed daily patterns of gene activity using brain samples from people who died at different times of day. In younger and middle-aged adults, daily clock genes showed coordinated patterns in neurons. In older adults, those patterns were weaker and less synchronized. "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. The researchers also built molecular profiles for individual donors who had Alzheimer's, and identified differences in gene regulation and predicted interactions between cell types among individuals. "This helps explain biological variation among people with the same diagnosis, and provides a foundation for investigating more individualized treatment strategies," Roussos said.