Researchers have published the largest map to date of gene activity in the human prefrontal cortex, drawing on sequencing data from more than six million individual cells across nearly 1,500 people. Released in a collection of studies, the landmark resource aims to advance research into Alzheimer’s disease and other neurodegenerative and psychiatric conditions.
Building the Largest Single-Cell Brain Map
A detailed brain map has been produced that describes gene activity in neurons, immune cells, and vascular cells within the prefrontal cortex, a brain region that supports planning, decision-making, and behavioural and emotional regulation. The landmark map draws on sequencing data from more than six million individual cells collected from almost 1,500 people, offering unprecedented detail for the study of neurodegenerative and psychiatric diseases.
The research was published in a collection of eight studies, including three papers in Nature. Zhichao Miao, a computational biologist at the Guangzhou National Laboratory in China who was not involved in the work, noted the scale of the undertaking. The scale of this project and the amount of work required to assemble it are genuinely impressive,
Miao said. Single-cell studies of the human brain have traditionally been limited to relatively small numbers of individuals. Pushing us into a population-scale setting changes the kinds of questions we can ask.
To build these maps, the team studied tissue from nearly 1,500 people whose brains were donated to science after their deaths. Donors ranged from infants to a 108-year-old individual, encompassing diverse ancestries and including both neurotypical controls and people diagnosed with one of eight brain disorders: Alzheimer’s disease, dementia with Lewy bodies, Parkinson’s disease, vascular dementia, tauopathy, frontotemporal dementia, schizophrenia, and bipolar disorder.
Consortium Origins and Lifespan Remodelling
Panos Roussos, director of the Center for Disease Neurogenomics at the Icahn School of Medicine at Mount Sinai in New York City and a co-author on all eight papers, explained that the work is the culmination of an effort that began in 2019. The PsychAD Consortium, an NIH-funded partnership between several US institutions, was established to connect genetic variation, ageing, and disease to changes in specific brain cells.
The group focused on the prefrontal cortex because of its role in working memory and executive function. Disruptions to a subregion called the dorsolateral prefrontal cortex are implicated in several psychiatric disorders and types of dementia. To begin their investigation, the researchers conducted a foundational study examining how the human dorsolateral prefrontal cortex changes over a person’s lifespan using healthy brains collected from individuals between less than one and 97 years old.
- A rapid remodelling phase during early life.
- Stability through the mid-life period, beginning from age 24 and older.
- A second phase of remodelling starting at around age 65.
Different cell types displayed distinct patterns of gene activity, including changes linked to early-life brain development and late-life alterations related to immune activity, stress responses, and the brain’s circadian rhythms.
Harmonizing Metadata Across Brain Banks
Brain tissue specimens were sourced from multiple brain banks and prospective cohort studies, including the Mount Sinai NIH Neurobiobank, the NIMH-IRP Human Brain Collection Core, and five prospective cohort studies conducted at the Rush Alzheimer’s Disease Center. Because clinical metadata varied by source, researchers used a harmonization scheme to standardize clinical, pathological, and demographic variables.
To measure Alzheimer’s disease neuropathology, the team utilized the CERAD scoring scheme for neuritic plaque density and the Braak AD-staging score to measure the progression of neurofibrillary tangle neuropathology. For cognitive impairment, researchers used a harmonized variable of cognitive status based on the Clinical Dementia Rating scale and consensus summary diagnoses.
Studying the same region under different conditions enables more consistent comparisons and helps connect our results to existing genetic and molecular studies,
Roussos said. This is an important window into brain disease, but additional regions will be needed to understand the full picture.