Scientists have identified how a small number of overactive genes may drive widespread changes in brain function in Down syndrome, helping explain how an extra chromosome affects learning and memory.
SINGAPORE, 26 FEBRUARY 2026—Scientists from Duke-NUS Medical School, working with collaborators at Imperial College London and partners in Europe and the United States, have uncovered new insights into how an additional copy of chromosome 21 alters brain development in Down syndrome.
Down syndrome is caused by an additional copy of chromosome 21, but for decades, scientists have struggled to understand how this extra chromosome leads to intellectual disability. The new study, published in Nature Medicine, helps open this long standing “black box” by identifying three key genes on chromosome 21 that act as master regulators of brain-related genetic activity.
The researchers found that these three genes are overactive in human brain cells derived from individuals with Down Syndrome, disrupting the normal activity of hundreds of other genes involved in learning and memory. Together, these widespread changes may help explain how an extra chromosome reshapes brain function.
To explore whether these effects could be modulated, the team used a modern molecular approach known as antisense oligonucleotides or ASOs: short, synthetic strands of genetic material designed to precisely reduce the activity of specific genes. When the researchers “turned down” the activity of the three overactive genes in laboratory-grown human brain cells, they observed a partial restoration of more typical gene activity patterns.
While this work is early-stage and conducted entirely in the lab, it provides proof of concept that some of the molecular changes associated with Down Syndrome may be biologically adjustable, offering a new framework for understanding the condition.
Dr Michael Lattke, Department of Brain Sciences, Faculty of Medicine at Imperial College London and first author of the study, said:
“Our study shows how combining advanced technologies for analysing, modelling and modulating gene activity can reveal new biological insights into complex conditions. By identifying key genetic regulators and demonstrating that their activity can be adjusted in human brain cells, we provide a foundation for future research into Down syndrome.”
Down syndrome is also the most common genetic cause of Alzheimer’s disease, and individuals with Down syndrome have a much higher lifetime risk of developing Alzheimer’s-related brain changes. By clarifying how chromosome 21 disrupts gene regulation in brain cells, the findings may help inform future studies into shared biological pathways between these conditions, though the researchers stress that clinical applications remain a long-term goal.
Professor Vincenzo De Paola, is from the Neuroscience & Behavioural Disorders Signature Research Programme at Duke-NUS. The senior author of the study, who is also Honorary Professor in the Department of Brain Sciences, Faculty of Medicine at Imperial College London, said:
“This discovery would have been impossible without the families who contributed to this research, and we are profoundly grateful for their generosity. By analysing individual cells at unprecedented scale and depth, we uncovered previously unresolved molecular mechanisms and moved closer to understanding the root causes of Down syndrome’s neurological features. Benchmarking current in vitro and humanised in vivo models against primary fetal tissue allowed us to define a practical roadmap to help the field choose the most appropriate experimental systems to study specific aspects of the condition.”
Professor Lok Sheemei, Duke-NUS’ Interim Vice-Dean for Research, said:
“This study exemplifies how fundamental research can illuminate the biological mechanisms behind complex conditions. The result is more than a dataset. It is a new framework for understanding how Down syndrome unfolds at the cellular level. The atlas pinpoints specific genes, pathways, and cell populations that may drive neurological changes, offering potential targets for future therapies.”
The research team is now focused on understanding the functional consequences of adjusting these key drivers, including whether normalising their activity can influence how brain cells grow and form connections. The researchers have filed a patent related to their methods and are using advanced human neural models to test whether targeting specific combinations of genes may be necessary to meaningfully influence brain cell function.
Duke-NUS is a global leader in medical education and a biomedical research powerhouse, combining basic scientific research with translational know-how to bring a better understanding to common diseases and develop new treatment approaches to improve the lives of people in Singapore and beyond.