Irvine, Calif., November 12, 2025 — Scientists at the UC Irvine Charlie Dunlop School of Biological Sciences have uncovered how subtle changes in gene regulation may drive the onset and progression of Alzheimer’s disease and Pick’s disease, two devastating brain disorders that rob millions of memory, personality and independence. The study, led by Associate Professor Vivek Swarup and published in Science Advances, opens new doors for understanding why these diseases unfold differently and how future treatments could target the root causes of brain cell deterioration.
Both Alzheimer’s and Pick’s disease belong to a family of neurodegenerative disorders called “tauopathies,” characterized by the abnormal buildup of tau protein in the brain. While these diseases share some features, their symptoms and progression can vary dramatically. Alzheimer’s disease typically affects memory and thinking, while Pick’s disease primarily alters personality and behavior. Until now, scientists have not fully understood why.
“Our findings show that gene regulation — not just gene expression — drives neurodegeneration in tauopathies like Alzheimer’s and Pick’s,” said Sudeshna Das, a postdoctoral scholar and co-first author of the study. “By integrating single-nucleus transcriptomic and epigenomic analyses, we pinpointed disease- and cell-type–specific enhancer-promoter interactions and transcription factor networks that underlie pathological changes.” Das added that discovering both shared and distinct genetic mechanisms “provides new insight into why these disorders diverge clinically.”
Using a powerful combination of single-cell technologies, the team examined brain tissue at an unprecedented level of detail, analyzing how DNA and its regulatory switches behave differently in healthy and diseased brains. This “multi-omics” approach allowed them to map the interactions between genetic regions that control which genes are turned on or off in specific brain cells.
One key breakthrough was the discovery of a human-evolved enhancer — a kind of molecular “on switch” — that regulates a gene called UBE3A, known for its critical role in maintaining healthy brain function. When the team experimentally disrupted this enhancer in lab-grown neurons using CRISPR gene-editing tools, the cells showed a decrease in UBE3A expression, confirming the enhancer’s vital role in brain cell health.
“The biggest challenge was uncovering meaningful regulatory signals within millions of single-cell profiles spanning different brain regions and diseases,” said Zechuan Shi, a PhD candidate and lead author. “We built tailored computational approaches to investigate these complex data and validated key predictions in stem-cell–derived neurons. This allowed us to bridge computational discovery with biological mechanisms.”
The researchers also created an interactive online database, scROAD, enabling scientists worldwide to explore the regulatory maps revealed in the study. This open-access tool is expected to accelerate discoveries across the field of neurodegenerative disease research.
Associate Professor Swarup emphasized that the study not only advances scientific understanding but also charts a course for precision medicine. “Future research needs to focus on using large-scale genomic and molecular data to better understand what drives these conditions at the cellular level,” he said. “By combining information from DNA, RNA and epigenetic studies, scientists can uncover how genetic changes influence brain function and disease progression. Artificial intelligence will play a key role in analyzing these massive datasets, identifying hidden patterns and predicting which molecular pathways are most critical for disease development.”
The study was supported by funding from the National Institute on Aging, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Adelson Medical Research Foundation, and National Institute on Aging predoctoral fellowships. Federal investment in foundational research like this remains crucial to unraveling the complex biology of neurodegenerative diseases and to paving the way for new, life-changing treatments.
About the University of California, Irvine Charlie Dunlop School of Biological Sciences:
Recognized for its pioneering research and academic excellence, the Charlie Dunlop School of Biological Sciences plays a crucial role in the university’s status among the nation’s top 10 public universities, as ranked by U.S. News & World Report. It offers a broad spectrum of degree programs in the biological sciences, fostering innovation and preparing students for leadership in research, education, medicine and industry. Nestled in a globally acclaimed and economically vibrant community, the school contributes to the university’s impact as Orange County’s largest employer and a significant economic contributor. Through its commitment to exploring life’s complexities, the Dunlop School embodies the UC Irvine legacy of innovation and societal impact. For more on the Charlie Dunlop School of Biological Sciences, visit https://www.bio.uci.edu/.