Dr. Cao heads the Laboratory of Single-Cell Genomics and Population Dynamics, which has pioneered efficient methods for profiling the organization of DNA in millions of brain cells and tracking dynamic changes in the brain in real time. The lab’s work has revealed region-specific and cell-type-specific changes in human Alzheimer’s brains, as well as shown that Alzheimer’s is not only linked to altered cellular states but also to shifts in cellular dynamics. These findings have provided valuable insights into the vulnerability of Alzheimer’s and set the stage for future investigations aimed at identifying the key genes and cells contributing to the disease.

Dr. Cao’s lab is now focusing on the use of artificial intelligence (AI) to devise state-of-the-art genomic techniques to map the human brain. They have recently developed TrackerSci, a powerful technique that allows scientists to observe how brain cells change across different stages of life. By labeling and tracking tens of thousands of individual cells, this method reveals how certain types of brain cells decrease with age while others—especially inflammatory cells—become more common. These observations will help researchers understand the early biological changes that lead to Alzheimer’s disease. (A patent application for TrackerSci has been filed.)

• The first objective is to systematically map cellular interactions in the brain and decipher the driver cells behind Alzheimer’s onset and progression. Dr. Cao’s team has developed a scalable brain-mapping method, named IRIS (Imaging Reconstruction by Indexed Sequencing), to reconstruct brain cell connections on an unprecedented scale. Unlike conventional microscopy, IRIS utilizes DNA barcoded beads to capture gene expression across each of thousands of spatial locations, with the global spatial positions of these beads decoded through their interaction signals with adjacent beads. With this technique, Dr. Cao and his colleagues aim to track changes in cellular interactions within Alzheimer’s brains, as well as to clarify changes in the expression of molecules responsible for altered cellular interactions. This in-depth exploration will enable them to identify driver cells that transmit molecular signals influencing changes in other cell types. These driver cells and their outgoing signals will then be targeted therapeutically in lab experiments to evaluate their potential for delaying the initiation and the progression of Alzheimer’s disease.
• The lab’s second objective is to develop effective single-cell screening techniques to pinpoint the crucial genes driving Alzheimer’s disease. To reverse the brain changes observed in Alzheimer’s patients, it is critical to identify the specific genes responsible for these alterations across various cell types. Dr. Cao’s team has developed innovative approaches for large-scale genetic screening to that end. One of them is PerturbSci-Kinetics, a method that enables single-cell-resolution assessment of gene expression and RNA dynamics following thousands of genetic perturbations and genetic inhibitions. This technique has made it possible to assess millions of cellular state changes in response to thousands of genetic perturbations across various cell types associated with Alzheimer’s disease. It will allow scientists to systematically identify the key gene drivers contributing to the cell state changes occurring in Alzheimer’s disease. These gene drivers will form the basis of potential therapeutic targets to reverse cellular changes and restore brain function in Alzheimer’s patients.

Dr. Cao believes both of these objectives are well within reach, thanks to close partnerships with other research teams at The Rockefeller University, including the Zachary and Elizabeth M. Fisher Center for Research on Alzheimer’s Disease, which has pioneered groundbreaking approaches to the study of cellular and pathological transformations in Alzheimer’s disease. These collaborations, combined with novel genomics methodologies, will enable Dr. Cao’s team to gain a better understanding of the molecular and cellular alterations of Alzheimer’s disease. This will help them to identify key components of the disease, with the ultimate aim of improving therapeutic strategies, restoring normal brain function, and finding a cure.