More than seven million Americans aged 65 years and older currently live with Alzheimer’s disease, according to recent estimates from the Alzheimer’s Association. As the prevalence of the disease increases, so does the need for research that identifies underlying mechanisms of disease to enhance the effectiveness of current therapies and inform new therapeutic strategies.
At the frontline of this effort are Feinberg investigators, who are taking innovative new approaches to addressing the gaps in treatment. One investigator, David Gate, PhD, assistant professor in the Ken and Ruth Davee Department of Neurology’s Division of Behavioral Neurology, leads Feinberg’s new Abrams Research Center on Neurogenomics. Gate’s research aims to understand how the brain and the immune system communicate and how mitigating changes to the immune system in Alzheimer’s patients could help fight disease, a growing field in Alzheimer’s research over the last decade.
The center, which was founded in fall 2024 and part of the Feinberg Neuroscience Institute, is unique in that it seeks to leverage artificial intelligence to generate datasets that reveal genes and cell types affected by Alzheimer’s disease, findings that can further elucidate new therapeutic targets. The center was established with support from Jim and Wendy Abrams and the Eleven Eleven Foundation.
“Our mission is to discover new biology of Alzheimer’s disease using novel analytic approaches,” Gate said.
At the heart of the center is collaboration, Gate said. The center collaborates with research institutions across the U.S. and around the world to analyze tissue samples from patients both currently living with Alzheimer’s disease and deceased people with Alzheimer’s disease.
The center is also home to state-of-the-art lab equipment, including a first-of-its-kind spatial transcriptomics machine called CytAssist. Data that is generated by the center is also widely shared with the Alzheimer’s disease research community, a top priority for the center, according to Gate.
“We are not keeping all these data for ourselves. We want to share it with the world so that other people can utilize these important datasets,” Gate said.
Harnessing the Brain’s Immune Response
In March, Gate’s team discovered that the brain’s immune cells, called microglia, cleared amyloid-beta plaques, a key feature of Alzheimer’s disease, in brain tissue samples from deceased people with Alzheimer’s disease who received amyloid-beta immunization therapy. The scientists, who used spatial transcriptomics to identify the spatial location of gene activity inside the tissue samples, also discovered these microglia helped promote a healthier brain environment.
Their findings, published in Nature Medicine, could help shift therapeutic approaches for Alzheimer’s disease, from removing these plaques to instead harnessing the brain’s natural immune response.
“Our study is highly novel because we had the rare opportunity to analyze one of the largest post-mortem brain cohorts of Alzheimer’s patients treated with amyloid-targeting drugs, similar to those now approved by the FDA for Alzheimer’s disease,” said Lynn van Olst, PhD, research assistant professor of Neurology who was lead author of the study. “This allowed us to investigate the brain mechanisms that determine why some individuals respond well to these treatments and successfully clear toxic amyloid-beta, while others do not. We found that brain immune cells play a crucial role in this process and identified the molecular genetic factors that drive these differences.”
Building off their findings, Gate said his team will study immune response to these drugs in patients living with Alzheimer’s to better understand why some patients respond to the drug better than others.
“These kinds of studies are very complicated. It’s very difficult to run a study of patients who are on drugs like this, so it requires a lot of collaboration with the clinicians who we work closely with,” Gate said. “If we can define the mechanisms that are associated with clearance of the pathology, and we can find the genetic makeup of immune cells that are associated with people that are really responding well to the drug, then maybe one day we can circumvent the whole drug process and just target these specific cells.”
Pinpointing Therapeutic Targets and Disease Risk
Research from the Mesulam Center for Cognitive Neurology and Alzheimer’s Disease has long contributed to what we know about Alzheimer’s disease. In a recent review published in Neurotherapeutics, Robert Vassar, PhD, the Davee Professor of Alzheimer Research and director of Mesulam Center, discussed the role of the gut microbiome in the regulation of astrocytes — a subtype of glial cells that make up the central nervous system — in Alzheimer’s disease. Further, he outlined how the gut microbiome’s regulation of innate and adaptive immunity could be a promising therapeutic avenue for Alzheimer’s disease.
“We’ve discovered that a short-chain fatty acid, propionate, made in the gut by certain bacteria, can suppress specific adaptive immune cells linked with inflammation. The result is less inflamed astrocytes and fewer amyloid plaques in the brain,“ Vassar said.
Vassar said propionate may represent a new therapeutic agent for Alzheimer’s disease, and that another study is forthcoming, accepted for publication by the Journal of Clinical Investigation.
Another study published in the journal Molecular Psychiatry, in which Vassar was a co-collaborator, revealed new insights into how the previously understudied duplicate X chromosome in women may contribute to Alzheimer’s disease risk.
In the study, the investigators performed an X-chromosome-wide association study of more than 115,000 cases of Alzheimer’s disease and more than 613,000 controls. From their analysis, they identified seven X-chromosome-wide significant loci, on the genome where mutations were associated with increased risk of Alzheimer’s.
“Genetics has been the foundation of all of the advances we’ve seen in Alzheimer’s disease research over the last three decades,” Vassar said. “I think this, along with the immunotherapies that have been developed from that genetic research, do indicate that we’re on the right track. If we keep staying the course, we hope to see a day when Alzheimer’s disease will be just a memory.”
