Building a molecular brain map to understand Alzheimer’s disease

Less than a decade ago, when Dr. Hansruedi Mathys launched an ambitious project to create an annotated library of all the gene readouts stored within 100 individual brain cells, the task felt daunting.

Now, with technological advances, Mathys successfully mapped out such ‘transcriptomes’ from not just 100, but from 1.3 million brain cortex cells from 48 individuals with and without Alzheimer’s disease.

Mathys, who pioneered single-cell transcriptomic analysis on post-mortem human brain tissue during his postdoctoral training and is now an assistant professor of neurobiology at the University of Pittsburgh School of Medicine, says that the resulting atlas of the aging human brain holds molecular insights into the brain’s vulnerability and resilience.

“I am extremely interested in understanding the phenomenon of cognitive resilience where, despite the characteristic signs of Alzheimer’s tissue pathology, individuals display no cognitive impairment,” Dr. Mathys said. “Our recent findings have made me more hopeful than ever that it might be possible to artificially induce such resilience in people who otherwise are susceptible to memory loss.”

In the study, published this week in Nature, Mathys and his colleagues at the Massachusetts Institute of Technology analyzed transcriptomes of cells across six distinct brain regions that are often affected by Alzheimer's pathology. The resulting atlas, which is now available online to researchers worldwide, could be used as a tool for gene and molecular discovery across pathways affecting brain health.

By tracking how transcriptomic changes are linked to cognitive decline and Alzheimer's pathology, Mathys and his colleagues discovered that astrocytes – one of the cell types that make up the brain tissue scaffold alongside maintaining a host of other crucial functions – could be holding a key to cognitive resilience. Mathys’ ongoing research, which resulted from the transcriptome mapping, aims to explore the functional significance of altering astrocyte metabolic pathways to affect cognitive function.

“There is still a lot to learn about Alzheimer’s disease and the human brain,” said Mathys. “This project is just the beginning.”