Targeting Alzheimer's with cell-specific genetics

Developing treatments for Alzheimer's disease (AD) is difficult because complex underlying mechanisms drive different types of cells that may contribute to the disorder. Microglia and astrocytes, resident immune and support cells in the central nervous system, are known to exclusively express several genes linked to risk of AD -; particularly AD dementia. However, it was previously unclear exactly how and when these genetic risk factors contributed to other, distinct stages of AD progression, such as the accumulation of amyloid-β plaques and tau tangles.

Researchers led by a team at Brigham and Women's Hospital, a founding member of the Mass General Brigham healthcare system, identified the impact of AD genetic risk specific to each major brain cell type on key disease processes. They implemented single nucleus RNA sequencing to calculate cell-type-specific AD polygenic risk scores from two large clinical research study datasets.

Using autopsy data spanning all stages of disease severity, along with independent neuroimaging data from asymptomatic, preclinical stages of AD, the investigators were able to characterize the contributions of cell-specific risk genes. Astrocyte-specific genetic risk contributed to earlier stages of disease progress, like amyloid-β accumulation, while microglia-specific risk played a part in later phases of plaque and tau tangle accumulation, and cognitive decline.

Our results provide human evidence for how genetic risk in specific brain cells affects AD processes, some even before the onset of clinical symptoms. Future studies could extend our technique to other aspects of AD or even other diseases, in order to help develop targeted treatments."

Hyun-Sik Yang, MD, Department of Neurology, Brigham and Women's Hospital