Cell type-specific Alzheimer’s disease polygenic risk scores (ADPRS). A A diagram of cell type-specific PRS derivation. b An UpSetR plot of cell type-specific gene sets used to define cell type-specific ADPRS. Each cell type-specific gene set includes genes in the top 10% of cell type specificity (not = 1343). Each row of the matrix represents each set of cell type-specific genes, and each column of the matrix represents an intersection of one or more sets. The gene sets at each intersection were indicated by filled black circles connected by a black vertical line. The vertical bar graph at the top shows the number of genes in each intersection. The 15 most frequent intersections have been visualized. vs, d Correlation matrix between cell type specific ADPRS (vs ROSMAP; d A4). The Pearson correlation coefficient was positive for all pairs, and the square of the Pearson correlation coefficient (R2) between pairs of cell types was visualized. The source data is provided as a source data file. Ast astrocytes, excitatory Ex neurons, in inhibitory neurons, Mic microglia, Oli oligodendrocytes, Opc oligodendroglial progenitor cells, single core RNA sequencing snRNA-Seq. Credit: Natural communications(2023). DOI: 10.1038/s41467-023-43132-2
Developing treatments for Alzheimer’s disease (AD) is challenging because complex underlying mechanisms determine different cell types that may contribute to the disease. Microglia and astrocytes, resident immune and supportive cells of the central nervous system, are known to exclusively express several genes linked to AD risk, particularly AD dementia.
However, it was unclear how and when these genetic risk factors contribute to other distinct stages of AD progression, such as the accumulation of amyloid-β plaques and tau tangles.
Researchers led by a team from Brigham and Women’s Hospital, a founding member of the Mass General Brigham Health 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, as well as independent neuroimaging data from asymptomatic and preclinical stages of AD, investigators were able to characterize the contributions of cell-specific risk genes. Astrocyte-specific genetic risk contributed to early stages of disease progression, such as amyloid-β accumulation, while microglia-specific risk played a role in later stages of plaque accumulation and d entanglements of tau and cognitive decline.
“Our results provide human evidence of how genetic risk in specific brain cells affects AD processes, some even before clinical symptoms appear,” said Hyun-Sik Yang, MD, of the Department of Neurology. . “Future studies could extend our technique to other aspects of AD or even other diseases to contribute to the development of targeted treatments.”
The research is published in the journal Natural communications .
More information:
Hyun-Sik Yang et al, Cell type-specific Alzheimer’s disease polygenic risk scores are associated with distinct pathological processes in Alzheimer’s disease, Natural communications(2023). DOI: 10.1038/s41467-023-43132-2
Provided by Brigham and Women’s Hospital
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