Summary

The peripheral immune system in Alzheimer's disease (AD) has not been thoroughly studied with modern sequencing methods. To investigate epigenetic and transcriptional alterations to the AD peripheral immune system, we used single-cell sequencing strategies, including assay for transposase-accessible chromatin and RNA sequencing. We reveal a striking amount of open chromatin in peripheral immune cells in AD. In CD8 T cells, we uncover a cis-regulatory DNA element co-accessible with the CXC motif chemokine receptor 3 gene promoter. In monocytes, we identify a novel AD-specific RELA transcription factor binding site adjacent to an open chromatin region in the nuclear factor kappa B subunit 2 gene. We also demonstrate apolipoprotein E genotype-dependent epigenetic changes in monocytes. Surprisingly, we also identify differentially accessible chromatin regions in genes associated with sporadic AD risk. Our findings provide novel insights into the complex relationship between epigenetics and genetic risk factors in AD peripheral immunity.

Overall design

Peripheral blood mononuclear cells from healthy control and Alzheimer's disease patients, matched for age, sex, and APOE genotype. Samples were thawed, FACS sorted for live cells, and profiled using scRNA-seq and scV(D)J-seq (BCR and TCR). Peripheral blood mononuclear cells from healthy control and Alzheimer's disease patients, matched for age, sex, and APOE genotype. Samples were thawed, FACS sorted for live cells, lysed to isolate nuclei, and profiled using scATAC-seq.

Contributors

Abhirami Ramakrishnan†, David Gate✉️

Contact

dgate@northwestern.edu(David Gate)