Peripheral immunomodulatory effects of Apolipoprotein E4 on Alzheimer's disease - Immune Enrichment

Apolipoprotein E (APOE) is a lipid and cholesterol transport molecule known to influence Alzheimer's disease (AD) risk in an isoform-specific manner. In particular, the APOE E4 allele is the largest genetic risk factor for late-onset sporadic AD. Our recent findings uncovered activated, clonally expanded T cells in AD cerebrospinal fluid (CSF). This T cell phenotype occurred concomitantly with altered expression of APOE in CSF monocytes. Yet, whether APOE variants differentially affect peripheral immunity systems remains unknown. In this study, we performed targeted immune profiling using single-cell epigenetic and transcriptomic analysis of peripheral blood mononuclear cells (PBMC). We analyzed 55 age-matched healthy control (HC) and AD patients with equal distribution of APOE E3/E3, E3/E4, and E4/E4 genotypes. We reveal dysregulation in monocytes and clonally expanded T cells that are distinct to AD patients carrying the APOE E4/E4 genotype. Additionally, we find APOE isoform-dependent chromatin accessibility differences that correspond to RNA expression changes. Cumulatively, these results uncover APOE isoform-dependent changes to peripheral immunity in AD.