Authors: Sirkis, D. W., Warly Solsberg, C., Johnson, T. P., Bonham, L. W., Oddi, A. P., Geier, E. G., Miller, B. L., Rabinovici, G. D., & Yokoyama, J. S.

Abstract: Introduction: Altered immune signatures are emerging as a central theme in neurodegenerative disease, yet little is known about immune responses in early-onset Alzheimer’s disease (EOAD).

Methods: We examined single-cell RNA-sequencing (scRNA-seq) data from peripheral blood mononuclear cells (PBMCs) and droplet digital polymerase chain reaction (ddPCR) data from CD4 T cells from participants with EOAD and clinically normal controls.

Results: We analyzed PBMCs from 16 individuals by scRNA-seq and discovered increased interferon signaling-associated gene (ISAG) expression and striking expansion of antiviral-like ISAGhi T cells in EOAD. Isolating CD4 T cells from 19 individuals, including four cases analyzed by scRNA-seq, we confirmed increased expression of ISAGhi marker genes. Publicly available cerebrospinal fluid leukocyte scRNA-seq data from late-onset mild cognitive impairment and AD also revealed increased expression of interferon-response genes.

Discussion: Antiviral-like ISAGhi T cells are expanded in EOAD. Additional research into these cells and the role of heightened peripheral IFN signaling in neurodegeneration is warranted.

Highlights: Interferon-responsive T cells expanded in early-onset Alzheimer’s disease (AD). Increased interferon-associated gene expression present in early- and late-onset AD. Peripheral immune changes in T and NK cells driven by females with early-onset AD.