Expansion of highly interferon‐responsive T cells in early‐onset Alzheimer's disease

Abstract

INTRODUCTIONAltered 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).METHODSWe 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.RESULTSWe 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.DISCUSSIONAntiviral‐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.