Recent advances in transcriptomics research have uncovered heightened interferon (IFN) responses in neurodegenerative diseases including Alzheimer's disease, primary tauopathy, Parkinson's disease, TDP-43 proteinopathy, and related mouse models. Augmented IFN signaling is now relatively well established for microglia in these contexts, but emerging work has highlighted a novel role for IFN-responsive T cells in the brain and peripheral blood in some types of neurodegeneration. These findings complement a body of literature implicating dysregulated IFN signaling in neuropsychiatric disorders including major depression and post-traumatic stress disorder. In this review, we will characterize and integrate advances in our understanding of IFN responses in neurodegenerative and neuropsychiatric disease, discuss how sex and ancestry modulate the IFN response, and examine potential mechanistic explanations for the upregulation of antiviral-like IFN signaling pathways in these seemingly non-viral neurological and psychiatric disorders.

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 ISAG^hi T cells in EOAD. Isolating CD4 T cells from 19 individuals, including four cases analyzed by scRNA-seq, we confirmed increased expression of ISAG^hi 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 ISAG^hi 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.