Expansion of interferon signaling-associated gene (ISAG)-hi T cells in early-onset Alzheimer's disease

Abstract

Importance: Altered immune signatures are emerging as a central theme in neurodegenerative disease, yet little is known about immune responses in early-onset Alzheimer9s disease (EOAD). Objective: To determine whether an EOAD-specific immune signal can be detected in blood. Design: We examined single-cell RNA-sequencing (scRNA-seq) data from peripheral blood mononuclear cells (PBMCs) and droplet digital (dd)PCR data from CD4 T cells from participants with EOAD and clinically normal controls. Setting: University of California, San Francisco Memory and Aging Center. Participants: Samples were collected for the study from 2017 to 2021. Participants with EOAD were diagnosed with AD prior to age 65. Data were last analyzed September 2023. Main Outcomes and Measures: The primary analysis (scRNA-seq) examined whether EOAD was associated with altered frequency of any PBMC subsets. Secondary analysis (ddPCR) measured marker gene expression in CD4 T cells. Results: Over 182,000 individual PBMC transcriptomes were analyzed by scRNA-seq from 16 individuals (mean [SD] age at sample collection, 52.2 [9.6] years; 8 [50.0%] were female; 8 [50.0%] had clinical diagnosis of AD). The relative abundance of PBMC subsets was tested for association with EOAD while controlling for age and sex. Of 19 PBMC clusters, one cluster, representing interferon signaling-associated gene (ISAG)-hi T cells, was significantly expanded in EOAD (P = 0.005). A validation cohort consisting of 19 individuals (mean [SD] age at sample collection, 57.7 [4.1] years; 13 [68.4%] were female; 9 [47.4%] had clinical diagnosis of AD) was used for CD4 T cell isolation and ddPCR analysis. Expression of MX1 and IFI6, marker genes for ISAG-hi T cells, was significantly elevated in participants with EOAD (P = 0.002 and P = 0.04, respectively). Secondary analyses of independent scRNA-seq datasets from later-onset AD and familial tauopathy indicated that ISAG-hi T cells are detected but not elevated in these related diseases. Conclusions and Relevance: ISAG-hi T cells, which appear primed for antiviral activity, are significantly and specifically expanded in EOAD. Additional research into the role of this rare cell type in neurodegeneration is warranted.