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

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 (dd)PCR data from CD4 T cells from participants with EOAD and clinically normal controls. RESULTS: We analyzed ~182,000 PBMCs by scRNA-seq and discovered increased interferon signaling-associated gene (ISAG) expression and striking expansion of antiviral-like ISAG-hi T cells in EOAD. We isolated CD4 T cells from additional EOAD cases and 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: ISAG-hi T cells, apparently primed for antiviral activity, are expanded in EOAD. Additional research into these cells and the role of heightened peripheral IFN signaling in neurodegeneration is warranted. ### Competing Interest Statement Sources of Funding: J.S.Y. receives funding from NIH-NIA R01AG062588, R01AG057234, P30AG062422, P01AG019724, and U19AG079774; NIH-NINDS U54NS123985; NIH-NIDA 75N95022C00031; the Rainwater Charitable Foundation; the Bluefield Project to Cure Frontotemporal Dementia; the Alzheimer's Association; the Global Brain Health Institute; the French Foundation; and the Mary Oakley Foundation. C.W.S. is supported in part by the NIH Intramural Center for Alzheimer's and Related Dementias (CARD), project NIH-NIA ZIAAG000534. G.D.R. receives research funding from Avid Radiopharmaceuticals, GE Healthcare, Life Molecular Imaging, and Genentech. The content of this publication is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Disclosures: J.S.Y. serves on the scientific advisory board for the Epstein Family Alzheimer's Research Collaboration. G.D.R. has received consulting fees from Alector, Eli Lilly, Genentech, Roche, and Merck. He receives fees for serving on a DSMB for Johnson & Johnson. B.L.M. serves as medical advisor for the French Foundation; serves as scientific advisor for the Larry L. Hillblom Foundation, the Association for Frontotemporal Degeneration, the NIHR Cambridge Biomedical Research Centre and its subunit, the Biomedical Research Unit in Dementia, and the Buck Institute for Research on Aging; serves as external advisor for the University of Washington ADRC, Stanford University ADRC, Arizona Alzheimer's Disease Center, and Massachusetts ADRC; and serves on the external advisory committee for the University of Southern California P01 Urban Air Pollution and Alzheimer's Disease: Risk, Heterogeneity and Mechanisms.