Altered T-cell reactivity in the early stages of Alzheimer's disease.

The adaptive immune system and neurodegenerative Alzheimer's disease (AD) are intertwined in multiple ways. Recent studies have reported alterations of the adaptive immune system in early AD stages, such as preclinical AD and mild cognitive impairment (MCI) due to AD. However, the identity of specific antigenic targets and whether the respective response is beneficial or detrimental during disease progression are still open questions. Herein, we describe cross-sectional analyses of blood and CSF from three different study populations covering early AD stages. We employed high-dimensional mass cytometry, single-cell RNA-sequencing, ex vivo T-cell secretome analysis, and antigen presentation assays to achieve a comprehensive characterization of adaptive immune cell populations. Our results show that subjects at the stage of asymptomatic, preclinical AD can mount a CD4+ T helper cell response towards amyloid-β peptide and display an early enrichment of CD8+ T effector memory cells re-expressing CD45RA (TEMRA cells) in CSF, combined with a less immunosuppressive gene signature of peripheral regulatory T cells. Conversely, in MCI we observed increased frequencies of CD8+ TEMRA/effector cells in the periphery characterized by a pro-inflammatory gene expression profile, and generally decreased antigen responsiveness. Our results demonstrate the complexity of adaptive immune changes in early AD and suggest that it may be beneficial to promote specific CD4+ T-cell responses in the preclinical stage, while in MCI it may be important to therapeutically target CD8+ T-cell responses if these prove to be harmful.