The Peripheral Immune-Sleep- Cognition Axis Across Diagnostic Stages of Alzheimer’s Disease

Peripheral immune dysregulation and sleep disturbances are recognized early features of Alzheimer’s disease (AD), but the mechanistic interplay between these domains is poorly understood. Here, we present a large-scale, integrated single-cell analysis of the peripheral immune landscape across the AD spectrum. We performed paired single-cell RNA sequencing (scRNA-seq) and T cell receptor sequencing (scTCR-seq) on peripheral blood mononuclear cells (PBMCs) from 79 deeply phenotyped individuals, including 26 healthy controls (HC), 25 people with mild cognitive impairment (MCI) and 28 with mild dementia due to AD. By integrating transcriptomic profiles with sleep monitoring (actigraphy and self-report), multi-domain cognitive testing, and structural neuroimaging, we identified disease stage-specific remodeling of the cytotoxic landscape. Specifically, we characterized distinct natural killer (NK) and T cell immunophenotypes and restricted TCR repertoires that change with disease progression. Our analysis reveals a systemic signature linking cytotoxic lymphocyte activation and systemic inflammatory cytokines to impaired sleep quality and cognitive performance. Crucially, we demonstrate that these alterations are potentially reversible: Ex-vivo mixed lymphocyte reaction (MLR) assays using an anti-PD-L1 antibody reveal significant differences in CD8 ⁺ and CD4 ⁺ T cell responses in MCI, showing pronounced sensitivity to checkpoint modulation. Furthermore, we identify cerebrospinal fluid (CSF) TREM2 as a potential predictive biomarker for response to immune stimulation. Collectively, our study establishes novel links between peripheral immunosurveillance, cognition and sleep disturbances, supporting the modulation of the peripheral immune system as a novel therapeutic strategy in AD.