A systems immunology analysis of Alzheimer's disease reveals an age‐ and environmental exposure‐independent disturbance in B cell maturation

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INTRODUCTION: Alzheimer's disease is a severe neurodegenerative disorder, with multifactorial mechanisms of disease development and progression. Evidence from genetic association studies, animal models, and clinical investigation suggests a neuroimmunological component to disease, with links to the peripheral immune system. METHODS: Here we applied a systems immunology approach to determine the immunological correlates of Alzheimer's disease. Using high-dimensional flow cytometry and machine learning, we comprehensively assessed the cellular component of the peripheral immune system in a well-characterized cohort of 184 Alzheimer's patients and 105 healthy spouses. RESULTS: Using this approach, Alzheimer's patients demonstrated a disturbance in B cell maturation, a feature that was associated not only with disease status but also with cognitive decline. This effect was age and environmental exposure independent, suggesting a disease-intrinsic relationship between Alzheimer's disease and B cell maturation. DISCUSSION: These results provide an underexplored avenue for improving both mechanistic understanding and therapeutic design in Alzheimer's disease. HIGHLIGHTS: A systems immunology analysis on a cohort of 184 patients with Alzheimer's disease (AD) and 105 healthy spouses. AD demonstrated a defect in B cell maturation, associated with more cognitive decline. The B cell maturation association was age and environmental exposure independent. Additional peripheral immunological changes were associated with AD.

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