Abstract

Fast and minimally invasive approaches for early, preclinical diagnosis of neurodegenerative Alzheimers disease (AD) are highly anticipated. Evidence of adaptive immune cells responding to cerebral {beta}-amyloidosis, one of the pathological hallmarks of AD, has raised the question of whether immune markers could be used as proxies for {beta}-amyloid accumulation in the brain. Here, we deploy multidimensional mass cytometry combined with unbiased machine learning techniques to immunophenotype peripheral blood mononuclear cells from study participants in cross-sectional and longitudinal cohorts. We show that increases in antigen-experienced adaptive immune cells in the blood, particularly CD45RA-reactivated T effector memory (TEMRA) cells, are associated with early accumulation of brain {beta}-amyloid and with changes in plasma AD biomarkers in still cognitively healthy subjects. Our results suggest that preclinical AD pathology is linked to systemic alterations of the adaptive immune system. These immunophenotype changes may help in the future to identify and develop novel diagnostic tools for early AD assessment and to better understand clinical outcomes.