Peripheral innate immunophenotype in neurodegenerative disease: blood-based profiles and links to survival

Abstract

AbstractThe innate immune system plays an integral role in the progression of many neurodegenerative diseases. In addition to central innate immune cells (e.g. cerebral microglia), peripheral innate immune cells (e.g. blood monocytes, natural killer cells, and dendritic cells) may also differ in these conditions. However, the characterization of peripheral innate immune cell types across different neurodegenerative diseases remains incomplete. This study aimed to characterize peripheral innate immune profiles using flow cytometry for immunophenotyping of peripheral blood mononuclear cells, in n=148 people with Alzheimer’s disease (AD), Frontotemporal Dementia (FTD), Corticobasal syndrome (CBS), Progressive Supranuclear Palsy (PSP), Lewy Body Disease (LBD) as compared to n=37 healthy controls. To compare groups, we used Principal Component Analysis and multivariate Dissimilarity analysis across 19 innate immune cell types. We identified pro-inflammatory profiles that significantly differ between patients with all-cause dementia and healthy controls, with some significant differences between groups. Regression analysis confirmed that time to death following the blood test correlated with the individuals’ immune profile weighting, positively to TREM2+ and nonclassical monocytes and negatively to classical monocytes. Taken together, these results describe transdiagnostic peripheral immune profiles and highlight the link between prognosis and the monocyte cellular subdivision and function (as measured by surface protein expression). The results suggest that blood-derived innate immune profiles can inform sub-populations of cells relevant for specific neurodegenerative diseases that are significantly linked to accelerated disease progression and worse survival outcomes across diagnoses. Blood-based innate immune profiles may contribute to enhanced precision medicine approaches dementia, helping to identify and monitor therapeutic targets and stratify patients for candidate immunotherapies.