Blood-based immunophenotyping of T cell profiles in patients with neurodegenerative disorders

BackgroundThere is increasing evidence for the role of central and peripheral inflammation across neurodegenerative disorders, with animal models and post-mortem studies identifying T-cell infiltration in the brain associated with pathology and neurodegeneration. Peripheral T-cell changes have been measured in Alzheimers disease (AD) with conflicting results and limited characterization. This study examines blood-based T-cell profiles across a range of neurodegenerative dementias including AD, dementia with Lewy bodies (DLB), frontotemporal dementia (FTD), corticobasal syndrome (CBS), progressive supranuclear palsy (PSP), and aged-matched healthy controls, testing for associations with dementia-relevant plasma biomarkers and clinical outcomes. MethodsFreshly prepared peripheral blood mononuclear cells (PBMCs) from 174 participants (AD=20, DLB=24, FTD=19, CBS=18, PSP=58, controls=35) were studied using a flow-cytometry panel designed to analyse major T-cell subpopulations, including memory and T-helper subtypes. Neurodegeneration-relevant biomarkers (p-tau217, p-tau231, GFAP, NFL, and A-beta42/40) were measured in plasma samples. T-cell populations were compared between groups and in association with biomarkers, and principal components analysis (PCA) was used to identify T-cell profiles and their association with dementia-relevant biomarkers in diagnostic classification and survival prediction. ResultsThere was a significant reduction in the proportion of CD3+ cells in patients with DLB compared to other diagnostic groups, and an increase in relative Th1/17 cell levels in patients with AD and FTD compared to controls. This increase in Th1/17 cells correlated with NfL and GFAP plasma levels in FTD. PCA identified four components primarily representing CD4+ memory cell population subsets. There was an increase in Th1/17 and Th17 effector memory profiles in AD and FTD. These cellular profiles were limited in diagnostic classification compared to p-tau217 or NfL, but the profile of increased naive CD4+ cells with decreased Th1 effector memory cells was associated with mortality across all diseases. ConclusionsThis study provides evidence for T-cell dysregulation and diagnosis-specific profiles in neurodegenerative diseases, further establishing adaptive immunity as a key contributor to disease heterogeneity. Although plasma biomarkers such as NfL and p-tau217 exhibit superior diagnostic accuracy for clinical classification, peripheral T-cell signatures were associated with survival outcomes across diagnostic groups, highlighting their promise for prognostic applications and disease monitoring. The characterisation of T-cell populations across neurodegenerative conditions may inform target development and patient stratification for new interventional trials.