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

BACKGROUND: There 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 Alzheimer's disease (AD), dementia with Lewy bodies (DLB), frontotemporal dementia (FTD) and progressive supranuclear palsy (PSP). This study examines a unique cohort of blood-based T-cell profiles across a range of neurodegenerative dementias including AD, DLB, FTD, corticobasal syndrome (CBS), PSP, and aged-matched healthy controls. Then it also explores their associations with dementia-relevant plasma biomarkers and clinical outcomes. METHODS: Freshly 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. RESULTS: There was a significant reduction in the fraction of CD3+ cells in patients with DLB compared to other diagnostic groups, and an increase in relative Th1/17-like cell levels in patients with FTD compared to controls. This increase in Th1/17-like cells correlated with NfL and GFAP plasma levels in patients with FTD. PCA identified five components primarily representing CD4+ memory cell population subsets. After sex and age adjustments, component 4 marked by effector memory types including Th2-like, Th-like1 and Th1/17-like cells was a significant predictor of FTD, however was not as accurate as plasma NfL. Higher scores in specific T-cell components (1 and 3) were associated with reduced mortality across all diseases, with component 3 remaining a significant predictor even when controlling for traditional neurodegenerative biomarkers like NfL and p-tau217. CONCLUSIONS: This study provides evidence that T-cell dysregulation is not unified in patients with neurodegenerative diseases. We observe different involvement across different dementia types establishing adaptive immunity as a key contributor to disease heterogeneity. However, although plasma biomarkers such as NfL and p-tau217 exhibit superior diagnostic accuracy for clinical classification, peripheral T-cell signature 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.