Peripheral T-cell co-signalling states mark vulnerability and resilience to cerebral Aβ pathology

This bioRxiv preprint investigates how adaptive immune responses may influence vulnerability and resilience in Alzheimer's disease (AD), focusing on T-cell states. Using mass cytometry to profile peripheral immune cells from 200 participants across distinct age groups, early AD, and exceptional old age without dementia, the researchers related immune features to amyloid-beta (Aβ) PET, plasma biomarkers, and longitudinal structural and cognitive outcomes.

Inducible T-cell co-stimulator (ICOS) expression across CD4 and CD8 memory T-cells was associated with cerebral Aβ pathology. In mild cognitive impairment (MCI), higher ICOS expression on CD8 memory T-cells strengthened the association between Aβ load and hippocampal atrophy, suggesting a vulnerability-promoting role. In an independent cohort, Aβ-derived peptides induced proliferative ICOS+CD25+ memory CD4 and CD8 T-cell responses predominantly in Aβ-positive participants, indicating an antigen-specific T-cell reaction.

Conversely, higher programmed cell death protein 1 (PD-1) expression on CD8 effector-memory T-cells was associated with attenuated Aβ-related episodic-memory decline in exceptionally old participants and was higher in stable MCI than in MCI-to-AD converters, pointing to a resilience-associated co-inhibitory state. The findings identify distinct co-stimulatory and co-inhibitory T-cell correlates of vulnerability and resilience, highlighting peripheral adaptive immunity as a potential modifier of AD progression.