Terminally differentiated effector memory T cells associate with cognitive and AD-related biomarkers in an aging-based community cohort.

Background and purpose: The immune response changes during aging and the progression of Alzheimer's disease (AD) and related dementia (ADRD). Terminally differentiated effector memory T cells (called T_EMRA) are important during aging and AD due to their cytotoxic phenotype and association with cognitive decline. However, it is not clear if the changes seen in T_EMRAs are specific to AD-related cognitive decline specifically or are more generally correlated with cognitive decline. This study aimed to examine whether T_EMRAs are associated with cognition and plasma biomarkers of AD, neurodegeneration, and neuroinflammation in a community-based cohort of older adults.

Methods: Study participants from a University of Kentucky Alzheimer's Disease Research Center (UK-ADRC) community-based cohort of aging and dementia were used to test our hypothesis. There were 84 participants, 44 women and 40 men. Participants underwent physical examination, neurological examination, medical history, cognitive testing, and blood collection to determine plasma biomarker levels (Aβ42/Aβ40 ratio, total tau, Neurofilament Light chain (Nf-L), Glial Fibrillary Acidic Protein (GFAP)) and to isolate peripheral blood mononuclear cells (PBMCs). Flow cytometry was used to analyze PBMCs from study participants for effector and memory T cell populations, including CD4⁺ and CD8⁺ central memory T cells (T_CM), Naïve T cells, effector memory T cells (T_EM), and effector memory CD45RA⁺ T cells (T_EMRA) immune cell markers.

Results: CD8⁺ T_EMRAs were positively correlated with Nf-L and GFAP. We found no significant difference in CD8⁺ T_EMRAs based on cognitive scores and no associations between CD8⁺ T_EMRAs and AD-related biomarkers. CD4⁺ T_EMRAs were associated with cognitive impairment on the MMSE. Gender was not associated with T_EMRAs, but it did show an association with other T cell populations.

Conclusion: These findings suggest that the accumulation of CD8⁺ T_EMRAs may be a response to neuronal injury (Nf-L) and neuroinflammation (GFAP) during aging or the progression of AD and ADRD. As our findings in a community-based cohort were not clinically-defined AD participants but included all ADRDs, this suggests that T_EMRAs may be associated with changes in systemic immune T cell subsets associated with the onset of pathology.