Levels of blood memory CD8 T cells that induce AD‐like pathology in mice correlate with decreased Aβ42 and increased total Tau in CSF of AD patients

Abstract Background We previously engineered mice to accumulate elevated levels of age‐related, antigen‐specific memory CD8 T cells as in humans. These mice spontaneously develop all major hallmarks of AD with aging. Analogous T cells reactive to an epitope on Amyloid Precursor Protein (APP) were found in aging humans, accumulated in AD brain, and decreased in AD blood. Here, we examine whether their levels are associated with established AD biomarkers in CSF. Method Antigen‐specific CD8 T cells in blood were quantified by flow cytometric analysis after staining with anti‐CD8, anti‐KLRG1 and APP peptide‐HLA‐A2 multimers in normal aging, MCI with or without AD biomarkers, and confirmed late‐onset AD patient cohorts (n = 50). Aβ1‐42, total Tau, and pTau181 were quantified in CSF, and cognitive performance assessed by MMSE. Result Percentage of APP‐specific memory CD8 T cells was significantly decreased with dementia (0.68 + 0.29% for MMSE <25; 1.63 + 0.32% for MMSE >24), reaching minimal levels in AD blood, which precluded meaningful correlations in AD patients. Nevertheless, increasing levels of APP‐specific memory CD8 T cells in blood from all subjects combined corresponded with increased CSF Aβ1‐42 (r = 0.373, P < 0.0004) and decreased total Tau but not pTau181 or MMSE (r = ‐0.234, P < 0.0292; r = ‐0.208, P < 0.0531; and r = ‐0.009, P < 0.9410, respectively). Decreases in the larger parental (KLRG1 + ) memory CD8 T cell population also correlated with decreased CSF Aβ1‐42 in AD patients alone (r = 0.511, P = 0.003 for % KLRG1 + of CD8 T cells; r = 0.682, P < 0.00009 for % KLRG1 + CD8 + cells; n = 31). Conclusion Our results reveal that age‐related memory CD8 T cells in blood decrease with dementia, and in proportion to decreased CSF Aβ1‐42 and total Tau in all patients, while their parental KLRG1 + population is directly proportional to Aβ1‐42 in AD patients only. This validates our previous findings that loss of APP‐specific memory CD8 T cells from blood accurately tracks the AD continuum, and support the notion that antigen‐specific memory CD8 T cells are associated with the earliest detectable pathologic changes in AD.