Levels of circulating memory CD8 T cells that induce AD‐like pathology in mice correlate with cognition and decreased CSF Aβ1‐42 in AD and control patients

Abstract Background We previously engineered mice to accumulate 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 where their levels accurately tracked the disease in initial analysis. Here, we examine whether levels of these blood T cells are associated with established AD biomarkers. 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. Although the paucity of APP‐specific CD8 T cells in AD blood precluded meaningful correlations, decreases in the larger parental (KLRG1 + ) memory CD8 T cell population correlated with decreased CSF Aβ1‐42 in AD (r = 0.511; P = 0.003; n = 31). Decreasing APP‐specific CD8 T cells in blood also correlated with lower CSF Ab1‐42 in normal aging patients (r = 0.518; P = 0.028; n = 18). No significant correlations between T cell levels and total Tau or pTau181 were observed. Conclusion Our results reveal that age‐related memory CD8 T cells in blood decrease with dementia, and in proportion to decreased CSF Aβ1‐42 in both AD and normal aging. Given that decreased CSF Aβ1‐42 is among the earliest biomarkers for AD, this validates our previous findings that loss of APP‐specific memory CD8 T cells from blood accurately tracks the AD continuum in humans. Our findings also support the notion that antigen‐specific memory CD8 T cells are associated with the earliest detectable pathologic changes in AD, and as such may represent novel cause‐associated biomarker candidates to predict and track the disease.