Investigating a CD8+ T cell age‐associated gene signature in Alzheimer's disease

Abstract

AbstractBackgroundNeuroinflammation has been linked with the pathologic progression of Alzheimer’s disease (AD). Previous studies focused primarily on the innate immune system; however, there are few human studies evaluating the potential relationships between adaptive immune cells and the development of AD pathology. Alterations in the immune system occur with aging, likely contributing to increased infection, malignancy and inflammation in older adults. One of the most prominent immune changes with age includes the expansion of memory CD8+ T cells in peripheral blood. Notably, cytotoxic IL‐7 receptor alpha low (IL‐7Rα or CD127low) CD45RA+ effector memory (EM) CD8+ T cells (TEMRA) have been associated with dementia and mild cognitive impairment (MCI) due to AD. In addition, our lab recently discovered an age‐associated gene expression signature of IL‐7Rα low EM CD8+ T cells. Thus, we hypothesized that individuals with AD have altered levels of IL‐7Rα low EM CD8+ T cell aging gene expression.MethodsA total of 40 genes which include 9 IL‐7Rαlow aging genes and 31 genes previously reported to be associated with AD and/or memory were analyzed in peripheral blood of 82 participants with AD and 40 cognitively normal age‐balanced participants by quantitative polymerase chain reaction (qPCR). Gene expression data was analyzed utilizing one‐way ANOVA, principal component analysis (PCA), and unbiased hierarchical clustering analysis.ResultsEight genes were differentially expressed (P < 0.05) between cognitively normal participants and participants with MCI or dementia due to AD. These genes included 5 IL‐7Ralow aging genes (GZMH, NUAK1, TGFBR3, PRSS23, OSBPL5), 2 genes related to AD and/or memory (CD163, CYP4F3) and a gene related to both aging and AD (PADI4). The expression levels of IL‐7Ralow aging genes moderately correlated with those of AD and memory genes. PCA and clustering analysis suggest IL‐7Ralow aging genes may be associated with disease status in a subset of AD subjects.ConclusionsAn altered CD8+ T cell age‐associated gene signature is present in AD patients, warranting further studies investigating biological implications of CD8+ T cells, especially highly cytotoxic and inflammatory IL‐7Rαlow EM CD8+ T cells, in AD.