Aging gene signature of memory CD8+ T cells is associated with neurocognitive functioning in Alzheimer's disease.

Background: Memory CD8⁺ T cells expand with age. We previously demonstrated an age-associated expansion of effector memory (EM) CD8⁺ T cells expressing low levels of IL-7 receptor alpha (IL-7Rα^low) and the presence of its gene signature (i.e., IL-7Rα^low aging genes) in peripheral blood of older adults without Alzheimer's disease (AD). Considering age as the strongest risk factor for AD and the recent finding of EM CD8⁺ T cell expansion, mostly IL-7Rα^low cells, in AD, we investigated whether subjects with AD have alterations in IL-7Rα^low aging gene signature, especially in relation to genes possibly associated with AD and disease severity.

Results: We identified a set of 29 candidate genes (i.e., putative AD genes) which could be differentially expressed in peripheral blood of patients with AD through the systematic search of publicly available datasets. Of the 29 putative AD genes, 9 genes (31%) were IL-7Rα^low aging genes (P < 0.001), suggesting the possible implication of IL-7Rα^low aging genes in AD. These findings were validated by RT-qPCR analysis of 40 genes, including 29 putative AD genes, additional 9 top IL-7R⍺^low aging but not the putative AD genes, and 2 inflammatory control genes in peripheral blood of cognitively normal persons (CN, 38 subjects) and patients with AD (40 mild cognitive impairment and 43 dementia subjects). The RT-qPCR results showed 8 differentially expressed genes between AD and CN groups; five (62.5%) of which were top IL-7Rα^low aging genes (FGFBP2, GZMH, NUAK1, PRSS23, TGFBR3) not previously reported to be altered in AD. Unbiased clustering analysis revealed 3 clusters of dementia patients with distinct expression levels of the 40 analyzed genes, including IL-7Rα^low aging genes, which were associated with neurocognitive function as determined by MoCA, CDRsob and neuropsychological testing.

Conclusions: We report differential expression of "normal" aging genes associated with IL-7Rα^low EM CD8⁺ T cells in peripheral blood of patients with AD, and the significance of such gene expression in clustering subjects with dementia due to AD into groups with different levels of cognitive functioning. These results provide a platform for studies investigating the possible implications of age-related immune changes, including those associated with CD8⁺ T cells, in AD.