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

• Published in: Immunity & ageing Vol. 20; no. 1; pp. 71 - 13
• Main Authors: Young, Juan Joseph, Park, Hong-Jai, Kim, Minhyung, Par-Young, Jennefer, Bartlett, Hugh, Kim, Hye Sun, Unlu, Serhan, Osmani, Lais, Shin, Min Sun, Bucala, Richard, van Dyck, Christopher H., Allore, Heather, Mecca, Adam P., You, Sungyong, Kang, Insoo
• Format: Journal Article
• Language: English
• Published: London BioMed Central 02.12.2023; Springer Nature B.V; BMC
• Subjects: Adaptive immunity; Aging; Alzheimer's disease; Antibodies; Biomedical and Life Sciences; Biomedicine; CD8 antigen; Clinical Nutrition; Cognition; Cognitive ability; Cytokines; Cytotoxicity; Datasets; Dementia; Dementia disorders; DNA methylation; Gene expression; Geriatrics/Gerontology; Immune system; Immunological memory; Immunology; Inflammation; Lymphocytes; Lymphocytes T; Measuring techniques; Memory; Memory cells; Neurodegenerative diseases; Older people; Pathogenesis; Pathology; Peripheral blood; Psychology; Public Health; Risk factors; Senescence; T cell; Transcriptomics; Aging; Senescence; Adaptive immunity; Alzheimer’s disease; Transcriptomics; T cell
• ISSN: 1742-4933; 1742-4933
• DOI: 10.1186/s12979-023-00396-y

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.