APOE ε4-associated downregulation of the IL-7/IL-7R pathway in effector memory T cells: Implications for Alzheimer's disease

Abstract

Introduction: The apolipoprotein E (APOE) ε4 allele exerts a significant influence on peripheral inflammation and neuroinflammation, yet the underlying mechanisms remain elusive.

Methods: The present study enrolled 54 patients diagnosed with late-onset Alzheimer's disease (AD; including 28 APOE ε4 carriers and 26 non-carriers). Plasma inflammatory cytokine concentration was assessed, alongside bulk RNA sequencing (RNA-seq) and single-cell RNA sequencing (scRNA-seq) analysis of peripheral blood mononuclear cells (PBMCs).

Results: Plasma tumor necrosis factor α, interferon γ, and interleukin (IL)-33 levels increased in the APOE ε4 carriers but IL-7 expression notably decreased. A negative correlation was observed between plasma IL-7 level and the hippocampal atrophy degree. Additionally, the expression of IL-7R and CD28 also decreased in PBMCs of APOE ε4 carriers. ScRNA-seq data results indicated that the changes were mainly related to the CD4+ Tem (effector memory) and CD8+ Tem T cells.

Discussion: These findings shed light on the role of the downregulated IL-7/IL-7R pathway associated with the APOE ε4 allele in modulating neuroinflammation and hippocampal atrophy.

Highlights: The apolipoprotein E (APOE) ε4 allele decreases plasma interleukin (IL)-7 and aggravates hippocampal atrophy in Alzheimer's disease. Plasma IL-7 level is negatively associated with the degree of hippocampal atrophy. The expression of IL-7R signaling decreased in peripheral blood mononuclear cells of APOE ε4 carriers Dysregulation of the IL-7/IL-7R signal pathways enriches T cells.

Keywords: Alzheimer's disease; apolipoprotein E allele 4; bulk RNA sequencing; hippocampal atrophy; interleukin 7R signaling pathway; peripheral blood mononuclear cells; single‐cell RNA sequencing.

FIGURE 1

Impact of APOE ε4 allele on hippocampal atrophy. (A) Illustration of the method used for measuring hippocampal dimensions. This measurement involves assessing the distance from the upper region of the hippocampus to the lower region of the hippocampus, or to the TB, as observed in MRI oblique coronal slices of the HH and HB. B, In the case of HH slices, APOE ε4 allele carriers exhibited greater height measurements from the left HH to the TB, as well as the height of the right HH, compared to non‐carriers. This difference in measurements highlights the more pronounced hippocampal atrophy observed in APOE ε4 carriers. APOE, apolipoprotein E; HB, hippocampal body; HH, hippocampal head; MRI, magnetic resonance imaging; TB, temporal bottom

FIGURE 2

Correlation of IL‐7 with hippocampal atrophy. A, Correlation analysis illustrating the relationship between 13 inflammatory cytokines and the degree of hippocampal atrophy in the left HH slices. B, Correlation analysis shows the association between 13 inflammatory cytokines and hippocampal atrophy in the right HH slices. C, A significant correlation was observed between IL‐7 levels and the height measurement from the L‐HH to the L‐TB in the L‐HH slice. D, A significant correlation was observed between IL‐7 levels and the height measurement of the L‐HH in the L‐HH slice. E, Strong correlation between IL‐7 levels and the height measurement from the L‐HB to the L‐TB in the L‐HB slice. F, Noteworthy correlation between IL‐7 levels and the height measurement of the L‐HB in the L‐HB slice. HB, hippocampal body; HH, hippocampal head; IL, interleukin; L‐HB, left hippocampal body; L‐HH, left hippocampal head; L‐TB, left temporal bottom

FIGURE 3

Transcriptomic analysis of PBMCs in AD patients with different APOE genotypes. A, PCA reveals distinct gene expression profiles among PBMCs from AD patients with different APOE genotypes, emphasizing the presence of unique transcriptomic profiles associated with varying APOE genotypes. B, A heatmap visualizes the DEGs that distinguish between different APOE genotypes, providing a comprehensive overview of gene expression variations. C, Volcano plots present the DEGs between different APOE genotypes, highlighting specific genes with significant differential expression. D, Bar plots depict the results of Gene Ontology term enrichment analysis for biological processes associated with the DEGs between different APOE genotypes. Notably, terms related to “lymphocyte activation” are among the enriched processes. AD, Alzheimer's disease; APOE, apolipoprotein E; DEGs, differentially expressed genes; PBMCs, peripheral blood mononuclear cells; PCA, principal component analysis

FIGURE 4

Expression of IL‐7R in various PBMCs and its relationship to APOE genotypes. A, This panel visualizes the expression levels of IL‐7R in different PBMC types, providing an overview of IL‐7R expression across distinct cell populations. B, Distribution analysis reveals the prevalence of T cells among different experimental groups, shedding light on variations in T cell populations associated with APOE genotypes. C, A heatmap displays the DEGs identified between individuals with different APOE genotypes within various PBMC populations. This heatmap helps elucidate the specific gene expression differences associated with APOE genotypes within distinct cell types. APOE, apolipoprotein E; DEGs, differentially expressed genes; IL, interleukin; NK, natural killer; PBMC, peripheral blood mononuclear cell

FIGURE 5

Expression of IL7R and associated pathway genes in key cell subpopulations of APOE ε4 carriers and non‐carriers. This figure provides insight into the expression profiles of IL7R and relevant pathway genes within critical cell subpopulations of both APOE ε4 carriers and non‐carriers. It offers a comparative view of how these genes are expressed in distinct cell clusters associated with different APOE genotypes, highlighting potential differences in gene expression patterns. APOE, apolipoprotein E