IL7R⁺ T Cell-Macrophage Crosstalk Links Asthma to Alzheimer's Pathogenesis: Integrating Mendelian Randomization and...

Epidemiological investigation has revealed a higher incidence of Alzheimer's disease (AD) in individuals with severe asthma. However, the causality of this relationship remains uncertain. The current research aimed to examine the potential link between genetically predicted moderate to severe asthma and the risk of AD using Mendelian randomization (MR) analysis.

Summary statistics obtained from genome-wide association studies of AD (n = 455,258) and moderate to severe asthma (n = 57,695) in individuals of European ancestry were utilized in this MR study. SMR analysis was also performed to investigate whether the expression of these genes was correlated with AD or moderate to severe asthma outcomes to detect a causal relationship between moderate to severe asthma and AD. Genome-wide genetic correlation between moderate to severe asthma and AD was estimated using linkage disequilibrium score regression (LDSC). Single-cell RNA sequencing (scRNA-seq) datasets of asthma-related peripheral blood mononuclear cell (PBMC) data and AD cerebrospinal fluid (CSF) were obtained to further investigate the crosstalk between the different biological pathways in asthma and AD.

The impact of moderate to severe asthma on AD risk persisted (OR_IVW = 1.01, 95% CI = 1.00-1.02, p = 3.85 × 10^-3) after controlling for confounder risk factors in multivariable MR analyses. Additionally, the study showed that 1.8% of the total effect (moderate to severe asthma) was mediated by eosinophils. SMR analysis and the gene-wide MR analysis revealed numerous gene targets linked to the susceptibility of AD and moderate to severe asthma. Among these targets, FPR1 (Formyl Peptide Receptor 1), IL1RAP (Interleukin 1 Receptor Accessory Protein), IL7R (Interleukin 7 Receptor), and IL18RAP (Interleukin 18 Receptor Accessory Protein) warrant additional exploration as potential therapeutic targets for AD and moderate to severe asthma. LDSC analysis revealed no significant overlap between asthma and AD (rg = 0.0436, SE = 0.0813, p = 0.592), suggesting distinct genetic architectures. Integrated single-cell RNA sequencing analysis of asthma PBMCs and AD CSF revealed IL7R may utilize the MIF-CD74-CXCR4 pathway to complete crosstalk between CD4 T cells and macrophages and contribute to AD disease development.