Neuroinflammation-induced neurodegeneration and immune cell infiltration are two features of Alzheimer disease (AD). This study aimed to identify potential peripheral biomarkers that interact with cerebrospinal fluid (CSF) and infiltrating immune cells in AD. Blood and CSF data were downloaded from the Alzheimer’s disease Neuroimaging Initiative database. We identified differentially expressed genes (DEGs) in AD and assessed infiltrating immune cells using the Immune Cell Abundance Identifier (ImmuCellAI) algorithm. Blood-brain barrier (BBB) and immune-related genes were identified from medical databases, and common genes were used to construct a protein-protein interaction network (PPI). Potential biomarkers reflecting the clinical features of AD were screened using Pearson correlations and logistic regression analysis. We identified 210 DEGs in the AD group. ImmuCellAI indicated that blood samples from patients with AD had a higher abundance of exhausted T (Tex; 0.196 vs. 0.132) and induced regulatory T (iTreg; 0.180 vs. 0.137) cells than controls. Thirty-two genes overlapped between the BBB and immune-related genes, and 27 genes in the PPI network were associated with eight pathways, including the cytokine-cytokine receptor interaction pathway (hsa04060) and the chemokine signaling pathway (hsa04062). Pearson correlations showed that five genes were associated with the CSF biomarkers, Aβ, total, and phosphorylated tau. Logistics analysis showed that the B cell-associated genes, CXCL12 and TNFRSF13C, were independent risk factors for AD diagnosis. Peripheral CXCL12 and TNFRSF13C genes that correlated with immune cell infiltration in AD might serve as easily accessible biomarkers for the early diagnosis of AD.

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