Exploring peripheral immune mechanisms and potential therapeutic drugs for Alzheimer's disease.

Alzheimer's disease (AD) is a neurodegenerative disorder characterised by cognitive decline. Peripheral immune dysregulation often precedes central immune abnormalities and may therefore provide valuable clues for the early diagnosis and stratification of AD. Current research on peripheral immunity in AD remains limited. This study provides new insights into the pathogenesis and therapeutic strategies for AD. Bioinformatics and single-cell RNA sequencing were used to analyse peripheral immune-related gene expression in AD. Key genes and immune cell populations linked to AD were identified. Quercetin (Que) was selected as a potential therapeutic agent using drug prediction methods. Molecular docking, Western blotting (WB), and qRT-PCR were further performed to preliminarily assess the regulation of these hub genes by quercetin in an H2O2-induced HT22 neuronal oxidative stress model. Several immune-related genes, including ACTB, TP53, HIF1A, and BCL-2, were differentially expressed in AD. Gene function analysis revealed their involvement in processes like apoptosis and viral response. Pathway enrichment analysis highlighted the significance of the p53, apoptosis, and HIF-1 signaling pathways in AD. Single-cell sequencing identified key immune cell populations, such as CD4 + memory cells and NK cells. Drug prediction and experimental results indicated that quercetin may modulate these genes in a neuronal stress context, providing preliminary experimental support for its regulatory effects on AD-related hub genes. This study identified peripheral immune-related molecular features of AD and highlighted several hub genes that may represent shared molecular nodes linking peripheral immune alterations and central neuronal stress responses. The in vitro findings provide preliminary support for the regulatory effects of quercetin on these AD-related hub genes, although further validation in peripheral immune cell and in vivo models is still required.