Molecular Mechanisms of Perivascular Macrophages in Alzheimer's Disease: Insights from Single-Cell Sequencing and Mendelian Randomization.

Alzheimer's disease (AD) is a leading cause of dementia characterized by neuroinflammation and immune dysregulation. Perivascular macrophages (PVMs) play a crucial role in the onset and progression of AD, yet the specific molecular mechanisms remain understudied. This study explored the molecular mechanisms of PVMs in AD using single-cell sequencing combined with Mendelian randomization (MR) analysis. We analyzed data from GSE264648 and eQTLGen and identified four key genes that were significantly associated with AD risk: IFNGR1, KLHL5, NUMB, and WDFY4. Functional annotation revealed that PVMs were involved in immune regulation and metabolic pathways, particularly IL-6_JAK_STAT3 and Notch signaling. Immune infiltration analysis showed increased M2 macrophages in AD patients, suggesting their roles in neuroinflammation. Pseudo-time analysis highlighted developmental shifts in PVMs during disease progression. Our findings offer novel insights into the role of PVMs in AD and provide a foundation for future research on modulating neuroinflammation and slowing AD progression through PVM-targeted interventions.