Immune system-associated genes in patients with Alzheimer's disease

Background Alzheimer's disease (AD) has been linked to the immune system, but the role of immune-related genes in AD remains unclear. Objective To investigate the association between immune-related genes and AD risk systematically. Methods Whole-genome sequencing (WGS) was performed on 1516 AD patients and 2010 controls. Genetic analysis of 8260 immune-related genes was conducted using PLINK 1.9 for common variants (MAF ≥ 0.01) and SKAT-O test for rare variants (MAF < 0.01). Molecular docking and RNA-seq were used to investigate the effects of SAMD9 variants on protein function and their role in immune system and AD pathogenesis. In a subset of 184 AD patients and 118 controls, the relationship between polygenic risk scores (PRS) and plasma biomarkers was examined. Results Significant associations were observed between common variants in APOE and ABCA7 and AD. Two rare missense variants in SAMD9 (F222L, I1389T) were suggestively linked to AD. Molecular docking and RNA-seq indicated that SAMD9 F222L is a loss-of-function variant, affecting immune-related pathways. A rare missense variant in HRH1 was associated with the plasma Aβ 42 /Aβ 40 ratio. PRS of immune-related genes correlated with AD biomarkers (NfL, ptau181, ptau217, ptau231, and GFAP). Conclusions Common variants in APOE and ABCA7 , along with rare missense variants in SAMD9 and HRH1 , are linked to AD. The SAMD9 F222L variant was associated with altered immune-related gene expression, suggesting a potential link to AD pathogenesis. Immune-related gene PRS correlates with AD biomarkers, highlighting the immune system's role in AD in the Chinese population.