Functional Effects of CD33 SNP rs12459419 on Microglial Gene Regulation and Alzheimer’s Disease Risk

Abstract The SNP rs12459419 in exon 2 of the CD33 gene alters mRNA splicing, influencing the expression of a truncated isoform lacking the IgV domain. This isoform enhances amyloid-beta clearance by microglia and is associated with a reduced risk of Alzheimer’s disease (AD). In this study, we integrate transcriptomic, genomic, epigenomic, and population genetics data to test the hypothesis that rs12459419 regulates CD33 expression in a genotype-dependent manner. We leveraged public datasets including GTEx, 1000 Genomes, ENCODE, and UCSC Genome Browser. Our findings indicate that the T allele of rs12459419 is significantly associated with decreased CD33 expression in microglia-rich tissues, occurs within an accessible chromatin region marked by active histone modifications, and varies in frequency across global populations. These results support a regulatory role for rs12459419 in microglial gene expression with implications for AD pathogenesis and precision medicine. Competing Interest Statement The authors have declared no competing interest. Footnotes Add the keywords in the abstract section for better clarification.