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bioRxiv · 10.1101/2025.11.07.684725

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

Lu, Y.
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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 Alzheimers 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.

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Lu, Y.. 2025-11-08. Functional Effects of CD33 SNP rs12459419 on Microglial Gene Regulation and Alzheimer's Disease Risk. https://doi.org/10.1101/2025.11.07.684725

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