Interplay Between 3D Chromatin Architecture and Gene Regulation at the APOE Locus Contributes to Alzheimer’s Disease Risk

The ε4 allele of the apolipoprotein E (<i>APOE</i>) gene strongly increases Alzheimer's disease (AD) risk, though its molecular mechanisms remain unclear. AD-associated genetic signals also extend to neighboring genes <i>TOMM40</i> and <i>APOC1</i>, suggesting a complex cis-regulatory landscape. To investigate chromatin architecture and its impact on gene regulation across this region, we performed chromosome conformation capture in human cell lines and postmortem brain tissues, consistently identifying <i>TOMM40</i>-<i>APOE</i> and <i>APOE</i>-<i>APOC1</i> interactions. We further developed a digital PCR assay to quantify <i>APOE</i>-<i>APOC1</i> interaction strength and measured <i>APOC1</i> mRNA via RT-qPCR. Enhanced chromatin interaction correlated with elevated <i>APOC1</i> transcription in AD specimens. Genotypic analysis showed that ε3/ε4 carriers had strong chromatin interaction and transcriptional activation, whereas ε4/ε4 homozygotes exhibited minimal chromatin remodeling despite similar <i>APOC1</i> expression, suggesting a decoupling of chromatin architecture and transcriptional output. These findings underscore the interplay of AD status, <i>APOE</i> genotype, and locus-specific chromatin dynamics in disease susceptibility. Integration of 3D genome topology with transcriptomic profiling offers a framework to study <i>APOE</i>-related disorders and supports broader application across neurodegenerative loci for genotype-guided therapy development.