Genetic Burden and APOE Methylation in a Korean Multi-Generational Alzheimer’s Disease Family: An Exploratory Multi-Omics Case Study

<b>Background/Objectives</b>: Alzheimer's disease (AD) exhibits high heritability (60-80%), yet individual-level genetic risk prediction remains challenging. While <i>APOE</i> ε4 is the strongest genetic risk factor, incomplete penetrance complicates risk assessment. <b>Methods</b>: We analyzed seven blood-related members across three generations using the Korean Chip v2.0 genotyping (~1.2 M SNPs) and Illumina EPICv2 DNA methylation profiling. Genetic burden score (GBS) was calculated by summing risk alleles across 320 variants in six AD-associated genes (<i>APOE</i>, <i>PICALM</i>, <i>CLU</i>, <i>CR1</i>, <i>BIN1</i>, and <i>ABCA7</i>). <b>Results</b>: An unexpected pattern was observed in this family: the affected individual (J-003) had the lowest GBS (39 alleles), while individuals with higher genetic burden (51-61 alleles) remained cognitively healthy. J-003 also exhibited lower <i>APOE</i> methylation (β = 0.495) compared to the family mean (β = 0.523). <i>CR1</i> contributed the most risk alleles across the family, followed by <i>PICALM</i>. <b>Conclusions</b>: This single-case observation cannot establish causality, generalizability, or biological significance. The affected individual's lower APOE methylation may represent a causal factor, disease consequence, or coincidental variation-scenarios that cannot be distinguished from this dataset. Validation in larger cohorts with multiple affected individuals is required to determine whether integrated multi-omics approaches can inform personalized risk assessment in familial contexts.