Background/Objectives: Alzheimer’s disease (AD) exhibits high heritability (60–80%), yet individual-level genetic risk prediction remains challenging. While APOE ε4 is the strongest genetic risk factor, incomplete penetrance complicates risk assessment. Methods: 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 (APOE, PICALM, CLU, CR1, BIN1, and ABCA7). Results: 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 APOE methylation (β = 0.495) compared to the family mean (β = 0.523). CR1 contributed the most risk alleles across the family, followed by PICALM. Conclusions: 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.

Background/Objectives: Type 2 diabetes mellitus (T2DM) is closely associated with obesity, insulin resistance, and gut microbiota dysbiosis. This study investigated the effects of a probiotic combination of Lactiplantibacillus plantarum DM083 and Lacticaseibacillus rhamnosus DM163 on glycemic control, insulin resistance, gut microbiota composition, and metabolic parameters in high-fat-diet (HFD)-induced obese mice. Methods: Male C57BL/6 mice were fed a 60% HFD for 8 weeks and subsequently administered DM083/163 (1 × 10⁹, 5 × 10⁹, or 1 × 10¹⁰ CFU/day) or metformin (250 mg/kg/day) for 12 weeks. Glucose metabolism, insulin resistance, hepatic gene expression, gut microbiota composition, and fecal short-chain fatty acids (SCFAs) were evaluated. Results: DM083/163 supplementation at 1 × 10¹⁰ CFU/day significantly reduced fasting blood glucose, HbA1c, oral glucose tolerance test area under the curve, and HOMA-IR compared with the HFD control group (p < 0.05). Hepatic expression of the gluconeogenic genes Pck1 and G6pc was significantly downregulated, accompanied by reduced hepatic and serum TNF-α levels. Gut microbiota analysis revealed significant overall differences in beta diversity across groups (PERMANOVA, R² = 0.262, p = 0.001), driven primarily by diet, with a trend toward a reduced Bacillota/Bacteroidota ratio in the high-dose group. Conclusions: DM083/163 supplementation improved glycemic control and insulin resistance in HFD-induced obese mice. These effects were associated with suppression of hepatic gluconeogenesis, attenuation of inflammation, and increased SCFA production, findings that are consistent with, but do not establish, modulation of the gut–liver axis. These findings support the potential use of DM083/163 as a probiotic intervention for obesity-associated T2DM.