The rs6859 polymorphism in NECTIN2 demonstrates measurable effects on hippocampal brain volume, potentially explaining its established connection to Alzheimer's disease susceptibility. This genetic variant appears to influence neurodegeneration patterns in the brain region most critical for memory formation and early AD pathology. The finding provides a mechanistic bridge between genetic predisposition and observable brain changes that precede clinical symptoms. NECTIN2's role in cellular adhesion and immune function may create vulnerability pathways that compound over decades. This research strengthens the evidence for genetic risk stratification in neurodegenerative disease, where identifying high-risk individuals before symptom onset becomes increasingly valuable for preventive interventions. The hippocampal volume connection is particularly significant because structural changes in this region often appear years before cognitive decline becomes clinically apparent. While genetic variants like rs6859 represent non-modifiable risk factors, understanding their mechanisms opens avenues for targeted neuroprotective strategies. The work contributes to the growing recognition that Alzheimer's emerges from complex interactions between genetic susceptibility, environmental factors, and immune system dysfunction rather than single causative pathways.