Advanced optical imaging revealed that mice carrying the APOE4 genetic variant develop distinctive patterns of cerebral blood vessel dysfunction months before typical dementia symptoms emerge. The research identified 36 specific vascular parameters, with venular blood flow velocity reductions and increased vessel tortuosity achieving 90% diagnostic accuracy in distinguishing APOE4 carriers from protective APOE3 variants. The damage occurs in cortical layer-specific patterns, suggesting the brain's hierarchical organization influences vulnerability to vascular decline. This represents a significant advance in understanding how genetic risk translates into measurable brain changes. Current Alzheimer's diagnostics rely heavily on late-stage protein deposits or cognitive testing, often missing the critical window for intervention. These vascular biomarkers could enable detection during the presymptomatic phase when therapeutic interventions might be most effective. However, translation from mouse models to human applications faces substantial hurdles. The imaging techniques require sophisticated equipment and expertise not readily available in clinical settings. Additionally, APOE4 affects roughly 25% of the population, but not all carriers develop dementia, raising questions about specificity. The layer-specific findings suggest that targeted therapies might need to address distinct vascular compartments rather than applying broad neuroprotective approaches.