Although previous studies have provided conclusive evidence that recessive genetic variations within increase AD susceptibility and cause AD in Caucasian and Japanese populations [15–19], our results suggest that-high order recessive genetic interactions between PSEN1 and the set of genes reported herein have a significant modifier effect on ADAOO in individuals with AD from the Paisa genetic isolate. The gene discussed is PSEN1; the disease is Alzheimer disease.