Abstract Background A mutation in presenilin 1 (E280A) causes early‐onset Alzheimer's disease. Understanding the origin of this mutation will inform medical genetics. Methods We sequenced the genomes of 102 individuals from Antioquia, Colombia. We applied identity‐by‐descent analysis to identify regions of common ancestry. We estimated the age of the E280A mutation and the local ancestry of the haplotype harboring this mutation. Results All affected individuals share a minimal haplotype of 1.8 Mb containing E280A. We estimate a time to most recent common ancestor of E280A of 10 (95% credible interval, 7.2–12.6) generations. We date the de novo mutation event to 15 (95% credible interval, 11–25) generations ago. We infer a western European geographic origin of the shared haplotype. Conclusions The age and geographic origin of E280A are consistent with a single founder dating from the time of the Spanish Conquistadors who began colonizing Colombia during the early 16th century.