Origin of the PSEN1 E280A mutation causing early-onset Alzheimer's disease

Alzheimers Dement. 2014 Oct;10(5 Suppl):S277-S283.e10. doi: 10.1016/j.jalz.2013.09.005. Epub 2013 Nov 13.


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.

Keywords: Alzheimer’s disease; PSEN1; population genetics; whole-genome sequencing.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Age of Onset
  • Alzheimer Disease / genetics*
  • Colombia
  • European Continental Ancestry Group / genetics
  • Founder Effect
  • Genetic Predisposition to Disease*
  • Haplotypes
  • Humans
  • Inheritance Patterns
  • Mutation*
  • Presenilin-1 / genetics*


  • PSEN1 protein, human
  • Presenilin-1