APP and Alzheimer disease: A rare mutation (with a minor allele frequency [MAF] of <1%) in APP had a protective effect against AD in Icelanders [5], whilst a rare mutation in the Phospholipase D family member 3 (PLD3) gene segregates in two families with late-onset AD (LOAD) and doubles the risk of AD in European and African American cases/control samples [6], but this association failed to replicate in a subsequent study [7].