PSEN1 and Alzheimer disease: Several studies have pointed out how various PSEN1 and APP mutations lead to pathogenic phenotypes in isogenic human cell lines and how substitution of the mutant with the wild-type allele can reverse that pathology.40, 41, 42 Most PSEN1 mutations, such as PSEN1 M146L, lead to increased production of the more aggregation-prone Aβ42 that is known to form Aβ plaques in the AD brain.