APP and early-onset autosomal dominant Alzheimer disease: The pattern of cleavage of APP-C99 results in a primary isoform, Aβ40 consisting of 40 amino acids, in addition to minor isoforms including Aβ38 and Aβ42.2 Aberrant accumulation of Aβ42 over Aβ40 has been associated with the formation of amyloid-β plaques in the brain of Alzheimer's disease (AD) patients.2,3 As such, developing an understanding of the mechanism of cleavage of APP-C99 by γ-secretase is an important goal for the field.