Prior to 2007, rare autosomal dominant mutations in APP, PSEN1, and PSEN2 were known to cause early-onset familial AD. 27 These loci have atypically large effect sizes, which facilitated identification using “past generation” technologies like candidate gene association and genome-wide linkage studies (Table S2). Treatments for AD based on these findings have been developed and are undergoing testing. Rare SV duplications containing APP have been associated with AD. 28,29 Small exome sequencing studies of AD have been published, 30,31 and larger studies are in progress and should provide a more nuanced understanding of the role of rare exonic mutations in the pathogenesis of AD.
