In the past 10 years, next-generation sequencing (NGS) paved the way for groundbreaking discoveries in AD, showing that Mendelian rare disorders offer a unique window into the sporadic complex traits and, particularly, that rare alleles in TREM2, TYROBP, and NOTCH3, causative for adult-onset leukodystrophies, significantly influence the susceptibility for AD (Guerreiro et al., 2012, Guerreiro et al., 2013, Ma et al., 2015). This evidence concerns the gene TREM2 and Alzheimer disease.