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Only 5% of EOAD patients are carrying a pathogenic mutation in one of the AD genes or a apolipoprotein E (<jats:italic>APOE<\/jats:italic>) risk allele \u03b54, most of EOAD patients remain unexplained. Here, we aimed at summarizing the current knowledge of EOAD genetics and its role in ongoing approaches to understand the biology of AD and disease symptomatology as well as developing new therapeutics. Next, we explored the possible molecular mechanisms that might underlie the missing genetic etiology of EOAD and discussed how the use of massive parallel sequencing technologies triggered novel gene discoveries. 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