Here we review recent breakthroughs in our understanding of how the γ-secretase complex recognizes substrates, of how it binds and processes β-secretase cleaved APP into different Aβ species, as well as the progress made on a question of outstanding interest, namely how clinical AD mutations in the catalytic subunit presenilin and the γ-secretase cleavage region of APP lead to relative increases of Aβ42/43. The gene discussed is APP; the disease is Alzheimer disease.