APP and Alzheimer disease: The initial GWAS data rapidly led to a reappraisal of the amyloid cascade hypothesis based on Aβ accumulation and toxicity in both familial and early onset forms of AD where Aβ peptides rapidly accumulate due to their accelerated overproduction (e.g., associated with mutations in APP, PSEN1 and PSEN2), and in late-onset forms, due to a slight, insidious Aβ clearance impairment (associated with several GWAS-defined genes) [80].