The identification of amyloid-β precursor protein (APP) pathogenic mutations in familial early onset Alzheimer's disease (AD), along with knowledge that amyloid-β (Aβ) was the principle protein component of senile plaques, led to the establishment of the amyloid cascade hypothesis. Down syndrome substantiated the hypothesis, given an extra copy of the APP gene and invariable AD pathology hallmarks that occur by middle age. An abundance of support for the amyloid cascade hypothesis followed. Prion-like protein misfolding and non-Mendelian transmission of neurotoxicity are among recent areas of investigation. Aβ-targeted clinical trials have been disappointing, with negative results attributed to inadequacies in patient selection, challenges in pharmacology, and incomplete knowledge of the most appropriate target. There is evidence, however, that proof of concept has been achieved, i.e., clearance of Aβ during life, but with no significant changes in cognitive trajectory in AD. Whether the time, effort, and expense of Aβ-targeted therapy will prove valuable will be determined over time, as Aβ-centered clinical trials continue to dominate therapeutic strategies. It seems reasonable to hypothesize that the amyloid cascade is intimately involved in AD, in parallel with disease pathogenesis, but that removal of toxic Aβ is insufficient for an effective disease modification.