The amyloid cascade hypothesis of Alzheimer disease (AD) has been increasingly challenged. Here, we aim to refocus the amyloid cascade hypothesis on its original premise that the accumulation of amyloid beta (Aβ) peptide is the primary and earliest event in AD pathogenesis as based on current evidence, initiating several pathological events and ultimately leading to AD dementia. An ongoing debate about the validity of the amyloid cascade hypothesis for AD has been triggered by clinical trials with investigational disease-modifying drugs targeting Aβ that have not demonstrated consistent clinically meaningful benefits. It is an open question if monotherapy targeting Aβ pathology could be markedly beneficial at a stage when the brain has been irreversibly damaged by a cascade of pathological changes. Interventions in cognitively unimpaired individuals at risk for dementia, during amyloid-only and pre-amyloid stages, are more appropriate for proving or refuting the amyloid hypothesis. Our updated hypothesis states that anti-Aβ investigational therapies are likely to be most efficacious when initiated in the preclinical (asymptomatic) stages of AD and specifically when the disease is driven primarily by amyloid pathology. Given the young age at symptom onset and the deterministic nature of the mutations, autosomal dominant AD (ADAD) mutation carriers represent the ideal population to evaluate the efficacy of putative disease-modifying Aβ therapies. Key challenges of the amyloid hypothesis include the recognition that disrupted Aβ homeostasis alone is insufficient to produce the AD pathophysiologic process, poor correlation of Aβ with cognitive impairment, and inconclusive data regarding clinical efficacy of therapies targeting Aβ. Challenges of conducting ADAD research include the rarity of the disease and uncertainty of the generalizability of ADAD findings for the far more common "sporadic" late-onset AD. The amyloid cascade hypothesis, modified here to pertain to the preclinical stage of AD, still needs to be integrated with the development and effects of tauopathy and other co-pathologies, including neuroinflammation, vascular insults, synucleinopathy, and many others.