For decades, the hypothesis that brain deposition of the amyloid β protein initiates Alzheimer's disease has dominated research and clinical trials. Targeting amyloid β is starting to produce therapeutic benefit, although whether amyloid-lowering drugs will be widely and meaningfully effective is still unclear. Despite extensive in-vivo biomarker evidence in humans showing the importance of an amyloid cascade that drives cognitive decline, the amyloid hypothesis does not fully account for the complexity of late-life cognitive impairment. Multiple brain pathological changes, inflammation, and host factors of resilience might also be involved in contributing to the development of dementia. This variability suggests that the benefits of lowering amyloid β might depend on how strongly an amyloid pathway is manifest in an individual in relation to other coexisting pathophysiological processes. A new approach to research and treatment, which fully considers the multiple factors that drive cognitive decline, is necessary.