For more than three decades, the amyloid cascade hypothesis has framed Alzheimer’s disease (AD) as a disorder in which amyloid-β (Aβ) accumulation initiates a pathological cascade leading to neurodegeneration and cognitive decline. Aβ plaque deposition is a robust pathological feature of AD and a useful biomarker target, yet plaques alone do not explain disease onset, clinical heterogeneity, or the pace of symptomatic change. We propose that fibrillar amyloid plaques do not drive AD pathogenesis and instead represent intermediate products of a broader disease process. This amyloid-centered emphasis has shaped research priorities and drug development aimed at lowering amyloid burden. However, amyloid lowering has not produced consistent, clinically meaningful cognitive benefits, exposing a gap between target engagement and patient-centered outcomes. Here, we reevaluate the evidentiary basis and translational performance of the amyloid model using contemporary trial results, biomarker trajectories, and neuropathological observations. We also analyze the scientific, regulatory, and structural forces that sustained amyloid-centered strategies. We advance an integrative view of AD as a staged process involving tau pathology, neuroimmune dysfunction, vascular injury, and aging biology. Progress will depend on earlier and stage-matched intervention, mechanism-informed combination strategies, and regulatory standards anchored to outcomes patients value.
A Wed, study studied this question.