The amyloid cascade hypothesis proposes a specific sequence of pathological events initiated by the abnormal accumulation of amyloid-beta in the brain. The cascade is thought to begin with the aberrant processing of the amyloid precursor protein (APP), leading to either an overproduction or a decreased clearance of Aβ peptides, particularly the Aβ42 isoform. These Aβ peptides then undergo a process of aggregation, initially forming small, soluble oligomers. These oligomers are increasingly recognized as the primary toxic species in the cascade. Subsequently, these oligomers are believed to aggregate further, forming insoluble amyloid fibrils that eventually deposit in the extracellular space as amyloid plaques.  

According to the hypothesis, the presence and accumulation of these amyloid plaques, and particularly the more toxic soluble oligomers, then trigger a series of downstream pathological events within the brain. These events are thought to include the hyperphosphorylation of tau protein, leading to the formation of neurofibrillary tangles within neurons, the activation of glial cells resulting in chronic neuroinflammation, the disruption of synaptic function and loss of synapses, and ultimately, neuronal death. This cascade of pathological changes is proposed to be the underlying cause of the progressive cognitive decline and memory loss that are characteristic of Alzheimer's disease. The amyloid cascade hypothesis, therefore, provides a framework for understanding the temporal sequence of pathological events in AD, although the precise mechanisms and the relative importance of different Aβ forms, particularly the transition from plaques to oligomers as the main culprit, are areas of ongoing refinement and investigation.