The amyloid hypothesis of Alzheimer’s disease, proposed 25 years ago, suggests that an imbalance in the production and clearance of amyloid β (Aβ) peptides, particularly Aβ42, is a key early factor in the disease. This hypothesis is supported by evidence showing that mutations in the amyloid precursor protein (APP) and presenilin, which are involved in Aβ production, lead to early-onset Alzheimer’s. In Down’s syndrome, the duplication of the APP gene results in Aβ accumulation in adolescence, followed by neurofibrillary tangles and microgliosis. Apolipoprotein E4 (ApoE4) is associated with increased Aβ accumulation and impaired clearance. Soluble Aβ oligomers from AD patients can impair synaptic function and memory, and human oligomers induce tau hyperphosphorylation and neuritic dystrophy. Studies in transgenic mice show that Aβ can drive tau pathology, and Aβ clearance is impaired in ApoE4 carriers. Recent clinical trials of Aβ-targeting antibodies, such as solanezumab and aducanumab, have shown some slowing of cognitive decline in mild AD patients. The amyloid hypothesis remains the most validated therapeutic target, despite ongoing debates about alternative mechanisms. New evidence suggests that Aβ dyshomeostasis is upstream of other pathological changes in AD. The hypothesis is supported by genetic, cellular, and clinical studies, and recent trials have provided some evidence of its validity. However, further research is needed to confirm its role and develop effective therapies. The amyloid hypothesis continues to be a central focus in Alzheimer’s research, with ongoing efforts to understand the complex interplay between Aβ, tau, and other factors in the disease.The amyloid hypothesis of Alzheimer’s disease, proposed 25 years ago, suggests that an imbalance in the production and clearance of amyloid β (Aβ) peptides, particularly Aβ42, is a key early factor in the disease. This hypothesis is supported by evidence showing that mutations in the amyloid precursor protein (APP) and presenilin, which are involved in Aβ production, lead to early-onset Alzheimer’s. In Down’s syndrome, the duplication of the APP gene results in Aβ accumulation in adolescence, followed by neurofibrillary tangles and microgliosis. Apolipoprotein E4 (ApoE4) is associated with increased Aβ accumulation and impaired clearance. Soluble Aβ oligomers from AD patients can impair synaptic function and memory, and human oligomers induce tau hyperphosphorylation and neuritic dystrophy. Studies in transgenic mice show that Aβ can drive tau pathology, and Aβ clearance is impaired in ApoE4 carriers. Recent clinical trials of Aβ-targeting antibodies, such as solanezumab and aducanumab, have shown some slowing of cognitive decline in mild AD patients. The amyloid hypothesis remains the most validated therapeutic target, despite ongoing debates about alternative mechanisms. New evidence suggests that Aβ dyshomeostasis is upstream of other pathological changes in AD. The hypothesis is supported by genetic, cellular, and clinical studies, and recent trials have provided some evidence of its validity. However, further research is needed to confirm its role and develop effective therapies. The amyloid hypothesis continues to be a central focus in Alzheimer’s research, with ongoing efforts to understand the complex interplay between Aβ, tau, and other factors in the disease.