Alzheimer’s disease (AD) is characterized by two types of protein aggregates, neurofibrillary tangles and amyloid plaques, distributed in regions of the CNS that are involved in learning and memory. The neurofibrillary tangles consist of twisted filaments containing hyperphosphorylated tau whereas the amyloid plaques contain mainly β-amyloid (Aβ) peptide fibrils. Incomplete knowledge of the molecular process that causes AD has hindered advances in drug development. The available cholinergic therapies target essentially late aspects of the disease, improving temporarily the performance of the undamaged neurones, but do not stop the progressive mental decline. In the past years, important progress has been made in the understanding of the pathogenic mechanism of AD, and new therapeutic targets have become available that should allow the underlying disease process to be tackled directly. In this respect, the ‘amyloid hypothesis’ has become the dominant theory in the field. It is believed that Aβ accumulation in plaques or as partial soluble filaments initiates a The amyloid and tangle cascade hypothesis is the dominant explanation for the pathogenesis of Alzheimer’s disease (AD). A complete knowledge of the metabolic pathways leading to β-amyloid (Aβ) production and clearance in vivo and of the pathological events that lead to fibril formation and deposition into plaques is crucial for the development of an ‘anti-amyloid’ therapeutic strategy. Important advances in this respect have been achieved recently, revealing new candidate drug targets. Among the most promising potential treatments are β- and γ-secretase inhibitors, Aβ vaccination, Cu–Zn chelators, cholesterol- lowering drugs and non-steroidal anti-inflammatory drugs. Now, the major question is w hether these drugs w ill work in the clinic. 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