Editorial: Promising therapeutic strategies for Alzheimer’s disease: a focus on amyloid-β targeting

Alzheimer’s disease (AD) is the most prevalent neurodegenerative disorder and the most common form of dementia, affecting about 55 million people worldwide (source: Alzheimer’s Association). According to the amyloid hypothesis, the pathogenesis of AD is primarily triggered by the progressive accumulation and subsequent deposition of the amyloid-β (Aβ) peptide in the extracellular space of the brain cortex and hippocampus. Specifically, the Aβ peptide is 40- or 42-residues long (Aβ40 and Aβ42, respectively) and arises after the pathogenic cleavage of the amyloid precursor protein (APP) by β- and γ-secretases. Its abnormal aggregation further results in the formation of neurofibrillary tangles, composed of the hyperphosphorylated microtubule-associated Tau protein, culminating in neuronal and synaptic loss, finally leading to dementia. The intracerebral accumulation of Aβ aggregates takes place at least two-three decades before the occurrence of clinical symptoms of AD, and this long delay renders the course of the disease progressively independent from Aβ deposition, thus explaining the poor clinical efficacy of the greatest majority of Aβ-targeting clinical trials. Such trials should be thus initiated before the development of symptoms, in a therapeutic window allocated in the preclinical phase, at which the blockage of Aβ aggregation should have its maximal benefit. This explains the primary interest of research in identifying early disease-modifying therapies aimed at targeting Aβ peptide in order to prevent its neurotoxicity.