Alzheimer's disease (AD) is by far the most common form of dementia in the elderly and concerns one out of three individuals over 85. Like other neurodegenerative disorders such as Parkinson, Hungtington or prion diseases, AD is characterized by the formation of amyloid plaques in the central nervous system. In the brain of AD patients, the main component of these abnormal deposits is an aggregated form of the so-called amyloid β-peptide (Aβ), which is produced from a large trans-membrane type-1 protein, the β-amyloid precursor protein (βAPP), by the sequential action of the β- and γ-secretases. Beside these two amyloidogenic proteolytic attacks, βAPP is targeted by a third enzyme termed α-secretase. Of utmost importance, this cleavage, which can be of constitutive or regulated origin, occurs right in the middle of the Aβ sequence, thus precluding its production. For this reason, and because the sAPPα secreted fragment derived from this cleavage displays beneficial effects, tremendous efforts have been made recently in order to both identify the proteases involved and the way they are regulated. More recently, it emerged that α-secretase was also responsible for the physiological processing of the cellular prion protein (PrPc) in the middle of its toxic 106-126 sequence. This review will focus on the recent advances in the α-secretase pathways regulation and will discuss the putative therapeutic approaches that could be envisioned concerning the treatment of two apparently distinct diseases that share common denominators according to their metabolism.