Abstract: The etiology of Alzheimer’s disease is far from being completely understood. Genetic approaches have helped in this matter and have greatly supported the view that the β-amyloid precursor protein (βAPP) could be at the center of gravity of the pathology. Thus, mutations responsible for autosomal dominant aggressive forms of Alzheimer’s disease (AD) are all harbored by either βAPP itself or by its cleaving enzyme presenilins 1/2 referred to as γ-secretase. It was therefore convincing to note that fully independent gene products harboring AD-linked mutations, all concur to modulate βAPP proteolytic processing. These genetic clues combined with a bulk of anatomical observations and cellular manipulations pointed to the role of amyloid-β (Aβ), the main biochemical component of senile plaques that accumulate at late stages of AD. Unfortunately, a series of clinical trials designed to either abolish Aβ production or neutralize it once produced have consistently failed (Checler et al., 2021). It remains that the genetic arguments are strong and that a key role of βAPP proteolytic maturation remains of actuality. One way to reconcile genetic evidence and clinical trials failure could be to envision that additional βAPP-derived products could contribute to AD etiology. A close evaluation of biogenesis and toxicity of such pathogenic βAPP-derived products, distinct from genuine Aβ could help to better understand AD etiology.