Abstract: In this perspective article, I will discuss our recent publication (Hicks et al., 2020), specifically its major findings and integration with the published literature. Alzheimer’s disease (AD) is a progressive neurodegenerative disease of predominantly unknown aetiology. Its neuropathological hallmarks are extracellular plaques formed of the amyloid beta (Aβ) peptide and neurofibrillary tangles of tau protein. Aβ peptides (Aβ1–40 and Aβ1–42 are considered the most important) are generated by sequential proteolysis of the amyloid precursor protein (APP). This proteolysis can take one of two pathways: the nonamyloidogenic or amyloidogenic (Figure 1). The former is mediated by α-secretase, predominantly a disintegrin and metalloprotease domain-containing 10 (ADAM10) and the γ-secretase complex. This pathway releases the APP ectodomain as sAPPα, but crucially, results in cleavage of APP within the Aβ region, abrogating its generation. However, the amyloidogenic pathway is mediated by β-site APP cleaving enzyme 1 (BACE1, also known as β-secretase) and the γ-secretase complex, which results in the generation of Aβ species and the amyloid precursor protein intracellular domain. The amyloid precursor protein intracellular domain (AICD) has been shown to traffic to the nucleus where it can act as a transcriptional modifier. Although there are other minor APP secretases, those outlined herein represent the most significant. Alterations in APP processing have been linked to AD, insofar as the Aβ1–42: Aβ1–40 ratio is increased in the disease (Andrew et al., 2016).