Abstract: The amyloid cascade hypothesis of Alzheimer’s pathogenesis: The amyloid cascade hypothesis of Alzheimer’s disease (AD) pathogenesis will shortly celebrate its thirtieth birthday (Hardy and Higgins, 1992). Based on abundant genetic and biochemical evidence, it proposes that deposition of the amyloid-β (Aβ) peptide in brain parenchyma is an essential upstream trigger in AD pathogenesis that drives a cascade of events, specifically including the recruitment and pathological hyper-phosphorylation of the micro-tubule-associated protein tau, that culminate in derangement of synaptic function and, eventually, neuronal death. Although the hypothesis has been challenged many times over the last three decades, principally based on a number of observations of AD pathology and clinical progression that it appears not to readily explain (Makin, 2018), its fundamental assertions that Aβ deposition is a critical early event, and that this somehow leads to the later recruitment of hyperphosphorylated tau, still appear to hold true (Selkoe and Hardy, 2016). Therefore, and in spite of its difficulties, the amyloid cascade hypothesis, albeit slightly refined and qualified over the years, is still the dominant model of AD pathogenesis. The central importance of tau to the disease process has been confirmed by a number of more recent studies that demonstrate convincingly that tau is essential for many of the canonical AD-associated synaptic and behavioral phenotypes, which can be rescued in animal models of AD by tau knockout (Mucke and Selkoe, 2012). However, despite its clear significance in AD pathogenesis, the cellular mechanism by which Aβ recruits tau to bring about synaptic and cognitive decline has remained obscure.