The amyloid cascade hypothesis has had considerable importance in driving forward the molecular understanding of Alzheimer’s disease (AD) pathology. One component of that cascade might be glycogen synthase kinase-3 (GSK3), a kinase that appears to be activated by Aβ and in turn phosphorylates tau. GSK3 is also inhibited by insulin signalling and insulin resistance, and diabetes is a major risk factor for AD. We hypothesise, as others have done, that insulin signalling is central to the pathological process, with evidence that both genetic and environmental risk factors for AD involve the insulin pathway. We also postulate that transgenic mice provide only a partial model for AD, as insulin signalling acts as a protective factor against Aβ toxicity; also, the well-established relationship between insulin signalling and longevity might explain why the single most important risk factor for AD is age.