A second lesson to be learned involves the potential relationship between the pathogenesis of AD and the pathogenetic processes underlying other chronic disease states such as osteoporosis and neoplasia. Is it possible that the therapeutic failure to date in AD may have resulted, at least in part, from an incomplete understanding of the etiology and pathogenesis of AD? Any accurate theory of AD must explain a number of features (Table 1): for example, why is AD risk increased by such disparate factors as the ApoE ε4 allele, early oophorectomy (ovarian removal, for example as part of a total hysterectomy), metabolic syndrome, head trauma, inflammatory processes and hyperhomocysteinemia? What is the physiological role(s) of Aβ peptides, and how does it relate to the pathophysiology of AD? Moreover, recent results from a number of sources must be taken into account by any new theory: for example, both Aβ and tau may function as prions (de Calignon et al, 2012; Eisele et al, 2009; Yang et al, 1995). The four peptides derived from the amyloidogenic processing of β-amyloid precursor protein (APP) – sAPPβ, Aβ, Jcasp and C31 – have been shown to mediate neurite retraction, synaptic inhibition, caspase activation and programmed cell death (Bertrand et al, 2001; Lu et al, 2000, 2003; Nikolaev et al, 2009); whereas the two peptides derived from the non-amyloidogenic processing of APP – sAPPα and αCTF – support neurite extension, inhibit Aβ production, inhibit caspase activation and inhibit programmed cell death (Deyts et al, 2012; Guo et al, 1998; Tian et al, 2010). Thus, APP appears to function as a molecular switch, mediating plasticity-related processes and AD is associated, whether causally or incidentally, with an increase in the ratio of the neurite-retractive peptides to the neurite-extending peptides. Reducing this ratio, whether by affecting BACE (β-site APP cleaving enzyme) or other cleavage of APP, appears to mitigate the AD severity (Bredesen et al, 2010; Galvan et al, 2006; Jonsson et al, 2012).