The amyloid plaques is formed by amyloid β (Aβ) peptides organized in fibrils intermixed with non-fibrillar forms of this peptide and are surrounded by dystrophic dendrites, axons, reactive astrocytes and activated microglia. Aβ consists of small hydrophobic peptides with N- and C-terminal heterogeneity, that is Aβ1-40 and Aβ1-42 which are proteolytically released from a large Type 1 integral membrane glycoprotein, the APP, via sequential cleavage by two aspartyl proteases, the β- and γ-secretases [enzymatic complex, containing nicastrina, presenilina, preselin enhancer-2 (PEN-2), CD147] . Initial β-secretase cleavage generates a soluble fragment from the NH2-terminus of APP, whereas the c-terminal fragment (β-CTF) stays membrane bound. Aβ40/42 activates Ca2+ influx in neurons, hyperphosphorylation of τ protein (via activation of GSK3β and CDK5), leading to deposition of neurofibrillary tangles, impaired axonal transport and finally, to neuronal death (Fig. 2). Full-length APP can undergo alternative processing by α-secretase, generating a soluble APPsα ectodomain and a membrane-bound carboxy-terminal fragment, APP-CTFα. Processing of APP by α-secretase is postulated to be protective in the context of AD, because the enzyme cleaves within the Aβ-sequence, thereby preventing the production of Aβ. Several studies have indicated that increased α-secretase-mediated processing of APP reduces the processing of APP by β-secretase and decrease Aβ-production [113, 114], however this finding has not been universally replicated . Increasing α-secretase activity, as mentioned above, increases the production of APPsα, and has been reported to be neuroprotective and growth promoting , but the consequences of chronically up-regulating α-secretase-mediated cleavage of other substrates remain unknown. Besides, in a recent study, Adlerz et al. suggested that increased levels of APPsα and amyloid-precursor-like protein-1 (APLP1), in response to either IGF-1 or insulin, were mediated by activation of IGF-1 receptors . APP, αCTF and βCTF are further cleaved by γ-secretase to generate p83 fragment and Aβ, respectively . In a recent study, McElroy et al. suggested a possible link between IGF-1R and γ-secretase. IGF-1R, as several Type 1 membrane proteins, undergoes regulated intramembrane proteolysis. Afterwards metallo-protease-dependant ectodomain-shedding, IGF-1R carbossiterminal domain is cleaved by γ-secretase. These observations suggest that IGF-1R may be substrate for γ-secretase involved in mechanisms independent of its receptor tyrosine-kinase activity . Multiple lines of biochemical evidence have shown γ-secretases activity to reside in a high molecular weight complex, consisting of at least four components: presenilin (PS, PS1, PS2), nicastrin, anterior pharynx-defective (APH-1) and PEN-2 . The p83 fragment is rapidly degraded and widely believed to possess no important function, if any. γ-Secretase-mediated cleavage is unique in that the cleavage takes place within the membrane domain, although the exact site can vary. γ-cleavage can yield both Aβ1-40 and to a lesser extent Aβ1-42. Aβ are toxic, and their accumulation is currently seen as a key step in the pathogenesis of AD. Closer examination of the amyloidogenic β- and γ-secretates discovered the membrane-anchored aspartyl protease β-site BACE-1, which acts as β-secretase and presenelin 1-2, transmembrane proteins involved in formation of the γ-secretase complex, as the responsible cleavage enzymes. Thus, alteration of their activity might be a possible target for AD treatment . It has been shown that BACE-1 levels are increased in post-mortem brain sections from AD patients . During aging changes in the cerebral expression levels of the neurotrophin receptors tyrosine kinase receptor A (TrkA) and p75 neurotrophin receptorv (p75NTR) have been described. In the human neuroblastoma cell line SHSY5Y as well as primary cultured neurons, chronic treatment with IGF-1 leads to a switch from TrkA to p75NTR expression as seen in aging brains . This switch causes increased β-secretase activity indirectly by activation of neuronal sphingomyelinase, which is responsible for hydrolysis of sphingomyelin and active liberation of the second messenger ceramide . Ceramide is responsible for the molecular stabilization of BACE-1, the β-secretase which is rate limiting for generation of Aβ . This process leads to accumulation of Aβ, connecting IGF-1R signalling to neurotrophin action. Furthermore, Sotthibundhu et al. recently showed that treatment of wild-type embryonic mouse hippocampal neurons with Aβ1-42 as ligand for p75NTR resulted in significant cell death. In contrast, p75NTR deficient neurons are less affected by Aβ1-42 treatment . These data might provide a molecular link between aging, pathogenesis of AD and neuronal insulin-IGF-1 signalling. Lots of research has been performed on the formation and accumulation of Aβ, however, in the last years the mechanisms of amyloid clearance came into focus. Aβ spontaneously self-aggregates into multiple coexisting physical forms, such as oligomers (2–6 peptides), intermediate assemblies, fibrils that coalesce into β pleated sheets to form insoluble fibres and amyloid plaques . Although monomeric Aβ is not neurotoxic, the Aβ oligomers exhibits a marked toxicity . The physiological role of β peptides is still in part unclear, but it is involved in neuronal activation and connection mechanisms . Neuronal activation rapidly increase Aβ secretion at the synapse, during the process of neurotransmitters release. Normal levels of Aβ at this site may modulate neuronal transmission and prevent hyperactivity . It was assumed that imbalance between production, aggregation and clearance of peptides is considered initiating factor in AD . The molecular mechanisms involved in the secretion, aggregation and toxicity of Aβ are still in part unknown . For Aβ clearance several mechanisms have been described: (1) enzymatic degradation by activated microglia or by insulin-degrading enzyme (IDE), neprilysin, endothelin-converting enzyme (ECE) and angiotensin-converting enzyme (ACE); (2) receptor-mediated transport across the BBB by binding to the low-density lipoprotein receptor-related protein (LRP), either directly or after binding to APO E and/or α2-macroglobulin (α2M), to be delivered to peripheral sites of degradation, for example liver and kidney . Concerning insulin resistance it has been shown that IDE expression is stimulated by the insulin resistance-IGF-1R cascade (Fig. 3) . Furthermore, it has been suggested that increasing circulating IGF-1 levels lead to reduction of Aβ burden in aging rats . It has been recently reported that membrane associated G protein-coupled receptor kinase-5 (GRK5) deficiency occurs during early AD . In deficient GRK5 mice (tg2576-APPsw), Aβ accumulation resulted significantly increased . IGF-1 administration resulted in reduction of cerebral Aβ load in these mice, whereas Aβ was elevated in CSF suggesting an increased Aβ elimination across the BBB or the choroid plexus . Furthermore, it has been shown that the blockade of the IGF-1R in the choroid plexus triggers AD-like pathology . In contrast, Lanz et al.  analysed in vivo models using acute, subchronic and chronic IGF-1 treatment to evaluate Aβ levels in brain, CSF and plasma of rats and Tg2576 mice. However, no changes in Aβ were detected in any of these models. Furthermore, τ phosphorylation did not change significantly following chronic IGF-1 treatment in Tg2576 mice . A possible explanation could be that the chronic increase of IGF-1 by peripheral treatment might down-regulate IGF-1R signalling. This hypothesis is supported by the finding that in a cohort of individuals with exceptional longevity serum IGF-1 levels were high but IGF-1R activity was low leading to reduced IGF-1R signalling . However, induction of insulin resistance by high fat diet  or intake of sucrose-sweetened water  leads to an aggravation of amyloid pathology in mouse models of AD. Furthermore, peripheral injection of supra physiologically high insulin doses but not of physiological doses leads to transient cerebral τ phosphorylation , leading to the proposal that there is a dose-dependent effect of insulin resistance-IGF-1R signalling in the pathogenesis of AD.