35 High systolic blood pressure interacted with borderline diabetes36 and with frank diabetes11 multiplying the risk of AD. thenthereby diabetes almost doubled the risk of dementia and AD in the Rotterdam study, but diabetics taking insulin were at the sellckchem highest risk (RR 4.3, 1.7-10.5)8 suggesting that more severe diabetes increases dementia risk. Consistent with these observations, subjects with longer duration of diabetes18,19,22 or with diabetes complications34,35 had steeper cognitive decline. The potential mediating effect of APOE4 genotype and of age in the relationship between diabetes and dementia is less clear. Participants with diabetes and the APOE4 allele had a risk ratio of 5.5 (CI

Inhibitors,research,lifescience,medical 2.2-13.7) for AD compared with those with neither risk factors in the Honolulu Asia Aging Study,12 and this was consistent with neuropathological

findings. However, borderline diabetes was associated with AD only in non-APOE4 Inhibitors,research,lifescience,medical carriers in the Kongsholmen study. The effect of age on the relationships between diabetes and dementia is also difficult to interpret. The relationship between diabetes and dementia in the Framingham study was strongest for participants older than 7536,54 but diabetes was not associated with accelerated cognitive decline in 85+ years of age participants in another study.26 This suggests that factors Inhibitors,research,lifescience,medical other than CVRFs (ie, age, APOE genotype) inter act with diabetes to increase the risk of cognitive compromise. Several potential mechanisms underlying the association between diabetes Inhibitors,research,lifescience,medical and dementia have been proposed: – Diabetes is associated with micro- and/or macrovascular disease37 which in turn increase the risk of cognitive decline and dementia38,39 – Inhibitors,research,lifescience,medical Defective insulin receptor signaling pathway (IRSP) in the central nervous system40; the IRSP is associated

with vital brain processes including synaptic plasticity,41-43 neuroprotection, neurodegeneration, survival, growth, energy metabolism, and longevity.41,45 Insulin receptors (IR) are abundant throughout the brain,46 and are expressed in especially high abundance in regions that support cognitive lunction.47 Aβ , the main component of neuritic plaques, hallmark lesions of AD, decreases insulin affinity and reduces the binding of insulin to its receptor48 preventing rapid activation GSK-3 of specific kinases required for multiple cellular functions, including longterm potentiation (LTP).49 Soluble Aβ oligomers were recently shown to significantly lower IR responses to insulin and to cause rapid and substantial loss of neuronal surface IRs.50 The IR desensitization found in AD brains,51 hampers the release of A, from the intracellular to the extracellular compartment,52 which may be a mechanism for its neurotoxicity.53 – Advanced glycation end products (AGEs) may have a crucial role in the relationship between diabetes and dementia.