Both type 1 and type 2 diabetes are associated with cognitive impairments including deficits in processing speed, executive function, and declarative memory (Biessels et al., 2008), functions associated with the hippocampus and some other brain regions. Unsurprisingly, diabetes is associated with vascular dementia; unexpectedly, diabetes is also associated with Alzheimer's disease, whose incidence is increased even in merely borderline diabetics (Xu et al., 2007). Indeed, in healthy (nondiabetic) elderly subjects, HbA1c (glycosylated hemoglobin) levels within the normal range correlate with cognitive decrements (MacLullich et al., 2004). The underlying mechanisms of the effects of impaired glucose homeostasis on the central nervous system (CNS) are unclear. The possibilities include direct toxicity of hyperglycemia (glycation of CNS macromolecules, increased oxidative stress/reduced antioxidant capacity) or the effects of insulin deficiency on the brain (hippocampus expresses insulin receptors). There are also a host of potential indirect effects including deleterious CNS actions of concomitant cardiometabolic disorders (micro- and macrovascular disease, hypertension, dyslipidemia), inflammation and immune disturbances, and diabetic neuropathies (Figure 1).