Insulin, cognition, and dementia

Abstract

Cognitive disorders of aging represent a serious threat to the social and economic welfare of current society. It is now widely recognized that pathology related to such conditions, particularly Alzheimer's disease, likely begins years or decades prior to the onset of clinical dementia symptoms. This revelation has led researchers to consider candidate mechanisms precipitating the cascade of neuropathological events that eventually lead to clinical Alzheimer's disease. Insulin, a hormone with potent effects in the brain, has recently received a great deal of attention for its potential beneficial and protective role in cognitive function. Insulin resistance, which refers to the reduced sensitivity of target tissues to the favorable effects of insulin, is related to multiple chronic conditions known to impact cognition and increase dementia risk. With insulin resistance-associated conditions reaching epidemic proportions, the prevalence of Alzheimer's disease and other cognitive disorders will continue to rise exponentially. Fortunately, these chronic insulin-related conditions are amenable to pharmacological intervention. As a result, novel therapeutic strategies that focus on increasing insulin sensitivity in the brain may be an important target for protecting or treating cognitive decline. The following review will highlight our current understanding of the role of insulin in brain, potential mechanisms underlying the link between insulin resistance and dementia, and current experimental therapeutic strategies aimed at improving cognitive function via modifying the brain's insulin sensitivity.

Keywords: Aging; Alzheimer's disease; Cognition; Diabetes; Insulin.

Figure 1

Consequences of insulin and Aβ interactions on reduced neuronal insulin receptor signaling and promoting Alzheimer’s disease pathology. In type 2 diabetes, there can be decreased or increased levels of insulin in brain (depending on disease state), along with insulin receptor desensitization. Aβ peptide levels can be enhanced by reduced insulin receptor signaling, and soluble Aβ oligomers can also block these receptors. Increased Aβ levels will compete for insulin degrading enzyme with cerebral insulin. Aβ aggregates can also have direct membrane toxic effect on neuronal cells. Reduced insulin receptor signaling results in reduced phosphoinositide-3 kinase activity that leads to reduced protein kinase B/Akt activity. The consequences of this include reduced glucose metabolism and increased oxidative stress. Specifically reduced glycogen synthase kinase-3 phosphorylation leads to increased tau phosphorylation and Aβ formation.

Figure 2

Statistical parametric maps of task-specific activation for (A) normal adults and (B) adults with prediabetes/type 2 diabetes. Maps were constructed by subtracting resting scans from scans obtained while participants performed a memory encoding task. Yellow represents areas of greatest activation.

Figure 3

Sniffing insulin increases cerebrospinal fluid insulin concentrations in humans (Born et al., 2002). Concentrations of insulin in cerebrospinal fluid before and within 80 min after intranasal administration of human insulin (40 international units; solid lines, n=8) and placebo (dashed lines, n=5) Substances were administered with a nasal spray atomizer. Nose symbol indicates time of substance administration. Means ± standard errors are indicated. **P value smaller than 0.01, *P value smaller than 0.05, for pairwise comparisons of baseline adjusted values between both conditions.