Insulin and Alzheimer's disease: untangling the web.

The recognition of Alzheimer's disease (AD) as a heterogeneous disorder that results from incremental pathological changes in dynamic organismic systems is essential to move beyond the unidimensional approaches to prevention and therapy that have proven largely ineffective to date. Biological systems related to insulin metabolism are arguably the most critical regulators of longevity and corporeal aging. Our work has focused on identifying the relationship of the insulin network to brain aging, and determining the mechanisms through which insulin dysregulation promotes AD pathological processes. Candidate mechanisms include the effects of insulin on amyloid-β, cerebral glucose metabolism, vascular function, lipid metabolism, and inflammation/oxidative stress. It is likely that different nodes of the insulin network are perturbed for subgroups of AD patients, or that for some subgroups, pathways independent of insulin are critical pathogenetic factors. New methods from systems network analyses may help to identify these subgroups, which will be critical for devising tailored prevention and treatment strategies. In the following review, we will provide a brief description of the role of insulin in normal brain function, and then focus more closely on recent evidence regarding the mechanisms through which disruption of that role may promote AD pathological processes. Finally, we will discuss the implications of this area for AD therapeutics and prevention.