Insulin resistance in depressive disorders and Alzheimer's disease: revisiting the missing link hypothesis

Several lines of evidence suggest an association between depressive disorders and Alzheimer's disease (AD). We previously suggested central nervous system (CNS) effects of insulin resistance (IR) to be an important link between depressive disorders and AD. Although the exact mechanism of central IR is not known, it is thought that central IR results in inadequate glucose metabolism in the brain. According to our hypothesis, inadequate glucose utilization resulting from IR underlies neuronal changes in crucial brain regions (i.e. limbic system) observed among patients with depressive disorders, the same brain regions affected in AD. Further, in patients with undetected and/or untreated IR, such changes in glucose utilization, if unresolved, may lead to neurodegeneration. Our studies have demonstrated a high prevalence of IR in patients with depressive disorders, and reciprocally, a high prevalence of depression in patients with the primary IR disorder polycystic ovary syndrome (PCOS), and we believe these populations have significantly increased risk of cognitive decline. Herein, we review the IR link in depressive disorders and AD and describe the results of our studies and others in support of this hypothesis.