Shared Neuropathological Characteristics of Obesity, Type 2 Diabetes and Alzheimer's Disease: Impacts on Cognitive Decline

Abstract

In the past few decades, the prevalence of obesity and type 2 diabetes mellitus (T2DM), as well as older individuals at risk for Alzheimer's disease (AD), has increased. While the consumption of diets high in fat (total and saturated) have been linked to increased risk of AD, diets rich in antioxidants, polyunsaturated fats, and omega-3 fatty acids are associated with decreased risk. Additionally, AD patients are at increased risk for developing T2DM. Recent research suggests that there are stronger similarities between AD and T2DM than have previously been considered. Here we review the neurocognitive and inflammatory effects of high-fat diet consumption, its relationship to AD, and the treatment potential of dietary interventions that may decrease risk of cognitive decline and other associated neuropathological changes, such as insulin resistance, oxidative stress, and chronic inflammatory processes.

Keywords: Alzheimer’s disease; animal models; cognition; diet reversal; high fat diets; humans; inflammation; insulin resistance; obesity; type 2 diabetes mellitus.

Figure 1

Shared and distinct symptoms of Type 2 Diabetes and Alzheimer’s disease (AD). Venn diagram illustrating the shared and distinct characteristics of type 2 diabetes mellitus (T2DM) and Alzheimer’s disease. In the past few decades, the prevalence of both has increased substantially, and emerging research suggests that there may be a bidirectional relationship between these disease processes.

Figure 2

Shared pathological mechanisms of Alzheimer’s disease (AD) and type 2 diabetes mellitus (T2DM). Among the shared pathological mechanisms between the two disease states are inflammatory processes including the release of pro-inflammatory cytokines (some of which can cross the blood-brain barrier (BBB)), e.g., tumor necrosis factor alpha (TNF-α): from microglia in the central nervous system (CNS) in AD, and from macrophages in the periphery in T2DM. In turn, these processes activate cellular stress pathways, including stress kinases I κ-B kinase (IKK) and protein kinase RNA-activated (PKR), which eventually produce insulin/insulin growth factor 1 (IGF-1) resistance via inhibition of insulin receptor substrate 1 (IRS-1) in the CNS (AD) and the periphery (T2DM). Star symbols indicate areas in which diet interventions may exert beneficial effects.