Breakdown of the blood–brain barrier: A mediator of increased Alzheimer's risk in patients with metabolic disorders?

Metabolic disorders (MDs), including type 1 and 2 diabetes and chronic obesity, are among the faster growing diseases globally and are a primary risk factor for Alzheimer's disease (AD). The term “type-3 diabetes” has been proposed for AD due to the interrelated cellular, metabolic, and immune features shared by diabetes, insulin resistance (IR), and the cognitive impairment and neurodegeneration found in AD. Patients with MDs and/or AD commonly exhibit altered glucose homeostasis and IR; systemic chronic inflammation encompassing all of the periphery, blood–brain barrier (BBB), and central nervous system; pathological vascular remodeling; and increased BBB permeability that allows transfusion of neurotoxic molecules from the blood to the brain. This review summarizes the components of the BBB, mechanisms through which MDs alter BBB permeability via immune and metabolic pathways, the contribution of BBB dysfunction to the manifestation and progression of AD, and current avenues of therapeutic research that address BBB permeability. In addition, issues with the translational applicability of current animal models of AD regarding BBB dysfunction and proposals for future directions of research that address the relationship between MDs, BBB dysfunction, and AD are discussed.